[go: up one dir, main page]

US20080039521A1 - Anticancer Effect Enhancer - Google Patents

Anticancer Effect Enhancer Download PDF

Info

Publication number
US20080039521A1
US20080039521A1 US11/628,943 US62894305A US2008039521A1 US 20080039521 A1 US20080039521 A1 US 20080039521A1 US 62894305 A US62894305 A US 62894305A US 2008039521 A1 US2008039521 A1 US 2008039521A1
Authority
US
United States
Prior art keywords
cancer
patients
chemotherapy
once
donor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/628,943
Inventor
Hiroyasu Yasuda
Mutsuo Yamaya
Katsutoshi Nakayama
Hidetada Sasaki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Kayaku Co Ltd
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US11/628,943 priority Critical patent/US20080039521A1/en
Assigned to TOHOKU UNIVERSITY reassignment TOHOKU UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NAKAYAMA, KATSUTOSHI, YAMAYA, MUTSUO, YASUDA, HIROYASU, SASAKI, HIDETADA
Assigned to NIPPON KAYAKU KABUSHIKI KAISHA reassignment NIPPON KAYAKU KABUSHIKI KAISHA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TOHOKU UNIVERSITY
Publication of US20080039521A1 publication Critical patent/US20080039521A1/en
Priority to US12/318,061 priority patent/US8410175B2/en
Assigned to NIPPON KAYAKU KABUSHIKI KAISHA reassignment NIPPON KAYAKU KABUSHIKI KAISHA CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE'S CITY NAME FROM "TOYKO" TO "TOKYO", PREVIOUSLY RECORDED ON REEL 019288 FRAME 0357. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNORS INTEREST. Assignors: TOHOKU UNIVERSITY
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer.
  • hypoxic condition inside the solid cancer participates in resistance to its therapy.
  • Non-Patent Document 1 Mothews N E, Adams M A, Maxwell L R, Gofton T E, Graham C H. Nitric oxide-mediated regulation of chemosensitivity in cancer cells. J. Natl. Cancer Inst., 2001; 93: 1879-1885
  • hypoxic condition promotes the resistance of cancer cells to anticancer agent.
  • Non-Patent Document 3 Liang B C. Effects of hypoxia on drug resistance phenotype and genotype in human glioma cell lines. J. Neurooncol., 1996; 29: 149-155), it is made clear that, when glioma cell line is placed in hypoxic condition, it shows resistance to anticancer agent.
  • Non-Patent Document 4 Ste K, Rofstad E K. Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro. Int. J. Cancer, 1994; 58: 258-262
  • Non-Patent Document 1 and Non-Patent Document 2 suggest that a NO donor is able to effectively function in improvement of hypoxic condition inside the solid cancer.
  • Non-Patent Document 5 (Gallo O, Masini E, Morbidelli L, Franchi A, et al. Role of nitric oxide in angiogenesis in head and neck cancer. J. Natl.
  • NOS NO synthase
  • Non-Patent Document 6 (Edwards P, Cendab J C, Topping D B, Moldawer L L, Mackay S, Copeland E M, Lind D S. Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. J. Surg.
  • Non-Patent Document 8 (D C Jenkins, I G Charles, L L Thomsen, D W Moss, L S Holmes, S A Baylis, P Rhodes, K Westmore, P C Emson, S Moncada.
  • Non-Patent Document 9 (Lala P K, Chakraborty C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol., 2001; 2: 149-156), it is shown that NOS of a derived type participates in mutation of p53 of tumor of colon, lung and throat and that NO stimulates the growth of tumor via activation of cyclooxygenase-2 (COX-2).
  • COX-2 cyclooxygenase-2
  • Non-Patent Document 1 it is shown that resistance of cancer cell line to anticancer agent induced by hypoxic condition is improved by a NO donor in an experiment using cultured cells and, although such a finding will be surely valuable for showing one direction for future research, it is not possible to conclude from such a finding that a NO donor has an action of shrinking the cancer tissues or an action of enhancing the effect of anticancer agent. So, it is all the more that, in human clinical medicine, a conclusion that a NO donor enhances the effect of anticancer agent is unable to be done and should not be done.
  • Patent Document 1 JP 2004-508279 A
  • a method of administering a NO donor as a potassium channel activator as a method for a selective transfer of anticancer agent to cancer where permeability of blood vessel for sending blood to cancer cells to anticancer agent is enhanced.
  • issue of a jumped conclusion that a NO donor enhances the effect of anticancer agent only by appealing an increase in transition of an anticancer agent to tumor tissues by an increase in permeability through blood vessel without actual confirmation of enhancement of NO donor in the action of anticancer agent to cancer tissues even in animal experiment is not convincing at all under the present status where scientific evaluation for the action of NO to cancer is in chaos as mentioned above.
  • Patent Document 1 is far behind the conclusion that a NO donor results in enhancement of effect of anticancer agent in actual human clinical medicine. In fact, with regard to data showing that improvement in therapeutic effect for cancer was able to be achieved by that method, no data is available even for animal experiment in Patent Document 1.
  • an object of the present invention is to provide an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer.
  • a NO donor dramatically improves the therapeutic effect of an anticancer agent on non-small cell lung cancer which is believed to be one of the most difficult cancers for chemotherapy.
  • One of the backgrounds therefor is a retrospective clinical research in patients with either angina pectoris or old myocardial infarction treated with a NO donor.
  • response rate of the group where NO was used together was 90% (CR: 20%, 2/10; PR: 70%, 7/10; NC: 10%, 1/10; PD: 0%, 0/10) while response rate of the control group was 23% (CR: 0%, 0/44; PR: 23%, 10/44; NC: 50%, 22/44; PD: 27%, 12/44) (With regard to the method for judgment, refer to the Examples which will be mentioned later).
  • an enhancing agent for effect of anticancer agent which is characterized in that a NO donor is an effective ingredient.
  • the cancer which is an object for the treatment is solid cancer.
  • the solid cancer is non-small cell lung cancer.
  • the NO donor is an organic nitrate compound.
  • FIG. 1 is a drawing which shows survival rate curves in patients with advanced non-small cell lung cancer treated with NO donors ⁇ NO(+) ⁇ (solid line) and without NO donors ⁇ NO( ⁇ ) ⁇ (dotted line) during chemotherapy.
  • the P value was calculated by the log-rank test.
  • Tumor volume was calculated as 0.5 ⁇ tumor length (mm) ⁇ tumor width(mm) ⁇ 2 .
  • the P value was calculated by student t-test.
  • Tumor volume was calculated as 0.5 ⁇ tumor length (mm) ⁇ tumor width (mm) ⁇ 2 .
  • the P value was calculated by student t-test.
  • a nitric oxide (NO) donor means an agent which is able to release NO under a physiological condition.
  • organic nitrate compounds which are nitric esters of monohydric or polyhydric alcohol are included in this category. Their representative examples are nitroglycerin (NTG), pentaerythrityl tetranitrate (PETN), isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN).
  • an anticancer agent which is used in chemotherapy where effect is enhanced by the concomitant use of a NO donor and its examples are antimetabolites exemplified by 5-fluorouracil, methotrexate, doxifluridine, tegafur, cytarabine and gemcitabine; alkylating agents exemplified by cyclophosphamide, ifosfamide, thiotepa, carboquone and nimustine hydrochloride; anticancer antibiotics exemplified by mitomycin, doxorubicin hydrochloride, amurubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, aclarubicin hydrochloride, mitoxantrone hydrochloride, bleomycin hydrochloride and peplomycin sulfate; microtubule-acting agents exemplified by docetaxel, paclitaxel, vincris
  • a NO donor an example is that its administration is started to a patient who is subjected to a standard chemotherapy from 5 to 2 days before the start of the chemotherapy (preferably, 3 days before), the administration is continued during the period of chemotherapy and, at the stage where chemotherapy is finished, the administration is stopped.
  • the dosage form of the NO donor it is preferred to be an oral preparation or a subcutaneous preparation where control of concentration in blood is easy when risk of expression of resistance is taken into consideration.
  • the dose may be in accordance with a dose in the treatment of angina pectoris which is an inherent use of a NO donor.
