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WO2004062687A1 - Composition pharmaceutique pour le traitement du cancer, contenant la proteine p43 et du paclitaxel, procede de traitement mettant en oeuvre une telle composition et son utilisation - Google Patents

Composition pharmaceutique pour le traitement du cancer, contenant la proteine p43 et du paclitaxel, procede de traitement mettant en oeuvre une telle composition et son utilisation Download PDF

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Publication number
WO2004062687A1
WO2004062687A1 PCT/KR2003/000085 KR0300085W WO2004062687A1 WO 2004062687 A1 WO2004062687 A1 WO 2004062687A1 KR 0300085 W KR0300085 W KR 0300085W WO 2004062687 A1 WO2004062687 A1 WO 2004062687A1
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Prior art keywords
cancer
protein
paclitaxel
administration
pharmaceutical composition
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Sung-Hoon Kim
Tae-Hee Kang
Soo-Young Choi
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Imagene Co Ltd
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Imagene Co Ltd
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Priority to AU2003206144A priority Critical patent/AU2003206144A1/en
Priority to PCT/KR2003/000085 priority patent/WO2004062687A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • 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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol

Definitions

  • composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same and use thereof
  • the present invention relates to the pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same anduse thereof. More specifically, the present invention relates to the pharmaceutical composition, treatment method using the same, and their use in which p43 protein and paclitaxel are administered simultaneously, separately, or sequentially to obtain an increased anticancer effect.
  • anticancer agents Most common anticancer agents are doxorubicin and cisplatin, both developed during the 1970s. More recent anticancer agents include, paclitaxel, docetaxel, fiudarabine, cladribine and vinorelbine, and it has been reported that these agents are better than previously used agents in terms of their anticancer effects and application range.
  • Paclitaxel the most studied anticancer agent in recent days, contains a compound of taxane variety, which is isolated from plant stem of tctxus sp..
  • Paclitaxel is known to have treatment effect on leukemia and cancer by inhibiting spindle function during cell division.
  • paclitaxel is known to have cure rate of at least 30% on a patient with ovarian cancer, of at least 50% on a patient with breast cancer, and of at least 20% on a patient with lung cancer (refer to E. K. Rowinsky et al., J Natl. Cancer Inst., 82: 1247-1259, 1990).
  • the above-described anticancer agents have a drawback of losing their anticancer effects when the agents are administered repeatedly during a long period of time or when cancer recurs, and thus cancer cells develop a resistance to the anticancer agents.
  • most of the anticancer agents exert their anticancer effect by inhibiting the synthesis of nucleic acids in a cell, or by directly binding thereto and therefore damaging the functions of the nucleic acids. In doing so, the anticancer agents not only damage the cancer cells selectively but also hurt normal cells, especially tissue cells with active cell differentiation. Therefore, there is a risk of using such anticancer agents with side effects such as deterioration in bone marrow function, damage on gastrointestinal mucosa, and loss of hair, etc.
  • International patent publication No. 0152882 discloses a method of treating cancer by administering temozolomide and interferon alpha in combination to a cancer patient.
  • International patent publication No. 0234244 discloses a pharmaceutical composition for the treatment of cancer which comprises camptothecin and stilbene derivatives.
  • US patent No. 6,262,054 discloses a method of treating cancer by administering in combination publicly known anticancer agents edatrexate and taxane. Meanwhile, the present inventors described a new use of p43 protein as an anticancer and anti-angiogenic agent in International patent publication No.
  • the inventors of the present invention found that combined administration of said p43 protein and paclitaxel has much greater anticancer effect compared to a single administration of p43 protein or paclitaxel.
  • the present invention is accomplished, and therefore the new pharmaceutical composition comprising p43 protein and paclitaxel with an increased anticancer activity and cancer treatment method using the same are provided.
  • the object of the present invention is to provide a pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel, which can be used for cancer treatment.
  • Figure 1 shows a change in survival ratio of nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel.
  • Figure 2 shows a body weight change in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01).
  • Figure 3 shows a change in the absolute tumor size in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01).
  • Figure 4 shows a change in the relative tumor size in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel(*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01).
  • Figure 5 shows a change in the tumor weight in the nude mouse grafted with human lung cancer cell line NCI-H460, after the single or combined administration of p43 protein and paclitaxel (A: negative control, B: p43 protein 25 mg/kg administered, C: p43 protein 50mg/kg administered, D: p43 protein 25mg/kg + taxol 5mg/kg administered, E: p43 protein 50mg/kg + taxol 5mg/kg administered).