  • administration when nitroglycerin is used, administration may be in a dose of 1 to 50 mg/day (being divided into two administrations a day) in the case of oral administration by means of tablets or the like and 1 to 50 mg/day (applied once daily) in the case of transdermally administration by means of plaster or the like.
  • administration when isosorbide dinitrate is used, administration may be in a dose of 10 to 100 mg/day (being divided into two administrations a day) in the case of oral administration and 10 to 100 mg/day (applied once daily) in the case of transdermally administration.
  • the above description does not deny the administration of a NO donor in a form of a combined preparation with an anticancer agent.
  • cancer which is an object of the treatment in the present invention
  • any cancer may be applied so far as it is a cancer which is able to be an object of chemotherapy.
  • Specific examples thereof are solid cancer such as head and neck cancer, stomach cancer, colon cancer, rectum cancer, hepatic cancer, gall and bile duct cancer, pancreatic cancer, lung cancer, breast cancer, bladder cancer, prostate cancer and uterine neck cancer, and blood cancer such as malignant lymphoma and leukemia.
  • NSCLC non-small cell lung cancer
  • MVP mitomycin C + vinorelbine + cisplatin
  • CDDP cisplatin
  • DOC docetaxel
  • VNR vinorelbine.
  • NO donors were used between 3 days before the start of each course of chemotherapy and the finish of administration of anticancer agents.
  • CT computed tomography
  • the nodal staging of lung cancer was determined using a CT scan and a Gallium-67 citrate scintigram of the chest.
  • the metastasis in the brain, the abdomen and the bone was determined using a CT scan of the brain and abdomen, and a Technetium-99m scintigram of the bone.
  • Complete response (CR) was defined as the disappearance of all known disease determined by two observations not less than two weeks apart.
  • Partial response was defined as a 50% or more decrease in the total tumor size of those lesions measured during two observations not less than four weeks apart.
  • No change was defined as cases where a 50% decrease in the total tumor size could not be established, and also there was not a 25% or greater increase in the size of one or more measurable lesions.
  • Progressive disease was defined as a 25% or greater increase in the size of one or more measurable lesions or the appearance of new lesions.
  • the patients were categorized as responders when they experienced either PR or CR.
  • the patients with NC or PD were categorized as non-responders.
  • Response rate to chemotherapy was calculated by the number of responders divided by the number of responders plus non-responders. Survival was calculated from the date of the first day of first cycle of the chemotherapy to the date of death or a cutoff date for patients alive at the time of closure of the data set.
  • the factors associated with the response to the chemotherapy were assessed by univariate analysis (Chi-square test) and multivariate analysis (Logistic regression analysis). Cox regression analysis was performed to assess the prognostic significance of the variables.
  • ECOG Performance Status (PS): Grade ECOG 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 Dead * Am J Clin Oncol 5: 649-655, 1982. Explanation of Technical Term (No. 2) Brinkman Index: a smoking history calculated by multiplying the number of cigarettes consumed a day (number of packages of cigarettes) by smoking duration (years). Results
  • Treating advanced NSCLC, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma remains very difficult because advanced NSCLC is not operable and the response rate to anticancer agents even if the newest third-generation anticancer agents is very low.
  • the response rate to chemotherapy in small cell lung cancer is about 70-80% and is significantly higher than that in NSCLC.
  • the number of patients with lung cancer has been increasing in most countries in the world year by year in contrast to the number of patients with gastric cancer.
  • a large proportion of lung cancer consists of NSCLC. Therefore, amore effective new regimen in advanced NSCLC than currently exists should be established at once.
  • the present invention may have a great significance on improving the response rate to not only NSCLC but other kinds of advanced solid cancer.
  • LLC cells Murine Lewis lung carcinoma (LLC) cells, lung adenocarcinoma cells, were obtained from the Tohoku University Cell Resource Center for Biomedical Research and were incubated with DMEM plus 10% fetal bovine serum until cell proliferation was sufficient to perform the experiments.
  • the LLC cells were adjusted to concentrations of 2 ⁇ 10 5 cells/100 ⁇ l with phosphate buffer saline (PBS), and were inoculated
  • PBS phosphate buffer saline
  • mice were maintained under specific-pathogen-free conditions, and provided with sterile food and water.
  • Tumor volume was calculated as 0.5 ⁇ tumor length (mm) ⁇ tumor width (mm) ⁇ 2 .
  • mice were fed i.v. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 ⁇ l of 3.5 mg/kg cisplatin solution dissolved in PBS was administered i.v. into the mice 30 minutes after the nitroglycerin solution i.p. twice a week (once on Monday and once on Thursday).
  • the experiments were performed for two weeks.
  • Cisplatin and nitroglycerin were obtained from Nippon Kayaku Co., Ltd (Tokyo, Japan). Measurements of murine tumor volume and mice body weight were performed every two days after the start of injections into mice.
  • the tumor volume growth curve is shown in FIG. 2 . Significant diminishing of murine tumor volume was observed after day 9 in the NO plus chemotherapy group compared with that in the chemotherapy group. On the other hand, the NO donor group as well as the control group showed rapid tumor growth compared with that in the chemotherapy group and the NO plus chemotherapy group.
  • Colon 26 cells murine colon cancer cells, were obtained from the Tohoku University Cell Resource Center for Biomedical Research and were incubated with RPMI 1640 plus 10% fetal bovine serum until cell proliferation was sufficient to perform the experiments.
  • the colon 26 cells were adjusted to concentrations of 2 ⁇ 10 5 cells/100 ⁇ l with phosphate buffer saline (PBS), and were inoculated
  • PBS phosphate buffer saline
  • Six-week-old female BALB/c mice purchased from Charles River Japan, Inc. (Tokyo, Japan) and Clea Japan, Inc. (Tokyo, Japan) subcutanously (2 ⁇ 10 5 cells/100 ⁇ l/mouse) at the right hypochondrium. Mice were maintained under specific-pathogen-free conditions, and provided with sterile food and water.
  • Tumor volume was calculated as 0.5 ⁇ tumor length (mm) ⁇ tumor width(mm) ⁇ 2 .
  • 100 ⁇ l of PBS was administered by intra-peritoneal injection (i.p.) four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 ⁇ l of PBS was further administered by intravenous injection (i.v.) 30 minutes after the i.p.
  • mice were administered i.v. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 ⁇ l of 3.5 mg/kg cisplatin solution dissolved in PBS was administered i.v. into the mice 30 minutes after the PBS i.p. twice a week (once on Monday and once on Thursday). The experiments were performed for two weeks.
  • 100 ⁇ l of 0.02 mg/kg nitroglycerin diluted with PBS was administered i.p. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 ⁇ l of 3.5 mg/kg cisplatin solution dissolved in PBS was administered i.v.
  • mice 30 minutes after the nitroglycerin solution i.p. twice a week (once on Monday and once on Thursday). The experiments were performed for two weeks.
  • Cisplatin and nitroglycerin were obtained from Nippon Kayaku Co., Ltd. (Tokyo, Japan). Measurements of murine tumor volume and mice body weight were performed every two days after the start of injections into the mice.
  • the tumor volume growth curve is shown in FIG. 3 . Significant diminishing of murine tumor volume was observed after day 6 in the NO plus chemotherapy group compared with that in the chemotherapy group. On the other hand, the NO donor group as well as the control group showed rapid tumor growth compared with that in the chemotherapy group and the NO plus chemotherapy group.
  • the present invention is able to provide an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer whereby it has an industrial applicability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