  • Figure 6 shows a change in survival ratio of nude mouse grafted with human stomach cancer cell line NUGC-3, after with the single or combined administration of p43 protein and paclitaxel.
  • Figure 7 shows a body weight change in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01).
  • Figure 8 shows a change in the absolute tumor size in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel (*: significant difference for the values obtained from negative control group p ⁇ 0.05, **: significant difference for the values obtained from negative control group p ⁇ 0.01, a: five test animals from negative control group were dead on the 14 th day of the administration).
  • Figure 9 shows a change in the relative tumor size in the nude mouse grafted with human stomach cancer cell line NUGC-3, after the single or combined administration of p43 protein and paclitaxel.
  • the present invention provides a pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel, which can be used for the cancer treatment.
  • the present invention provides a method of treating cancer which includes administering to a patient the pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel.
  • the present invention provides a use of p43 protein and paclitaxel which can be used for the preparation of pharmaceutical composition which is administered to treat cancer.
  • the term "effective amount” as used herein means an amount of a compound that can be useful to treat cancer in mammalians.
  • the pharmaceutical composition comprising p43 protein and paclitaxel has a synergy effect on cancer treatment by having said agents administered in combination.
  • administered in combination means that a compound or component is administered together to a subject animal.
  • Administering each component or compound together means that, in order to obtain desired treatment effect, each component can be administered simultaneously, or sequentially at separate time in any order.
  • the present pharmaceutical composition for the treatment of cancer is characterized in that it comprises effective amount of p43 protein and paclitaxel.
  • p43 protein comprised in the pharmaceutical composition of the present invention has been disclosed in International patent publication No. 0195927 and Korean patent application publication No. 2001-112108, each previously filed by the present inventors. Said two documents are incorporated by reference herein.
  • p43 protein comprised in the pharmaceutical composition of the present invention refers to either natural or recombinant p43 protein, or the protein with the substantially equivalent biological activity.
  • the protein with the substantially equivalent biological activity includes functional equivalents and functional derivatives of natural/recombinant p43 protein.
  • “Functional equivalent” mentioned above represents the mutant with modified amino acid sequence in which a whole or a part of natural type p43 protein is substituted, or in which a part of the amino acid sequences is deleted or added, and substantially equivalent biological activity to the natural type p43 protein.
  • “Functional derivative” represents the modified p43 protein with increased or decreased physical/chemical protein property and substantially equivalent biological activity to the natural p43 protein.
  • p43 protein of the present invention can be obtained from mammalian, preferably from human. Most preferably, it refers to the protein with the publicly known sequence as disclosed before (International patent publication No. 0195927 and Korean patent application publication No. 2001-112108).
  • p43 protein used in the present invention can be produced from the above-mentioned known sequence using genetic engineering techniques (see, Park et al., J. Biol. Chem. 274: 166673-166676, 1999).
  • said p43 protein can be prepared according to the genetic engineering techniques described in International patent publication No. 0195927 and Korean patent application publication No. 2001-112108.
  • Paclitaxel comprised in the pharmaceutical composition of the present invention is well known in the art as an anticancer agent.
  • Paclitaxel comprised in the pharmaceutical composition of the present invention includes the extract from natural sources and chemically synthesized compounds according to US patent No. 5,440,056, and derivatives thereof. Chemical formula of paclitaxel is known (Kingston et al., Studies in Organic Chemistry, 26:219-235, 1986).
  • Paclitaxel can be prepared by known chemical synthesis method, extraction method, and culture method using a cell line producing paclitaxel, etc.
  • Paclitaxel is commercially available as the drug formulation.
  • the drug formulation containing paclitaxel mention can be made to TAXOL ⁇ which is distributed by Bristol-Myers Squibb of the United States.
  • GENEXOL which is commercially available from Samyang Genenx Korea, was used.
  • p43 protein and paclitaxel can be formulated into a form of a single composition, or a separate composition.
  • each component can be administered simultaneously, separately, or sequentially. For instance, when each component of the present pharmaceutical composition is in a single composition, all the components can be administered simultaneously. On the other hand, if the components are not in a single composition, one component can be administered before, or, after, and/or together with the administration of other components.