An object of the present invention is to provide an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer. The enhancing agent for effect of anticancer agent according to the present invention which is a solving means therefor is characterized in that a nitric oxide donor is an effective ingredient. In accordance with the present invention, an excellent therapeutic effect is able to be achieved on non-small cell lung cancer which is still in such a state that no effective therapeutic method has been established yet for a progressive cancer which is not operable and is one of cancers where chemotherapy is most difficult to apply.

Description

    TECHNICAL FIELD
  • The present invention relates to an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer.
    • BACKGROUND ART
  • It has been well known that, as a result of vigorous research and development of anticancer agents for many years, various kinds of anticancer agents are now being used in chemotherapy to various types of cancer and therapeutic effect is achieved thereby. However, it has been also known that there is no anticancer agent which is effective on all types of cancer and there is a limitation for the therapeutic effect of anticancer agent on cancer.
  • As one of the causes for the limitation in the therapeutic effect on cancer by anticancer agent, it has been reported that hypoxic condition inside the solid cancer participates in resistance to its therapy. For example, in Non-Patent Document 1 (Matthews N E, Adams M A, Maxwell L R, Gofton T E, Graham C H. Nitric oxide-mediated regulation of chemosensitivity in cancer cells. J. Natl. Cancer Inst., 2001; 93: 1879-1885), it is shown that, in experiments where several kinds of cancer cell lines are actually used, hypoxic condition promotes the resistance of cancer cells to anticancer agent. In this document, it is made clear that, when an anticancer agent is mixed with culture medium of cancer cell lines, the surviving rate is as high as two-fold or more even if the cancer cells are directly exposed to the anticancer agent as compared with the case where they are exposed in normoxic condition provided that they are exposed in hypoxic condition. It is also made clear that hypoxic condition suppresses an endogenous production of nitric oxide (NO) whereby it enhances the resistance of the cancer cells to anticancer agent and that administration of an exogenous NO donor improves the resistance to anticancer agent by hypoxic condition. Besides that, in Non-Patent Document 2 (Jordan B F, Misson P D, Demeure R, Baudelet C, Beghein N, Gallez B. Changes In tumor oxygenation/perfusion induced by the NO donor, Isosorbide dinitrate, In comparison with carbogen: monitoring by EPR and MRI. Int. J. Radiation Oncology Biol. Phys., 2000; 48: 565-570), it is suggested that isosorbide dinitrate which is a NO donor improves oxygen pressure inside the cancer due to an increase in blood flow. In Non-Patent Document 3 (Liang B C. Effects of hypoxia on drug resistance phenotype and genotype in human glioma cell lines. J. Neurooncol., 1996; 29: 149-155), it is made clear that, when glioma cell line is placed in hypoxic condition, it shows resistance to anticancer agent. In Non-Patent Document 4 (Sanna K, Rofstad E K. Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro. Int. J. Cancer, 1994; 58: 258-262), it is made clear that, when human melanoma cell line is placed in hypoxic condition, it shows resistance to anticancer agent. Thus, according to those reports, even when anticancer agent is merely distributed in large quantities in cancer cells, death of cancer cells is not accelerated unless hypoxic condition in tumor tissues is improved. Non-Patent Document 1 and Non-Patent Document 2 suggest that a NO donor is able to effectively function in improvement of hypoxic condition inside the solid cancer.
  • However, in any of the reports, it is not proved that NO actually enhances the therapeutic effect of anticancer agent on cancer in human clinical medicine. Rather, there are many reports which suggest that NO has an action of increasing the tumor size and promoting its progress. For example, in Non-Patent Document 5 (Gallo O, Masini E, Morbidelli L, Franchi A, et al. Role of nitric oxide in angiogenesis in head and neck cancer. J. Natl. Cancer Inst., 1998; 90: 587-596), a NO synthase (NOS) participating in NO production in tissue preparation of human head and neck cancer is investigated and it is shown that, in advanced cancer cases accompanied by metastasis to lymph node, expressed amount of NOS is high and blood vessel density in lymph node is high in a group where metastasis to lymph node is positive. In this document, an investigation using cornea of rabbit is also conducted for tumor angiogenetic effect of NO on cancer tissues prepared from human head and neck cancer cases. According to that, it is suggested that, in a group to which L-NAME which is a NOS inhibitor is administered, tumor angiogenesis is significantly little and progress of cancer is suppressed as compared with a control group and it is shown that NO has a promoting action for increase and progress of cancer tissues via tumor angiogenesis. In Non-Patent Document 6 (Edwards P, Cendab J C, Topping D B, Moldawer L L, Mackay S, Copeland E M, Lind D S. Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. J. Surg. Res., 1996; 63: 49-52), it is shown that, when an experiment using cultured cells where NO production is promoted by stimulation of LPS/IFN-γ using EMT-6 cells (breast cancer cell line of mice) is conducted, growth of tumor cells is suppressed while, when the same cells are transplanted to BALB/c mouse and stimulated by LPS/IFN-γ, tumor tissues and lung metastasis increased to an extent of two-fold as compared with a control group and that experimental results are entirely opposite between an experiment using cultured cells (in vitro experiment) and an animal experiment (in vivo experiment). In the Non-Patent Document 7 (Ambs S, Merriam W G, Ogunfusika M O, Bennett W P, Ishibe N, et al. p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nature Med., 1998; 4: 1371-1376), an influence of NO on angiogenesis and cancer progress is investigated in an animal experiment where a human cancer cell line into which NOS gene is introduced so as to conduct a NO synthesis in a constant manner is transplanted to nude mice having no thymus. Here, relation to the presence/absence of an activity of cancer suppressive gene p53 is investigated and it is shown that, in tumor tissues where cancer cell line having a p53 activity (wild type p53) is transplanted to nude mice, an endogenous NO suppresses the growth of tumor cells while, in tumor tissues where cancer cell line having poor p53 activity (mutant p53) is transplanted to nude mice, the endogenous NO promotes VEGF expression and angiogenesis, and promotes the growth of tumor cells. In Non-Patent Document 8 (D C Jenkins, I G Charles, L L Thomsen, D W Moss, L S Holmes, S A Baylis, P Rhodes, K Westmore, P C Emson, S Moncada. Roles of Nitric Oxide in Tumor Growth. Proc. Natl. Acad. Sci. USA, 1995; 92: 4392-4396), it is shown that, inhuman breast cancer and cancer in a gynecologic field, NO production and cancer growth show a positive correlation. In Non-Patent Document 9 (Lala P K, Chakraborty C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol., 2001; 2: 149-156), it is shown that NOS of a derived type participates in mutation of p53 of tumor of colon, lung and throat and that NO stimulates the growth of tumor via activation of cyclooxygenase-2 (COX-2). Thus, according to those reports, it is strongly suggested that, in establishing a therapy of cancer by anticancer agent in human clinical medicine, the use of NO has a possibility of causing adverse effects to patients such as increase or progress of cancer.
  • As mentioned above, with regard to an action of NO to cancer, each of the reports mentioning it participates in the direction of suppressing the cancer and the reports mentioning it participates in the direction of worsening the cancer are present in large numbers being supported by scientific proof and a scientific evaluation therefor is in a chaotic state. Moreover, as shown in Non-Patent Document 6, it is never rare that the experimental results are entirely contrary between an experiment using cultured cells and an animal experiment. In view of such circumstances, in Non-Patent Document 1 for example, it is shown that resistance of cancer cell line to anticancer agent induced by hypoxic condition is improved by a NO donor in an experiment using cultured cells and, although such a finding will be surely valuable for showing one direction for future research, it is not possible to conclude from such a finding that a NO donor has an action of shrinking the cancer tissues or an action of enhancing the effect of anticancer agent. So, it is all the more that, in human clinical medicine, a conclusion that a NO donor enhances the effect of anticancer agent is unable to be done and should not be done.
  • In Patent Document 1 (JP 2004-508279 A), there is proposed a method of administering a NO donor as a potassium channel activator as a method for a selective transfer of anticancer agent to cancer where permeability of blood vessel for sending blood to cancer cells to anticancer agent is enhanced. However, issue of a jumped conclusion that a NO donor enhances the effect of anticancer agent only by appealing an increase in transition of an anticancer agent to tumor tissues by an increase in permeability through blood vessel without actual confirmation of enhancement of NO donor in the action of anticancer agent to cancer tissues even in animal experiment is not convincing at all under the present status where scientific evaluation for the action of NO to cancer is in chaos as mentioned above. Patent Document 1 is far behind the conclusion that a NO donor results in enhancement of effect of anticancer agent in actual human clinical medicine. In fact, with regard to data showing that improvement in therapeutic effect for cancer was able to be achieved by that method, no data is available even for animal experiment in Patent Document 1.
  • Therefore, an object of the present invention is to provide an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer.
    • DISCLOSURE OF THE INVENTION
  • Under the circumstance where, even in animal experiments, no conclusion is issued what effect is available by administration of a NO donor to cancer tissues, the present inventors have at this time found that a NO donor dramatically improves the therapeutic effect of an anticancer agent on non-small cell lung cancer which is believed to be one of the most difficult cancers for chemotherapy. One of the backgrounds therefor is a retrospective clinical research in patients with either angina pectoris or old myocardial infarction treated with a NO donor. That is because there is a ground of a data analysis where response rate by chemotherapy is quite significantly higher in a group suffering from advanced non-small cell lung cancer and receiving a chemotherapy (MVP therapy) (group where NO is used together; age: 67±8; male ratio: 80%) than a group using no NO donor and receiving the same MVP therapy (control group; age: 65±9; male ratio: 76%) where odds ratio=30.6, 95% CI 3.5-270.4, p<0.0001, Chi-square test. In the data, response rate of the group where NO was used together was 90% (CR: 20%, 2/10; PR: 70%, 7/10; NC: 10%, 1/10; PD: 0%, 0/10) while response rate of the control group was 23% (CR: 0%, 0/44; PR: 23%, 10/44; NC: 50%, 22/44; PD: 27%, 12/44) (With regard to the method for judgment, refer to the Examples which will be mentioned later).
  • The present invention has been achieved on the basis of the above-mentioned finding, and according to a first aspect and feature of the present invention, there is provided an enhancing agent for effect of anticancer agent which is characterized in that a NO donor is an effective ingredient.
  • According to a second aspect and feature of the present invention, in addition to the first feature, the cancer which is an object for the treatment is solid cancer.
  • According to a third aspect and feature of the present invention, in addition to the second feature, the solid cancer is non-small cell lung cancer.
  • According to a fourth aspect and feature of the present invention, in addition to the first feature, the NO donor is an organic nitrate compound.
  • In accordance with the present invention, it is possible to provide an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer.
    • BRIEF DESCRIPTION OF DRAWINGS
  • FIG. 1 is a drawing which shows survival rate curves in patients with advanced non-small cell lung cancer treated with NO donors {NO(+)} (solid line) and without NO donors {NO(−)} (dotted line) during chemotherapy. The P value was calculated by the log-rank test.
  • FIG. 2 shows the tumor volume growth curves in lung cancer model (Murine Lewis lung carcinoma; LLC cells) in C57BL6 mice (Control group, n=6; C, NO donor group, n=6; N, Chemotherapy group, n=6; CTX, and NO plus chemotherapy group, n=6; N+CTX). Tumor volume was calculated as 0.5×{tumor length (mm)}×{tumor width(mm)}2. The P value was calculated by student t-test.
  • FIG. 3 shows the tumor volume growth curves in colon cancer model (Murine colon cancer cell line; colon 26 cells) in BALB/c mice (Control group, n=6; C, NO donor group, n=6; N, Chemotherapy group, n=6; CTX, and NO plus chemotherapy group, n=6; N+CTX). Tumor volume was calculated as 0.5×{tumor length (mm)}×{tumor width (mm)}2. The P value was calculated by student t-test.
    • BEST MODE FOR CARRYING OUT THE INVENTION
  • In the present invention, a nitric oxide (NO) donor means an agent which is able to release NO under a physiological condition. For example, organic nitrate compounds which are nitric esters of monohydric or polyhydric alcohol are included in this category. Their representative examples are nitroglycerin (NTG), pentaerythrityl tetranitrate (PETN), isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN).
  • There is no particular limitation for an anticancer agent which is used in chemotherapy where effect is enhanced by the concomitant use of a NO donor and its examples are antimetabolites exemplified by 5-fluorouracil, methotrexate, doxifluridine, tegafur, cytarabine and gemcitabine; alkylating agents exemplified by cyclophosphamide, ifosfamide, thiotepa, carboquone and nimustine hydrochloride; anticancer antibiotics exemplified by mitomycin, doxorubicin hydrochloride, amurubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, aclarubicin hydrochloride, mitoxantrone hydrochloride, bleomycin hydrochloride and peplomycin sulfate; microtubule-acting agents exemplified by docetaxel, paclitaxel, vincristine, vindesine and vinorelbine; platinum-based agents exemplified by cisplatin, carboplatin and nedaplatin; topoisomerase inhibitors exemplified by irinotecan and nogitecan hydrochloride; and alkaloidal anticancer agents exemplified by etoposide.
  • With regard to a NO donor, an example is that its administration is started to a patient who is subjected to a standard chemotherapy from 5 to 2 days before the start of the chemotherapy (preferably, 3 days before), the administration is continued during the period of chemotherapy and, at the stage where chemotherapy is finished, the administration is stopped. Although there is no particular limitation for the dosage form of the NO donor, it is preferred to be an oral preparation or a subcutaneous preparation where control of concentration in blood is easy when risk of expression of resistance is taken into consideration. The dose may be in accordance with a dose in the treatment of angina pectoris which is an inherent use of a NO donor. To be more specific, when nitroglycerin is used, administration may be in a dose of 1 to 50 mg/day (being divided into two administrations a day) in the case of oral administration by means of tablets or the like and 1 to 50 mg/day (applied once daily) in the case of transdermally administration by means of plaster or the like. When isosorbide dinitrate is used, administration may be in a dose of 10 to 100 mg/day (being divided into two administrations a day) in the case of oral administration and 10 to 100 mg/day (applied once daily) in the case of transdermally administration. Incidentally, the above description does not deny the administration of a NO donor in a form of a combined preparation with an anticancer agent.
  • There is no particular limitation for the cancer which is an object of the treatment in the present invention but any cancer may be applied so far as it is a cancer which is able to be an object of chemotherapy. Specific examples thereof are solid cancer such as head and neck cancer, stomach cancer, colon cancer, rectum cancer, hepatic cancer, gall and bile duct cancer, pancreatic cancer, lung cancer, breast cancer, bladder cancer, prostate cancer and uterine neck cancer, and blood cancer such as malignant lymphoma and leukemia.
    • EXAMPLES
  • The present invention shall be described as following. Any limitations in interpretation will not arise according to following documents.
    • Example 1 A Study of the Effect of Concomitant Use of NO Donors with Anticancer Agents on Response to Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer in a Prospective Randomised Controlled Trial
  • Characteristics of the Subjects
  • Sixty five patients with inoperable advanced non-small cell lung cancer (NSCLC) fit the following five criteria and were recruited in this study: (a) stage IIIB or stage IV; (b) no prior chemotherapy or radiotherapy; (c) good performance status: a performance status of 0-2 according to the Eastern Cooperative Oncology Group (ECOG) scale; (d) without brain metastasis; (e) adequate renal function, hepatic function, hematological function and cardiac function.
  • Of the 65 patients with advanced NSCLC, 31 patients had squamous cell carcinoma (19 patients in stage IIIB and 12 patients in stage IV), 29 patients had adenocarcinoma (9 patients in stage IIIB and 20 patients in stage IV), 5 patients had large cell carcinoma (4 patients in stage IIIB and 1 patients in stage IV), and all patients were randomly assigned to receive anticancer agents with or without NO donors during chemotherapy in a prospective cohort study.
  • Thirty two of the 65 patients with advanced NSCLC were treated with chemotherapy with a NO donor (transdermally applied nitroglycerin, Nitroderm TTS®, 25 mg/body daily, or orally administered isosorbide dinitrate, Nitrol R®, 40 mg/body daily divided into two administrations, between 3 days before the start of each course of chemotherapy and the finish of administration of anticancer agents). In group treated with a NO donor, 21 of 32 patients were treated with MVP, cisplatin (CDDP) plus vinorelbine (VNR) plus mitomycin (CDDP 80 mg/m2 day 1, VNR 25 mg/m2 day 1 and 8, mitomycin 8 mg/m2 day 1, in every 21 days), 6 of 32 patients were treated with CDDP plus docetaxel (DOC) (CDDP 80 mg/m2 day 1, DOC; 75 mg/m2 day 1, in every 21 days), and 5 of 32 patients were treated with CDDP plus VNR (CDDP 80 mg/m2 day 1, VNR 25 mg/m2 day 1 and 8, in every 21 days). Another 33 of the 65 patients with advanced NSCLC were treated with chemotherapy without a NO donor. In group treated without a NO donor, 18 of 33 patients were treated with MVP, CDDP plus VNR plus mitomycin (CDDP 80 mg/m2 day 1, VNR 25 mg/m2 day 1 and 8, mitomycin 8 mg/m2 day 1, in every 21 days), 8 of 33 patients were treated with CDDP plus DOC (CDDP 80 mg/m2 day 1, DOC; 75 mg/m2 day 1, in every 21 days), and 7 of 33 patients were treated with CDDP plus VNR (CDDP 80 mg/m2 day 1, VNR 25 mg/m2 day 1 and 8, in every 21 days). Characteristics of the subjects in arm A and arm B are shown in Table 1.
    TABLE 1
    Characteristics of patients with advanced non-small cell lung cancer.
    With NO
    mimetics Without NO mimetics
    Characteristics (Arm A, n = 32) (Arm B, n = 33) P value
    Age (year)
    Median 68 67 0.2615*
    Range 41-83 48-84
    Gender
    (No. of patients)
    Male 29 24 0.063
    Female  3  9
    Performance Status
    (No. of patients)
    0 23 23 0.8469
    1  6  6 0.9529
    2  3  4 0.721
    Brinkman Index
    (pack-year)
    Median 49 47 0.6334*
    Range  0-120  0-125
    Cell type
    (No. of patients)
    Squamous cell 18 13 0.1737
    Adenocarcinoma 10 19 0.0328
    Large cell  4  1 0.1520
    Stage
    (No. of patients)
    III B 17 15 0.5363
    IV 15 18
    Chemotherapy
    (No. of patients)
    MVP 21 18 0.362
    CDDP + DOC  6  8 0.5902
    CDDP + VNR  5  7 0.5616