  • the administration order for the pharmaceutical composition of the present invention i.e., whether and at what point, simultaneous, separate or sequential administration take place, may be decided by a doctor or an expert in this field. The administration order varies greatly depending on many factors to be considered.
  • p43 protein is administered first and the other component, i.e., paclitaxel, is administered after the lapse of time. More preferably, p43 protein is administered everyday from the beginning day of the administration while paclitaxel is initially administered at the beginning day and continues to be administered later on every 2 or 3 days. For example, p43 protein is administered once everyday and paclitaxel is administered five times; at the beginning day, and 2 days, 5 days, 8 days and 11 days after the administration has began.
  • the pharmaceutical composition of the present invention can be administered either systemically or locally in the administration order as described before.
  • oral or parenteral administration can be considered.
  • Example of parenteral administration includes; intravenous, subcutaneous, intraperitoneal, lateral, rectal, dermal, nasal, tracheal or bronchial administration and inhalation into lung .
  • a preferred route of administration is parenteral, more preferably intraperitoneal or dermal.
  • the pharmaceutical composition of the present invention which is administered according to the route of administration described above, it can be formulated into an appropriate form by further comprising a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes an inert diluent, a filling agent, water, or various kinds of organic solvents.
  • the pharmaceutical composition of the present invention can comprise additional components such as flavoring agent, binder and excipient, etc.
  • the pharmaceutical composition of the present invention can comprise a carrier for oral administration, for example, lactose, starch, cellulose derivative, magnesium stearate, and stearic acid, etc.
  • active compounds can be mixed with excipients and prepared into different forms such as tablet, lateral tablet, troche, capsule, elixir, suspension, syrup and wafer, etc.
  • the pharmaceutical composition of the present invention can comprise a carrier for parenteral administration, such as water, suitable oil, saline, aqueous glucose and glycol, etc.
  • Additional carrier for the parenteral administration may include a stabilizer and a preservative.
  • Suitable stabilizer includes an antioxidant such as sodium bisulphite, sodium sulphite or ascorbic acid.
  • Suitable preservative includes benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • the pharmaceutical composition of the present invention can be formulated into the parenteral administration composition, for example, an injection formulation.
  • the injection formulation can be prepared according to the techniques known in the art, using an appropriate dispersant, humectant and emulsifier.
  • each component can be solubilized in saline or buffer solution and can be formulated into the injection formulation.
  • paclitaxel comprised in the pharmaceutical composition of the present invention can be prepared in an oily phase microemulsion in which lipid containing olive oil or sunflower oil and PEG-linked lipid are mixed with paclitaxel, as described in US patent No. 5,478,860.
  • paclitaxel can be encapsulated in liposomes.
  • it can be formulated with a solubilizer such as anhydrous ethanol and polyethoxylated castor oil, or prepared in formulation forms for oral administration or injection, as described in US patent No. 5,424,073.
  • p43 protein comprised in the pharmaceutical composition of the present invention can be formulated into the general protein formulation.
  • liquid type formulation For example, after p43 protein is freeze-dried and solubilized in the buffer solution, a liquid type formulation can be obtained.
  • liquid type formulation further comprising above-described stabilizer can be prepared.
  • formulation type, administration route and administration method there is no limit for formulation type, administration route and administration method.
  • Inhibitory effect of the pharmaceutical composition of the present invention on tumor growth was observed when p43 protein is administered once everyday in a dose of 25 ⁇ 50mg/kg/day and paclitaxel is administered at the beginning day of the administration and 2 days, 5 days, 8 days, and 11 days later on in a dose of 5mg/kg, that is considered to be a minimum amount for inhibiting cancer cell growth. Therefore, p43 protein can be administered once or several times everyday in a dose of about lOmg/kg to about 50mg/kg, and paclitaxel can be administered once or several times at the beginning day of the administration and later once or several times every two or three days from the beginning day of the administration, in a dose of 1 mg/kg to lOmg/kg.
  • said p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel can be initially administered at once at the beginning day of the administration and every two or three days later on in once-a-day manner, in a dose of 5mg/kg.
  • final dose and dosing frequency can be adjusted within the allowed range that is clinically determined in view of characteristics of drug formulation, administration method and route , patient's condition, age, body weight, sex, nature of symptom, and severeness of sickness, etc.
  • the pharmaceutical composition of the present invention is very useful for the treatment of abnormal cell growth, i.e., cancer.