    MVP = mitomycin C + vinorelbine + cisplatin,

    CDDP = cisplatin,

    DOC = docetaxel,

    VNR = vinorelbine.

    Two factors marked * was statistically assessed with the Mann-Whitney U test.

    Other factors was assessed with the Chi-square test.

    Methods
  • NO donors were used between 3 days before the start of each course of chemotherapy and the finish of administration of anticancer agents. To assess the effects of NO donors on the chemosensitivity, we compared the tumor sizes with the chest computed tomography (CT) scan before and after treatment with anticancer agents. The nodal staging of lung cancer was determined using a CT scan and a Gallium-67 citrate scintigram of the chest. The metastasis in the brain, the abdomen and the bone was determined using a CT scan of the brain and abdomen, and a Technetium-99m scintigram of the bone. Complete response (CR) was defined as the disappearance of all known disease determined by two observations not less than two weeks apart. Partial response (PR) was defined as a 50% or more decrease in the total tumor size of those lesions measured during two observations not less than four weeks apart. No change (NC) was defined as cases where a 50% decrease in the total tumor size could not be established, and also there was not a 25% or greater increase in the size of one or more measurable lesions. Progressive disease (PD) was defined as a 25% or greater increase in the size of one or more measurable lesions or the appearance of new lesions. The patients were categorized as responders when they experienced either PR or CR. The patients with NC or PD were categorized as non-responders. Response rate to chemotherapy was calculated by the number of responders divided by the number of responders plus non-responders. Survival was calculated from the date of the first day of first cycle of the chemotherapy to the date of death or a cutoff date for patients alive at the time of closure of the data set.
  • The factors associated with the response to the chemotherapy were assessed by univariate analysis (Chi-square test) and multivariate analysis (Logistic regression analysis). Cox regression analysis was performed to assess the prognostic significance of the variables. We analyzed the survival rate with the Kaplan-Meire method, and the p-value of survival curves between patients treated with anticancer agents and NO donors and patients treated with anticancer agents alone with the Log-rank test. Significance was accepted at p<0.05.
  • Explanation of Technical Term (No. 1)
  • ECOG Performance Status (PS):
    Grade ECOG
    0 Fully active, able to carry on all pre-disease
    performance without restriction
    1 Restricted in physically strenuous activity but
    ambulatory and able to carry out work of a light or
    sedentary nature, e.g., light house work, office work
    2 Ambulatory and capable of all selfcare but unable to
    carry out any work activities. Up and about more than
    50% of waking hours
    3 Capable of only limited selfcare, confined to bed or
    chair more than 50% of waking hours
    4 Completely disabled. Cannot carry on any selfcare.
    Totally confined to bed or chair
    5 Dead

    * Am J Clin Oncol 5: 649-655, 1982.

    Explanation of Technical Term (No. 2)
    Brinkman Index: a smoking history calculated by multiplying the number of cigarettes consumed a day (number of packages of cigarettes) by smoking duration (years).
    Results
  • Characteristics of the subjects in responders and non-responders are shown in Table 2 and Table 3. Survival curves for the group treated with NO donors and the group treated without NO donors calculated by Kaplan-Meier analysis are shown in FIG. 1.
    TABLE 2
    Analysis of risk factors for chemosensitivity assessed
    by multivariate analysis.
    PR + CR NC + PD Multivariate
    (Responder) (Non-responder) analysis
    Characteristics (n = 39) (n = 26) p value
    Age (year)
    65≧ 30 (67%) 15 (33%) 0.792
    65<  9 (45%) 11 (55%)
    Gender (No. of patients)
    Male 35 (66%) 18 (34%) 0.438
    Female  4 (33%)  8 (67%)
    Performance Status
    (No. of patients)
    0 28 (61%) 18 (39%) 0.927
    1  6 (50%)  6 (50%)
    2  5 (71%)  2 (29%)
    Brinkman Index
    (pack-year)
    50≧ 20 (74%)  7 (26%) 0.899
    50< 19 (50%) 19 (50%)
    Cell type
    (No. of patients)
    Squamous cell 26 (84%)  5 (16%) 0.011
    Adenocarcinoma 10 (34%) 19 (66%) —
    Large cell  3 (60%)  2 (40%) 0.948
    Staging
    (No. of patients)
    III B 24 (75%)  8 (25%) 0.098
    IV 15 (45%) 18 (55%)
    Chemotherapy
    (No. of patients)
    MVP 26 (67%) 13 (33%) 0.199
    CDDP + DOC  7 (50%)  7 (50%) 0.358
    CDDP + VNR  6 (50%)  6 (50%) —
    Vital Capacity
    (% predicted)
    <80%  7 (78%)  2 (22%) 0.724
    ≧80% 32 (57%) 24 (43%)
    Forced Expiratory
    Volume in 1 second
    (% predicted)
    <70% 18 (72%)  7 (28%) 0.299
    ≧70% 21 (53%) 19 (47%)
    Use of NO Mimetics
    (No. of patients)
    yes 26 (81%)  6 (19%) 0.007
    No 13 (39%) 20 (61%)
    Use of vasodilator
    except for NO mimetics
    (No. of patients)
    yes 18 (69%)  8 (31%) 0.246
    No 21 (54%) 18 (46%)

    CR = complete response,

    PR = partial response,

    NC = no change,

    PD = progressive disease,

    NO = nitric oxide,

    MVP = mitomycin C + vinorelbine + cisplatin,

    CDDP = cisplatin,

    DOC = docetaxel,

    VNR = vinorelbine.

    Multivariate analysis was performed with Logistic regression analysis.
  • TABLE 3
    The relationship between the use of NO donors and anticancer drugs
    and chemosensitivity in a clinical research
    Responder; Non-responder;
    CR + PR NC + PD
    Anticancer drugs (Number) (Number)
    The use of MVP 17 26 4 6
    NO donors (+) CDDP + DOC 5 1
    CDDP + VNR 4 1
    The use of MVP 9 13 9 20
    NO donors (−) CDDP + DOC 2 6
    CDDP + VNR 2 5

    CR = complete response,

    PR = partial response,

    NC = no change,

    PD = progressive disease,

    NO = nitric oxide,

    MVP = mitomycin C + vinorelbine + cisplatin,

    CDDP = cisplatin,

    DOC = docetaxel,

    VNR = vinorelbine.
  • There were no statistical significances between patients with advanced NSCLC treated with anticancer agents and NO donors and patients treated with anticancer agents alone in age, gender, performance status, smoking history, stage of lung cancer and protocol of chemotherapy (Table 1). Remarkable strong effects of the use of NO donors combined with anticancer agents on response rate to chemotherapy in patients with advanced NSCLC were recognized as shown in Table 2 and Table 3. Response rate in patients treated with NO donors during chemotherapy (81%, 26 of 32 patients) was significantly higher than that in patients treated without NO donors (39%, 13 of 33 patients) (Odds ratio=6.7, 95% CI 2.2-20.7, p=0.0006, Chi-square test) (Table 2). The use of NO donors (p<0.01) was significantly associated with a positive response to anticancer agents in patients with advanced NSCLC (Logistic regression analysis) (Table 2). Kaplan-Meier analysis showed that the survival in patients treated with anticancer agents and NO donors was significantly longer than that in patients treated with anticancer agents alone (p<0.05) (Log-rank test). These results (Table 2 and Table 3) suggest that the use of NO donors, such as nitroglycerin and isosorbide dinitrate, may improve the response to chemotherapy in patients with stage IIIB or stage IV of advanced NSCLC.
  • Conclusions
  • The use of NO donors combined with anticancer agents turned out to have a great additional effect on the improvement of response rate to chemotherapy and overall survival in patients with advanced NSCLC compared with those in patients treated with anticancer agents without NO donors.
  • Treating advanced NSCLC, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma remains very difficult because advanced NSCLC is not operable and the response rate to anticancer agents even if the newest third-generation anticancer agents is very low. In contrast, the response rate to chemotherapy in small cell lung cancer is about 70-80% and is significantly higher than that in NSCLC. The number of patients with lung cancer has been increasing in most countries in the world year by year in contrast to the number of patients with gastric cancer. Furthermore, a large proportion of lung cancer consists of NSCLC. Therefore, amore effective new regimen in advanced NSCLC than currently exists should be established at once. On this point, the present invention may have a great significance on improving the response rate to not only NSCLC but other kinds of advanced solid cancer.
    • Example 2 Concomitant Use of a NO Donor, Nitroglycerin, Improves Chemosensitivity in Murine Lung Cancer Model
  • Methods
  • Murine Lewis lung carcinoma (LLC) cells, lung adenocarcinoma cells, were obtained from the Tohoku University Cell Resource Center for Biomedical Research and were incubated with DMEM plus 10% fetal bovine serum until cell proliferation was sufficient to perform the experiments. The LLC cells were adjusted to concentrations of 2×105 cells/100 μl with phosphate buffer saline (PBS), and were inoculated Six-week-old male C57BL6 mice purchased from Charles River Japan, Inc. (Tokyo, Japan) and Clea Japan, Inc. (Tokyo, Japan) subcutanously (2×105 cells/100 μl/mouse) at the right hypochondrium. Mice were maintained under specific-pathogen-free conditions, and provided with sterile food and water. When transplanted tumors grew to approximately 100 mm3 in tumor volume, animals were equally divided into four groups (Control group, n=6; C, NO donor group, n=6; N, Chemotherapy group, n=6; CTX, and NO plus chemotherapy group, n=6; N+CTX). Tumor volume was calculated as 0.5×{tumor length (mm)}×{tumor width (mm)}2. In the control group, 100 μl of PBS was administered by intra-peritoneal injection (i.p.) four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 μl of PBS was further administered by intravenous injection (i.v.) 30 minutes after the i.p. twice a week (once on Monday and once on Thursday) into the C57BL6 mice. The experiments were performed for two weeks. In the NO donor group, 100 μl of 0.02 mg/kg nitroglycerin diluted with PBS was administered i.p. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 μl of PBS was administered i.v. into the mice 30 minutes after the nitroglycerin solution i.p. twice a week (once on Monday and once on Thursday). The experiments were performed for two weeks. In the chemotherapy group, 100 μl of PBS was administered i.p. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 μl of 3.5 mg/kg cisplatin solution dissolved in PBS was administered i.v. into the mice 30 minutes after the PBS i.p. twice a week (once on Monday and once on Thursday). The experiments were performed for two weeks. In the NO plus chemotherapy group, 100 μl of 0.02 mg/kg nitroglycerin diluted with PBS was administered i.p. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 μl of 3.5 mg/kg cisplatin solution dissolved in PBS was administered i.v. into the mice 30 minutes after the nitroglycerin solution i.p. twice a week (once on Monday and once on Thursday). The experiments were performed for two weeks. Cisplatin and nitroglycerin were obtained from Nippon Kayaku Co., Ltd (Tokyo, Japan). Measurements of murine tumor volume and mice body weight were performed every two days after the start of injections into mice.
  • Results
  • The tumor volume growth curve is shown in FIG. 2. Significant diminishing of murine tumor volume was observed after day 9 in the NO plus chemotherapy group compared with that in the chemotherapy group. On the other hand, the NO donor group as well as the control group showed rapid tumor growth compared with that in the chemotherapy group and the NO plus chemotherapy group.
  • These data suggest that the chance of a new commercial use of NO donors as an enhancing agent for effect of anticancer agents can be enlarged because of their excellent effect on the improvement of chemosensitivity especially in difficult solid cancers to treat with chemotherapy.
    • Example 3 Concomitant Use of a NO Donor, Nitroglycerin, Improves Chemosensitivity in Murine Colon Cancer Model
  • Methods
  • Colon 26 cells, murine colon cancer cells, were obtained from the Tohoku University Cell Resource Center for Biomedical Research and were incubated with RPMI 1640 plus 10% fetal bovine serum until cell proliferation was sufficient to perform the experiments. The colon 26 cells were adjusted to concentrations of 2×105 cells/100 μl with phosphate buffer saline (PBS), and were inoculated Six-week-old female BALB/c mice purchased from Charles River Japan, Inc. (Tokyo, Japan) and Clea Japan, Inc. (Tokyo, Japan) subcutanously (2×105 cells/100 μl/mouse) at the right hypochondrium. Mice were maintained under specific-pathogen-free conditions, and provided with sterile food and water. When transplanted tumors grew to approximately 100 mm3 in tumor volume, animals were equally divided into four groups (Control group, n=6; C, NO donor group, n=6; N, Chemotherapy group, n=6; CTX, and NO plus chemotherapy group, n=6; N+CTX). Tumor volume was calculated as 0.5×{tumor length (mm)}×{tumor width(mm)}2. In the control group, 100 μl of PBS was administered by intra-peritoneal injection (i.p.) four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 μl of PBS was further administered by intravenous injection (i.v.) 30 minutes after the i.p. twice a week (once on Monday and once on Thursday) into the BALB/c mice. The experiments were performed for two weeks. In the NO donor group, 100 μl of 0.02 mg/kg nitroglycerin diluted with PBS was administered i.p. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 μl of PBS was administered i.v. into the mice 30 minutes after the nitroglycerin solution i.p. twice a week (once on Monday and once on Thursday). The experiments were performed for two weeks. In the chemotherapy group, 100 μl of PBS was administered i.p. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 μl of 3.5 mg/kg cisplatin solution dissolved in PBS was administered i.v. into the mice 30 minutes after the PBS i.p. twice a week (once on Monday and once on Thursday). The experiments were performed for two weeks. In the NO plus chemotherapy group, 100 μl of 0.02 mg/kg nitroglycerin diluted with PBS was administered i.p. into the mice four times a week (once on Sunday, once on Monday, once on Wednesday, once on Thursday) and 100 μl of 3.5 mg/kg cisplatin solution dissolved in PBS was administered i.v. into the mice 30 minutes after the nitroglycerin solution i.p. twice a week (once on Monday and once on Thursday). The experiments were performed for two weeks. Cisplatin and nitroglycerin were obtained from Nippon Kayaku Co., Ltd. (Tokyo, Japan). Measurements of murine tumor volume and mice body weight were performed every two days after the start of injections into the mice.
  • Results
  • The tumor volume growth curve is shown in FIG. 3. Significant diminishing of murine tumor volume was observed after day 6 in the NO plus chemotherapy group compared with that in the chemotherapy group. On the other hand, the NO donor group as well as the control group showed rapid tumor growth compared with that in the chemotherapy group and the NO plus chemotherapy group.
  • These data suggest that the use of NO donors combined with anticancer agents can enlarge the chance of a new commercial use of NO donors because of their excellent effect on the improvement of chemosensitivity not only in lung cancer but also in colon cancer.
    • INDUSTRIAL APPLICABILITY
  • The present invention is able to provide an enhancing agent for effect of anticancer agent for achieving an excellent therapeutic effect on cancer whereby it has an industrial applicability.

Claims (4)

1. An enhancing agent for effect of anticancer agent which is characterized in that a nitric oxide donor is an effective ingredient.
2. The enhancing agent for effect of anticancer agent according to claim 1, wherein the cancer which is an object for the treatment is solid cancer.
3. The enhancing agent for effect of anticancer agent according to claim 2, wherein the solid cancer is non-small cell lung cancer.
4. The enhancing agent for effect of anticancer agent according to claim 1, wherein the nitric oxide donor is an organic nitrate compound.
US11/628,943 2004-06-10 2005-06-10 Anticancer Effect Enhancer Abandoned US20080039521A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/628,943 US20080039521A1 (en) 2004-06-10 2005-06-10 Anticancer Effect Enhancer
US12/318,061 US8410175B2 (en) 2004-06-10 2008-12-22 Anticancer effect enhancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2004173174 2004-06-10
US2004-173174 2004-06-10
US11/628,943 US20080039521A1 (en) 2004-06-10 2005-06-10 Anticancer Effect Enhancer
PCT/JP2005/011078 WO2005120493A1 (en) 2004-06-10 2005-06-10 Anticancer effect enhancer

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/011078 A-371-Of-International WO2005120493A1 (en) 2004-06-10 2005-06-10 Anticancer effect enhancer