  • Example of cancer includes solid cancer such as lung cancer, stomach cancer, large intestinal cancer, liver cancer, bone cancer, spleen cancer, skin cancer, cephalic cancer, cervical cancer, cutaneous or intraocular melanoma, uterine sacoma , ovarian cancer, rectal cancer, cancer of anal region , colon cancer, breast cancer, Fallopian tube carcinoma, endometrium carcinoma, uterine cervical carcinoma, vagina carcinoma, vulval carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary track cancer, penis cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer, ureter cancer, kidney cell carcinoma, kidney bone carcinoma, CNS tumor, primary CNS lymphoma, bone marrow tumor, brain stem nerve glioma, and pituitary adrenoma, and combination thereof in which more than one
  • xenograft model was employed.
  • xenograft model is commonly used for the development of new anticancer agent. It is usually carried out using a nude mouse.
  • a nude mouse free of specific pathogen is grafted with human lung cancer cell line or human stomach cancer cell line, respectively. After administering p43 protein and paclitaxel either alone or in combination, survival ratio, body weight and cancer size of the treated mouse was measured and anticancer activity for each case was determined.
  • the present invention provides the method of treating cancer including administration of pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel to a patient in need of such treatment.
  • the present invention provides the method of treating cancer including administration of the pharmaceutical composition comprising the effective amount of p43 protein and paclitaxel to a patient, in which the two components are formulated into either a single or a separate composition.
  • the present invention provides the method of treating cancer including administration of the pharmaceutical composition comprising p43 protein and paclitaxel to a patient simultaneously, separately, or sequentially.
  • the present invention provides the method of treating cancer including administration of p43 protein everyday from the beginning day of the administration while administering paclitaxel initially on the beginning day and keeping its administration every 2 or 3 days from the beginning day.
  • the present invention provides the method of treating cancer including administration of p43 protein once or several times everyday in a dose of about lOmg/kg to about 50mg/kg and paclitaxel once or several times on the beginning day of the administration in a dose of 1 mg/kg to lOmg/kg and later once or several times every two or three days from the beginning day of the administration.
  • said p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel in a dose of 5mg/kg can be initially administered once on the beginning day of the administration and later on every two or three days in once-a-day manner.
  • the present invention provides the method of treating cancer which including administration of the pharmaceutical composition to a patient orally or parenterally.
  • Example of the oral or the parenteral administration is the same as described above.
  • the present invention also provides the method of treating cancer including administration of the pharmaceutical composition comprising effective amount of p43 protein and paclitaxel to a patient, and pharmaceutically acceptable carrier as an additional component.
  • the pharmaceutically acceptable carrier is the same as described above.
  • a 'patient' described above means a person diagnosed with the abnormal cell growth i.e., cancer. Cancer varieties are the same as those described in the above. Especially in the present invention, the term 'patient' refers to the patient diagnosed with a lung or stomach cancer.
  • the present invention also provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition used for cancer treatment in which the two components are administered in combination.
  • the present invention provides a use of p43 protein and Paclitaxel for preparing the pharmaceutical composition for cancer treatment in which said two components are formulated into either a single or a separate composition.
  • the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the two components are administered simultaneously, separately, or sequentially.
  • the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment, in which p43 protein is administered everyday from the beginning day of the administration while paclitaxel is administered initially on the beginning day and is later being kept administered every 2 or 3 days.
  • this invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment, in which p43 protein is administered once or several times everyday in a dose of about lOmg/kg to about 50mg/kg and paclitaxel is administered once or several times on the beginning day of the administration in a dose of 1 mg/kg to lOmg/kg and later once or several times every two or three days. More preferably, the p43 protein can be administered once everyday in a dose of about 25mg/kg/day to 50mg/kg/day and paclitaxel in a dose of 5 mg/kg can be initially administered once on the beginning day of the administration and later every two or three days in once-a-day manner.
  • the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the pharmaceutical composition is administered orally or parenterally.
  • Example of the oral or parenteral administration is the same as described above.
  • the present invention provides a use of p43 protein and paclitaxel for preparing the pharmaceutical composition for cancer treatment in which the pharmaceutical composition comprises the effective amount of p43 protein and paclitaxel, and further comprises pharmaceutically acceptable carrier.
  • Cancer varieties are the same as those described in the above. Especially in the present invention, it can be a lung or stomach cancer.
  • Example 1 Anticancer activity in the lung cancer xenograft mouse model by single or combined administration of p43 protein and paclitaxel
  • a nude mouse with BALB/C origin and specific pathogen free (SPF) was used as a test animal for the present invention (5 weeks old, Daehan Biolink Inc). After obtaining said animals, their appearance was visually examined. Animals were deemed for seven days in the animal room where tests will be carried out. General things were checked and only the healthy animals were chosen for the test. Said animals were kept in the animal keeping room where under condition had been maintained as temperature of 23+ 3 ° C, relative humidity of 50+ 15%, 12 hour of lighting (from 8AM to 8PM), ventilation frequency of 10-20 times/hr and light intensity of 150 ⁇ 300Lux.
  • NCI-H460 cell line was obtained from Cancer cell line Bank of the Korean Research Institute of Bioscience and Biological and used as a human ling cancer cell line for the present invention.
  • Cancer cell lines obtained as described above were cultured in a CO 2 incubator (Forma, USA) at temperature of 37 ° C and CO 2 concentration of 5%.
  • RPMI-1640 in which FBS (Fetal bovine serum, GibcoBRL, 16000-044) was added to the final concentration of 10% and 10% peniciline-streptomycin solution (GibcoBRL, 15140-122) was also added, was used as a the culture medium.
  • cancer cells isolated from the culture medium was stored in cold temperature . On the final day of culturing, all the cells were collected and counted. Then, using PBS (phosphate buffered saline), cell concentration was adjusted to 3x 10 7 cells /ml. Adjusted cell culture solution was subcutaneously injected to fifty opted and healthy mice in the amount of 3 ml/animal at axillia region between right side shoulder and chest wall.
  • PBS phosphate buffered saline
  • Test groups were formed by measuring cancer size and body weight of the nude mouse grafted with the lung cancer cells, as described in the above step 1-2).
  • the size of cancer found in the nude mouse grafted with the cancer cells was measured and ranked.
  • the measurement of cancer was carried out by determining width, length and thickness of the cancer cells using Vernier calipers.
  • the body weight of the animal was measured at the same time. Animals were put in order with their cancer size estimated from said measurements. Among the test animals, forty animals with the cancer size similar to the mean value were selected and allocated into a separate group using a computer so that the size of cancer is evenly distributed among each group.
  • p43 protein was administered either alone or in a combination with paclitaxel. Specifically, 25mg/kg of p43 protein was administered alone (low dose p43 administration group), 50mg/kg of p43 protein was administered alone (high dose p43 administration group), 25mg/kg of p43 protein was administered in combination with 5mg/kg of paclitaxel (GENEXOL , Samyang Genex Inc.) (combined administration group of low dose p43 and paclitaxel), or 50mg/kg of p43 protein was administered in combination with 5mg/kg paclitaxel (combined administration group of high dose p43 and paclitaxel).
  • paclitaxel GENEXOL , Samyang Genex Inc.
  • PBS phosphate buffered saline
  • glycerol 20% glycerol (Sigma)
  • Administration method involves fixing a mouse with an abdominal skin fixing method and administering the test compositions to the mouse in an intraperitoneal route .
  • p43 Protein was administered once everyday for 28 days " and paclitaxel was administered total of five times, i.e., at the beginning day of the administration, and 2 days, 5 days, 8 days and 11 days later. Test groups and administered dose are summarized in the following table.
  • V.C. lx PBS (Phosphate buffered saline) solution containing 20%) of glycerol
  • the body weight of all the animals in the above step 1-3 was measured on the beginning day of the administration, and twice per week during the administration period, and once per week during the observation period after the administration had been terminated.
  • Tumor size was measured on the beginning day of the administration and every other day during the administration period. Width, length and thickness of the tumor were measured using a vernier calipers. Tumor volumes were calculated using the equation described below. In addition, change in the relative tumor size was calculated by dividing the tumor size measured every other day with the tumor size before the administration, and is described in percentage value. Tumor weight was measured with the autopsied mouse after the test has been terminated. After the mean values for the body weight, tumor size and tumor weight and standard deviation values thereof were obtained for each test group, their statistical significance was determined using the student-t test.
  • the body weight of the test animal decreased in a dose dependent manner till the 3 rd day of the administration, except for the negative control group.
  • the body weight loss ratio for the test groups compared to the negative control group is as follows; 87% loss for the low-dose p43 protein administration group, 84% loss for the high-dose p43 protein administration group, 84% loss for the combined administration group of the low-dose p43 protein and paclitaxel, and 81% loss for the combined administration group of the high-dose p43 protein and paclitaxel. After three days of the administration, normal body weight gain was observed. Still, the body weight of the animals in all of the test groups is lower than that of the negative control group.
  • the tumor growth ratio for the negative control group and the test groups at the end of the administration, i.e., on 28 th day, is as follows; 5192% for the negative control group,
  • Table 2 and Figure 5 represent the test result for tumor weight change.
  • the results demonstrate that, compared to the control group, the tumor weight decreased in a dose dependent manner for both of the test groups; i.e., p43 protein single administration group (Gl: low-dose p43 protein administration group, G2: high-dose p43 protein administration group) and the combined administration group of p43 protein and Paclitaxel (G3: low-dose p43 protein and Paclitaxel, G4: high-dose p43 protein and Paclitaxel).
  • the tumor weight decreased most dramatically for the combined administration group of p43 protein and Paclitaxel.
  • the reason for having smaller weight gain ratio for the combined administration of p43 protein and paclitaxel compared to the single administration of p43 protein is believed to be due to the fact that, since the tumor weight decreased more in the combined administration group, the overall weight gain ratio becomes smaller than that of the single administration group.
  • tumor growth can be more significantly and more quickly inhibited by the combined administration of p43 protein and Paclitaxel than by the single administration of p43 protein.
  • human stomach cell line NUGC-3 was obtained from Cancer cell line Bank of the Korean Research Institute of
  • Test groups were formed by measuring cancer size and body weight of the nude mouse grafted with the human stomach cancer cells as described in the above step 2-1). Since the tumor growth varied a lot among the test mice grafted with the human stomach cancer cells, the test groups were formed by carrying our said measurements every other day. Total of 24 mice with the tumor size of 50 ⁇ 100mm 3 were selected and allocated into a separate test group using a computer so that the size of cancer is evenly distributed among each test group. After two days, another group of 24 mice with a similar tumor size were selected from the rest of the mice and allocated into the test group using the computer. To each of said groups constituted as described above, p43 protein was administered alone or in combination with paclitaxel following the same method as described in Example 1. Constitution of test groups and dose are described in Table 3 below. An animal group administered with 5ml kg of paclitaxel was taken as a positive control.
  • V.C lx PBS(Phosphate buffered saline) solution containing 20% of glycerol
  • the survival ratio for each test groups is as follows; 25%> for the negative control group to which the excipient was administered on the final day of administration (Day 28), 63% for the low dose p43 protein administration group, 25% for the high dose p43 protein administration group, 100%) for both of the combined administration groups of the low-dose p43 protein and paclitaxel and the high-dose p43 protein and paclitaxel, and 63 % for the positive control in which Paclitaxel is administered only.
  • survival ratio of more than 50% was observed for the combined administration group of p43 protein and paclitaxel. For other test groups, most of the test animals were perished.
  • the change in the body weight of the test animals is shown in Figure 7.
  • the body weight of the test animals was temporarily decreased after two days from the administration of p43 protein and paclitaxel in a single or combination. These are the same results as those observed for the mouse grafted with the human lung cancer cell line.
  • the test animals slowly started to regain their body weight from the 5 th day of the administration, and eventually recovered fully the original weight around the 10 th day.
  • the negative control group no such gain was observed and the body weight of the test animals kept decreasing.
  • the tumor weight cannot be compared between the control group and the test group, due to the high mortality among the control group and the single administration group of p43 protein. Since the high mortality, continuing weight loss and high incidents of tumor growth over the beginning period of the test were found for the test animals of the control group grafted with the human stomach cancer cell line, it is believed that the cancer cells grafted therein cause the animal death. Moreover, with respect to the high survival ratio and the inhibition of tumor growth at the early stage of the experiment for the group administered with p43 protein and paclitaxel in combination, it is believed that they are caused by the anticancer activity of said drugs. Taken together, it is found that the combined administration of p43 protein and paclitaxel is more efficient than the single administration of p43 protein or Paclitaxel, in terms of anticancer activity against stomach cancer.
  • the pharmaceutical composition comprising p43 protein and paclitaxel and the treatment method using the same of the present invention are advantageous in that, compared to the single administration, tumor growth can be more significantly inhibited by administering the two components in combination, and therefore can provide synergistic treatment effect.
  • the pharmaceutical composition and the treatment method using the same of the present invention can minimize the use of paclitaxel, of which side effects are in concern, and therefore can reduce the undesirable effects of the anticancer agents.

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  • Pharmacology & Pharmacy (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à une composition pharmaceutique pour le traitement du cancer, contenant la protéine p43 et du paclitaxel, procédé de traitement mettant en oeuvre une telle composition et son utilisation. Plus particulièrement, la présente invention a trait à une composition pharmaceutique, qui se caractérise en ce que la protéine p43 est administrée en combinaison avec un paclitaxel simultanément, séparément ou successivement, le procédé de traitement utilisant une telle composition et son procédé d'utilisation. La composition pharmaceutique et le procédé de traitement selon la présente invention, dans lequel la protéine p43 est administrée en combinaison avec le paclitaxel, peuvent améliorer l'efficacité de traitement du cancer par l'inhibition de la croissance des cellules cancéreuses en un court laps de temps. En outre, la présente invention peut réduire la toxicité de médicament par la réduction à un minimum de paclitaxel.
PCT/KR2003/000085 2003-01-15 2003-01-15 Composition pharmaceutique pour le traitement du cancer, contenant la proteine p43 et du paclitaxel, procede de traitement mettant en oeuvre une telle composition et son utilisation Ceased WO2004062687A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003206144A AU2003206144A1 (en) 2003-01-15 2003-01-15 Pharmaceutical composition for cancer treatment containing p43 protein and paclitaxel, therapy method using the same and use thereof
PCT/KR2003/000085 WO2004062687A1 (fr) 2003-01-15 2003-01-15 Composition pharmaceutique pour le traitement du cancer, contenant la proteine p43 et du paclitaxel, procede de traitement mettant en oeuvre une telle composition et son utilisation

Applications Claiming Priority (1)

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PCT/KR2003/000085 WO2004062687A1 (fr) 2003-01-15 2003-01-15 Composition pharmaceutique pour le traitement du cancer, contenant la proteine p43 et du paclitaxel, procede de traitement mettant en oeuvre une telle composition et son utilisation

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WO2004062687A1 true WO2004062687A1 (fr) 2004-07-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064596A1 (fr) * 2006-11-29 2008-06-05 Sine Pharmaceutical Laboratories Composition pharmaceutique comprenant la protéine p43 pour le traitement de l'adénocarcinome gastrique
CN101824082A (zh) * 2009-03-06 2010-09-08 信谊药厂 N端缺失型p43蛋白及其在肿瘤治疗药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001095927A1 (fr) * 2000-06-14 2001-12-20 Imagene Co., Ltd. Agent therapeutique antitumoral p43 et structure tridimensionnelle de son domaine de cytokine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001095927A1 (fr) * 2000-06-14 2001-12-20 Imagene Co., Ltd. Agent therapeutique antitumoral p43 et structure tridimensionnelle de son domaine de cytokine

Non-Patent Citations (3)

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Title
DENARDO ET AL.: "Synergy of taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts", PROC. NAT. ACAD. SCI., vol. 94, 1997, USA, pages 4000 - 4004, XP002238438, DOI: doi:10.1073/pnas.94.8.4000 *
NIELSEN ET AL.: "Combinative therapy with the farnesyl protein transferase inhibitor SCH66336 and SCH58500 (p53 adenovirus) in preclinical cancer models", CANCER RES., vol. 59, 1999, pages 5896 - 5901 *
PARK ET AL.: "Dose-dependent biphasic activity of tRNA synthetase-associating factor, p43, in angiogenesis", J. BIOL. CHEM., vol. 277, no. 47, 2002, pages 45243 - 45248, XP002261380, DOI: doi:10.1074/jbc.M207934200 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064596A1 (fr) * 2006-11-29 2008-06-05 Sine Pharmaceutical Laboratories Composition pharmaceutique comprenant la protéine p43 pour le traitement de l'adénocarcinome gastrique
CN101824082A (zh) * 2009-03-06 2010-09-08 信谊药厂 N端缺失型p43蛋白及其在肿瘤治疗药物中的应用

Also Published As

Publication number Publication date
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