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/318,061 Division US8410175B2 (en) 2004-06-10 2008-12-22 Anticancer effect enhancer

Publications (1)

Publication Number Publication Date
US20080039521A1 true US20080039521A1 (en) 2008-02-14

Family

ID=34970391

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/628,943 Abandoned US20080039521A1 (en) 2004-06-10 2005-06-10 Anticancer Effect Enhancer
US12/318,061 Expired - Fee Related US8410175B2 (en) 2004-06-10 2008-12-22 Anticancer effect enhancer

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/318,061 Expired - Fee Related US8410175B2 (en) 2004-06-10 2008-12-22 Anticancer effect enhancer

Country Status (8)

Country Link
US (2) US20080039521A1 (en)
EP (1) EP1778215B1 (en)
JP (2) JP4729503B2 (en)
KR (1) KR20070045187A (en)
CN (1) CN101001623B (en)
DE (1) DE602005018222D1 (en)
ES (1) ES2338022T3 (en)
WO (1) WO2005120493A1 (en)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100098733A1 (en) * 2008-10-16 2010-04-22 Novan, Inc. Nitric oxide releasing particles for oral care applications
US20100111850A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Delaware Compositions and methods for administering compartmentalized frozen particles
US20100111834A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111857A1 (en) * 2008-10-31 2010-05-06 Boyden Edward S Compositions and methods for surface abrasion with frozen particles
US20100111841A1 (en) * 2008-10-31 2010-05-06 Searete Llc Compositions and methods for surface abrasion with frozen particles
US20100114267A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100112067A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for biological remodeling with frozen particle compositions
US20100111831A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100111938A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for biological remodeling with frozen particle compositions
US20100114545A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100113615A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for delivery of frozen particle adhesives
US20100111844A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100114268A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100114497A1 (en) * 2008-10-31 2010-05-06 Searete Llc, S Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111843A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100114546A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111830A1 (en) * 2008-10-31 2010-05-06 Searete Llc Compositions and methods for surface abrasion with frozen particles
US20100111833A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100114496A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100111835A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111836A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111832A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100114592A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111855A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The States Of Delaware Frozen compositions and methods for piercing a substrate
US20100111842A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100168900A1 (en) * 2008-10-31 2010-07-01 Searete Llc Systems, devices, and methods for making or administering frozen particles
US20110086234A1 (en) * 2009-10-13 2011-04-14 Nathan Stasko Nitric oxide-releasing coatings
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9050251B2 (en) 2008-10-31 2015-06-09 The Invention Science Fund I, Llc Compositions and methods for delivery of frozen particle adhesives
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9889155B2 (en) 2014-02-20 2018-02-13 Hirofumi Yamamoto Enhancer of anti-tumor effect of anti-cancer agent
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US10214743B2 (en) 2014-03-04 2019-02-26 Hirofumi Yamamoto Colorectal cancer drug, and method for predicting prognosis of colorectal cancer patient

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010024170A (en) * 2008-07-17 2010-02-04 Hiroshi Maeda Local delivery-reinforcing agent for anti-malignant tumor agent to tumor tissue
CN102107009A (en) * 2009-12-25 2011-06-29 奇复康药物研发(苏州)有限公司 Mixed compound medicament of natural medicament components and nitric oxide donors and application thereof
JP5842367B2 (en) * 2011-04-07 2016-01-13 ニプロ株式会社 Anticancer sensitizer
US20140088034A1 (en) * 2011-05-11 2014-03-27 Stc.Unm NITRIC OXIDE/cGMP PATHWAY INHIBITION OF VLA-4 RELATED CELL ADHESION
CN103130815B (en) * 2013-02-07 2015-10-07 浙江工业大学 A kind of isosorbide mononitrate derivatives and its preparation method and application
US11186640B2 (en) * 2014-07-31 2021-11-30 The University Of Western Australia Method for the identification of immunotherapy-drug combinations using a network approach
CN107823644B (en) * 2017-11-07 2021-03-02 福州大学 Application of NO donor compound in preparation of drugs for inhibiting invasion and transfer capacity of tumor cells rich in sulfhydryl molecules
CN109498818B (en) * 2018-05-25 2021-08-31 福州大学 A kind of pH-sensitive liposome producing NO and preparation method thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0722320B1 (en) * 1993-10-08 2000-07-19 THE UNITED STATES OF AMERICA, as represented by the Secretary of the Department of Health and Human Services Use of nitric oxide-releasing compounds as medicaments for hypoxic cell radiation sensitization
EP0888458A4 (en) * 1996-02-20 2004-05-06 Sloan Kettering Institutefor C COMBINATION OF PROTEIN KINASE C INHIBITORS AND THERAPEUTIC AGENTS FOR THE TREATMENT OF CANCER
IT1282686B1 (en) * 1996-02-26 1998-03-31 Nicox Sa COMPOUNDS ABLE TO REDUCE DRUG TOXICITY
EP1251840A2 (en) 2000-01-26 2002-10-30 Cedars-Sinai Medical Center Method for using potassium channel activation for delivering a medicant to an abnormal brain region and/or a malignant tumor
US7678391B2 (en) * 2000-04-26 2010-03-16 Queen's University At Kingston Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype
TWI293878B (en) * 2000-06-30 2008-03-01 Taipei Veterans General Hospital A composition comprising a mevalonate-reducing compound for sensitizing cancer cells to cancer therapies and kits comprising said composition and an anti-cancer agent
AU2003208228A1 (en) * 2002-03-06 2003-09-16 Cellegy Pharmaceuticals, Inc Formulations and methods of using nitric oxide mimetics in cancer treatment

Cited By (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8956658B2 (en) 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US11691995B2 (en) 2005-05-27 2023-07-04 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403851B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403852B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8962029B2 (en) 2005-05-27 2015-02-24 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20100098733A1 (en) * 2008-10-16 2010-04-22 Novan, Inc. Nitric oxide releasing particles for oral care applications
US8725420B2 (en) 2008-10-31 2014-05-13 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8731841B2 (en) 2008-10-31 2014-05-20 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US20100111831A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100111938A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for biological remodeling with frozen particle compositions
US20100114545A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100113615A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for delivery of frozen particle adhesives
US20100111844A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100114547A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for biological remodeling wih frozen particle compositions
US20100114268A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US8762067B2 (en) 2008-10-31 2014-06-24 The Invention Science Fund I, Llc Methods and systems for ablation or abrasion with frozen particles and comparing tissue surface ablation or abrasion data to clinical outcome data
US20100111843A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100114546A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111830A1 (en) * 2008-10-31 2010-05-06 Searete Llc Compositions and methods for surface abrasion with frozen particles
US20100111833A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100114496A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100111835A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111836A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100112068A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for biological remodeling with frozen particle compositions
US20100111845A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111832A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US20100114592A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111855A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The States Of Delaware Frozen compositions and methods for piercing a substrate
US20100111842A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100119557A1 (en) * 2008-10-31 2010-05-13 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Frozen compositions and methods for piercing a substrate
US20100121466A1 (en) * 2008-10-31 2010-05-13 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Frozen compositions and methods for piercing a substrate
US20100152651A1 (en) * 2008-10-31 2010-06-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Frozen compositions and methods for piercing a substrate
US20100168900A1 (en) * 2008-10-31 2010-07-01 Searete Llc Systems, devices, and methods for making or administering frozen particles
US20110150765A1 (en) * 2008-10-31 2011-06-23 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Frozen compositions and methods for piercing a substrate
US8603496B2 (en) 2008-10-31 2013-12-10 The Invention Science Fund I, Llc Compositions and methods for biological remodeling with frozen particle compositions
US8603495B2 (en) 2008-10-31 2013-12-10 The Invention Science Fund I, Llc Compositions and methods for biological remodeling with frozen particle compositions
US8603494B2 (en) 2008-10-31 2013-12-10 The Invention Science Fund I, Llc Compositions and methods for administering compartmentalized frozen particles
US8613937B2 (en) 2008-10-31 2013-12-24 The Invention Science Fund I, Llc Compositions and methods for biological remodeling with frozen particle compositions
US8721583B2 (en) 2008-10-31 2014-05-13 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US20100114267A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for surface abrasion with frozen particles
US8722068B2 (en) 2008-10-31 2014-05-13 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US8731842B2 (en) 2008-10-31 2014-05-20 The Invention Science Fund I, Llc Compositions and methods for biological remodeling with frozen particle compositions
US20100112067A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for biological remodeling with frozen particle compositions
US8731840B2 (en) 2008-10-31 2014-05-20 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US20100114497A1 (en) * 2008-10-31 2010-05-06 Searete Llc, S Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US8788211B2 (en) 2008-10-31 2014-07-22 The Invention Science Fund I, Llc Method and system for comparing tissue ablation or abrasion data to data related to administration of a frozen particle composition
US8784385B2 (en) 2008-10-31 2014-07-22 The Invention Science Fund I, Llc Frozen piercing implements and methods for piercing a substrate
US8784384B2 (en) 2008-10-31 2014-07-22 The Invention Science Fund I, Llc Frozen compositions and array devices thereof
US8788212B2 (en) 2008-10-31 2014-07-22 The Invention Science Fund I, Llc Compositions and methods for biological remodeling with frozen particle compositions
US8793075B2 (en) 2008-10-31 2014-07-29 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US8798932B2 (en) 2008-10-31 2014-08-05 The Invention Science Fund I, Llc Frozen compositions and methods for piercing a substrate
US8798933B2 (en) 2008-10-31 2014-08-05 The Invention Science Fund I, Llc Frozen compositions and methods for piercing a substrate
US8849441B2 (en) 2008-10-31 2014-09-30 The Invention Science Fund I, Llc Systems, devices, and methods for making or administering frozen particles
US20100111841A1 (en) * 2008-10-31 2010-05-06 Searete Llc Compositions and methods for surface abrasion with frozen particles
US8858912B2 (en) 2008-10-31 2014-10-14 The Invention Science Fund I, Llc Frozen compositions and methods for piercing a substrate
US20100111850A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Delaware Compositions and methods for administering compartmentalized frozen particles
US20100111834A1 (en) * 2008-10-31 2010-05-06 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Compositions and methods for therapeutic delivery with frozen particles
US20100111857A1 (en) * 2008-10-31 2010-05-06 Boyden Edward S Compositions and methods for surface abrasion with frozen particles
US9040087B2 (en) 2008-10-31 2015-05-26 The Invention Science Fund I, Llc Frozen compositions and methods for piercing a substrate
US9050070B2 (en) 2008-10-31 2015-06-09 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US9050251B2 (en) 2008-10-31 2015-06-09 The Invention Science Fund I, Llc Compositions and methods for delivery of frozen particle adhesives
US9050317B2 (en) 2008-10-31 2015-06-09 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US9056047B2 (en) 2008-10-31 2015-06-16 The Invention Science Fund I, Llc Compositions and methods for delivery of frozen particle adhesives
US9060931B2 (en) 2008-10-31 2015-06-23 The Invention Science Fund I, Llc Compositions and methods for delivery of frozen particle adhesives
US9060926B2 (en) 2008-10-31 2015-06-23 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US9060934B2 (en) 2008-10-31 2015-06-23 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US9072799B2 (en) 2008-10-31 2015-07-07 The Invention Science Fund I, Llc Compositions and methods for surface abrasion with frozen particles
US9072688B2 (en) 2008-10-31 2015-07-07 The Invention Science Fund I, Llc Compositions and methods for therapeutic delivery with frozen particles
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9737561B2 (en) 2009-08-21 2017-08-22 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US10376538B2 (en) 2009-08-21 2019-08-13 Novan, Inc. Topical gels and methods of using the same
US11583608B2 (en) 2009-08-21 2023-02-21 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US20110086234A1 (en) * 2009-10-13 2011-04-14 Nathan Stasko Nitric oxide-releasing coatings
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9713652B2 (en) 2011-02-28 2017-07-25 The University Of North Carolina At Chapel Hill Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same
US9889155B2 (en) 2014-02-20 2018-02-13 Hirofumi Yamamoto Enhancer of anti-tumor effect of anti-cancer agent
US10214743B2 (en) 2014-03-04 2019-02-26 Hirofumi Yamamoto Colorectal cancer drug, and method for predicting prognosis of colorectal cancer patient

Also Published As

Publication number Publication date
US8410175B2 (en) 2013-04-02
EP1778215A1 (en) 2007-05-02
EP1778215B1 (en) 2009-12-09
JP2011144190A (en) 2011-07-28
ES2338022T3 (en) 2010-05-03
WO2005120493A1 (en) 2005-12-22
JP4729503B2 (en) 2011-07-20
DE602005018222D1 (en) 2010-01-21
KR20070045187A (en) 2007-05-02
WO2005120493A8 (en) 2007-03-22
CN101001623A (en) 2007-07-18
CN101001623B (en) 2010-11-17
JP2008501630A (en) 2008-01-24
US20090137683A1 (en) 2009-05-28

Similar Documents

Publication Publication Date Title
US8410175B2 (en) Anticancer effect enhancer
JP2008501630A6 (en) Anticancer drug effect enhancer
US12102613B2 (en) Compositions, methods, systems and/or kits for preventing and/or treating neoplasms
Ajani et al. A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma
Kaira et al. A phase II study of amrubicin, a synthetic 9-aminoanthracycline, in patients with previously treated lung cancer
Kelley et al. Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206
Mason et al. Biology-based combined-modality radiotherapy: workshop report
Pershing et al. Treatment with the nitric oxide synthase inhibitor L-NAME provides a survival advantage in a mouse model of Kras mutation-positive, non-small cell lung cancer
Poggi et al. Phase I study of weekly gemcitabine as a radiation sensitizer for unresectable pancreatic cancer
Celio et al. Pemetrexed in combination with oxaliplatin as a first-line therapy for advanced gastric cancer: a multi-institutional phase II study
Meyer et al. A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer
William Jr et al. Phase I trial of motexafin gadolinium in combination with docetaxel and cisplatin for the treatment of non-small cell lung cancer
Misirliogluo et al. Effect of concomitant use of pentoxifylline and alpha-tocopherol with radiotherapy on the clinical outcome of patients with stage IIIB non-small cell lung cancer: a randomized prospective clinical trial
Jeremić et al. Concurrent hyperfractionated radiation therapy and chemotherapy in locally advanced (Stage III) non-small-cell lung cancer: single institution experience with 600 patients
Kim et al. A phase II study with gemcitabine and split-dose cisplatin in patients with advanced non-small cell lung cancer
Messersmith et al. 588 A first-in-patient phase I study of the novel gamma secretase inhibitor PF-03084014 in patients with advanced solid tumor malignancies
Garces et al. Phase I North Central Cancer Treatment Group Trial-N9923 of escalating doses of twice-daily thoracic radiation therapy with amifostine and with alternating chemotherapy in limited stage small-cell lung cancer
Lochrin et al. Concurrent chemotherapy with hyperfractionated accelerated thoracic irradiation in stage III non-small cell lung cancer
CA2557857C (en) Cancer treatment with topoisomerase-ii inhibitor, a bis-dioxypiperazine and radiation
EP4093398B1 (en) Abt-751 and ionizing radiation for use in treating a brain tumor
Pergolizzi et al. Induction chemotherapy to weekly paclitaxel concurrent with curative radiotherapy in stage IV (M0) unresectable head and neck squamous cell carcinoma: a dose escalation study
Venate et al. Exploring the therapeutic synergism of Vardhamana Pippali Rasayana with a standard of care in nonsmall cell lung cancer
Wagner et al. 587 Phase 1 Dose-escalation Study of PF-04449913, an Oral Hedgehog Inhibitor in Patients with Select Solid Tumors
Patel Systemic therapy for advanced soft-tissue sarcomas
Czito et al. A phase I study of UFT/leucovorin, carboplatin, and paclitaxel in combination with external beam radiation therapy for advanced esophageal carcinoma

Legal Events

Date Code Title Description
AS Assignment

Owner name: TOHOKU UNIVERSITY, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:YASUDA, HIROYASU;YAMAYA, MUTSUO;NAKAYAMA, KATSUTOSHI;AND OTHERS;REEL/FRAME:018927/0713;SIGNING DATES FROM 20061219 TO 20070105

AS Assignment

Owner name: NIPPON KAYAKU KABUSHIKI KAISHA, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:TOHOKU UNIVERSITY;REEL/FRAME:019288/0357

Effective date: 20070413

AS Assignment

Owner name: NIPPON KAYAKU KABUSHIKI KAISHA, JAPAN

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE'S CITY NAME FROM "TOYKO" TO "TOKYO", PREVIOUSLY RECORDED ON REEL 019288 FRAME 0357;ASSIGNOR:TOHOKU UNIVERSITY;REEL/FRAME:022229/0639

Effective date: 20070413

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION