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WO2010095965A1 - Utilisation du sulindac et/ou son métabolite en tant que traitement adjuvant pour le cancer du côlon chez des humains - Google Patents

Utilisation du sulindac et/ou son métabolite en tant que traitement adjuvant pour le cancer du côlon chez des humains Download PDF

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Publication number
WO2010095965A1
WO2010095965A1 PCT/PL2010/000015 PL2010000015W WO2010095965A1 WO 2010095965 A1 WO2010095965 A1 WO 2010095965A1 PL 2010000015 W PL2010000015 W PL 2010000015W WO 2010095965 A1 WO2010095965 A1 WO 2010095965A1
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Prior art keywords
sulindac
cells
colon cancer
oxaliplatin
treatment
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Ceased
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PCT/PL2010/000015
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English (en)
Inventor
Jacek Splawinski
Sylwia Fiis
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Farma-Projekt Sp Z 00
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Farma-Projekt Sp Z 00
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    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • sulindac and/or its metabolite as adjuvant treatment for colon cancer in humans
  • the subject of the invention is the use of sulindac and/or its metabolite as adjuvant treatment for colon cancer in humans .
  • Colon cancer is one of the most common malignancies of the gastro-intestinal tract in humans. In Poland, the incidence is estimated at 11 000, which accounts for approximately 10% of all malignancies in women and men. In Poland, the mortality rate is very high, at 83%, which means that less than 20% of patients are successfully cured (Nowacki MP: Standards of diagnostic and therapeutic management in cases of colon cancer in: Standards of systemic treatment for malignant neoplasms in adults in Poland, ed by: M. Krzakowski and P. Siedlecki, in Polish) . In the USA, the survival rate is 66% compared to approximately 35% in Eastern Europe, including Tru (Parkin et al.: Global cancer statistics, 2002. CA Cancer J Clin 2005; 55:74- 108. ) .
  • Colon cancer occurs as transformation within polyps.
  • Polyps may develop in the course of familial adenomatous polyposis as well as spontaneous polyposis due to the APC gene mutation.
  • the development of colon cancer which may last over a few to a few dozen years, consists of excessive proliferation of intestinal epithelial cells (as the result of the mutation) leading to the formation of characteristic thickening, a polyp, which protrudes into the lumen. This lesion is adenomatous and with time as the cells continue to proliferate and become invasive, cancer develops.
  • Molecular basis is related to the genomic instability comprising chromosomal and microsatellite instability in addition to mutations in APC and P53 genes (Markowitz et al.: Molecular basis of colorectal cancer. New Engl J Med 2009; 361 : 2449) .
  • the tumour In advanced stages, when the tumour is no longer a local lesion, but spreads to adjacent or distant tissues, after surgical resection of the tumour, the patient is given adjuvant therapy with cytostatics. Its aim is to destroy potential mictrometastases and to reduce the likelihood of recurrence .
  • the cytostatics used are a group of natural and synthetic substances which have a toxic effect on rapidly dividing tumour cells. Cytostatic drugs act essentially by affecting the cell cycle and causing cell death or inhibiting cell development and divisions. The efficacy of treatment depends on the degree to which the population of cancer cells is destroyed. Usually, a chemotherapy regimen is multidrug and incorporates several drugs belonging to different groups of cytostatics to increase the efficacy of treatment. The drugs are selected in such a way that they have different mechanisms of action (cause the tumour cell kill in different ways) and have different adverse effects which helps to avoid intensification of the same toxicities.
  • chemotherapeutics also damage other rapidly dividing healthy cells (bone marrow, mucous membranes, hair cells) with the commonly observed adverse effects such as anaemia, nausea and vomiting, and hair loss.
  • Their disadvantage is a low therapeutic index, defined as the ratio the dose producing symptoms of toxicity to the dose producing therapeutic effects.
  • the therapeutic index (TI) is different for different drugs and is used to assess their safety. The higher the TI is, the safer is the drug.
  • Regimens incorporating drugs with high therapeutic indices are sought, but that is not always possible. Cytostatics, whose aim is to destroy living cells of the body, have a very low therapeutic index, approximately 0.25 and thus are dangerous drugs.
  • 5-fluorouracil is a pyrimidine antagonist
  • oxaliplatin is an alkylating agent
  • irinotecan is a derivative of camptothecin
  • capecitabine is a prodrug given orally, which is converted into fluorouracil in tumour tissue (it acts in the same way as 5-fluorouracil) while leucovorin (folinic acid) is used to enhance the inhibitory effect of 5- fluorouracil (5-FU) on thymidylate synthase (an enzyme involved in the synthesis of DNA) .
  • 5- fluorouracil 5- fluorouracil
  • Sulindac first aroused interest when it was found to cause regression of polyps of the colon (Waddell WR and Loughry RW: Sulindac for polyposis of the colon. J Surg Oncol 1983; 24:83-87) . Since then there have been many reports confirming that sulindac reduces the number of polyps of the colon (Ishikawa H: Chemoprevention of carcinogenesis in familial tumors. Int J Clin Oncol 2004; 9:299 - 303) but the drug has not been used in the clinic because it has adverse gastro-intestinal effects and cannot be administered in long- term treatment.
  • the drug does not prevent the development of adenomas in patients with familial adenomatous polyposis (Giardiello FM et al: Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 2002; 346:1054-1059) .
  • Sulindac - as all anti-inflammatory drugs - is an inhibitor of the enzyme cyclooxygenase (COX) .
  • COX cyclooxygenase
  • Sulindac acts mostly on COX-I with small effect on COX-2.
  • Overexpression of COX-2 has been found in polyposis of the colon.
  • Celecoxib (Celebrex), however, is a specific COX-2 inhibitor and it slows down the development of adenomas in the colon of humans .
  • celecoxib Although the findings have been confirmed and the approved therapeutic indications of celecoxib include "to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis", the drug is not used in long-term treatment because of the risk of cardio-vascular events, including myocardial infarction.
  • the fact that celecoxib prevents polyp growth suggested that it may be effective in adjuvant treatment for colon cancer in humans.
  • a phase II study did not produce positive results. It was found that celecoxib neither enhanced the effects of cytostatic drugs nor decreased their toxicity. As sulindac was not ultimately approved for use in the prevention of polyposis of the colon, there was no interest in its use as adjuvant treatment of colon cancer.
  • Sulindac is a non-steroidal anti-inflammatory drug used for the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder and acute gouty arthritis (Physician Desk Reference, 56 edition, Medical Economic Company 2002, www. PDR. net) . No indications are approved for treatment of polyposis, prevention of cancer development (although relevant studies were conducted) and adjuvant treatment for colon cancer.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • sulindac non-steroidal anti-inflammatory drugs
  • piroxicam non-steroidal anti-inflammatory drugs
  • fermenting dietary fibres such as inulin found in chicory or oligofructose or their combination, had a synergistic anti- tumour effect in humans and in other vertebrates.
  • sulindac in combination with ursodeoxycholic acid (a bile acid) for prevention of the recurrence of colon adenoma is known from the patent specification No Mx 9700190.
  • NSAIDs including sulindac and/or its metabolites
  • oxidants such as hydrogen peroxide or arsenic (III) oxide
  • the patent specification No PL 3532267 disclosed the effect of NSAIDs, including sulindac with an EFGR kinase inhibitor for the treatment and inhibition of growth of colon polyps and the treatment of colorectal cancer.
  • sulindac sulfide Concentrations of sulindac sulfide used in studies on cell lines (up to 200 ⁇ M) corresponded to concentrations achieved in vivo after oral administration of sulindac. Sulindac sulfide was found to potently induce apoptosis in the cells of colon cancer, hence the conclusion that sulindac sulfide (and thus sulindac administered in vivo) may synergistically potentiate the action of classical cytostatic drugs used in the treatment of colon cancer.
  • the invention consists of the use of sulindac and/or is metabolite in combination with cytostatic drugs as adjuvant treatment for colon cancer.
  • cytostatic drugs including 5-FU and oxaliplatin
  • 5-FU 5-FU
  • oxaliplatin cytostatic drugs
  • the cytostatic drugs used belong to the group including 5-fluorouracil and its precursor capecitabine as well as oxaliplatin, leucovorin and irinotecan and/or their combinations.
  • the inclusion of 5-fluorouracil and oxaliplatin was advantageous.
  • the example describes the study method and illustrates the synergistic effect of sulindac with oxaliplatin or 5- fluorouracil .
  • Human cell lines of colon cancer SW48, HT-29 and Colo- 205 were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA) . The cells were cultured on RPMI- 1640 medium (IITD, Wroclaw, Tru) with the addition of 5% fetal bovine serum - FBS (Gibco) , 2 mM glutamax (Gibco) , 10 mM sodium pyruvate (Polpharma, Poland), and antibiotics: 100 IU/ml penicillin sodium, 100 ⁇ g/ml streptomycin and 250 ng/ml amphotericin B (Gibco) .
  • the cells were pre-incubated overnight at 37 °C and next study substances dissolved in DMSO at relevant concentrations were added to the medium and incubated for 24, 48 and 72 hours at 37 °C in 5%CC> 2 . After the incubation, the cells were viewed in an inverted light microscope and next trypsinized. To do so, the medium was transferred to a new test tube, the cells adhering to the medium were rinsed with phosphate buffer (PBS) without Ca 2+ and Mg 2+ ions (CMF) and trypsin was added (0.25% trypsin solution/0.03% EDTA), and the cells were incubaded at 37 °C until they became detached . After trypsin inactivation by addition of the culture medium, the detached cells were transferred into a test tube with the earlier collected medium and used in the assays.
  • PBS phosphate buffer
  • CMF Ca 2+ and Mg 2+ ions
  • oxaliplatin oxaliplatin, 5-FU and sulindac sulfide (Sigma, St. Luis, MI, USA) at the concentration range from 3 to 200 ⁇ M.
  • the substances were dissolved in 100% DMSO (Sigma) and then for the purposes of the experiment diluted in the culture medium to an appropriate concentration. Cells with DMSO served as controls. The final DMSO concentration in the medium did not exceed 0.2% (the value which does not affect cell survival) .
  • the MTT cytotoxicity assay was used to evaluate the percentage of live cells.
  • water-soluble tetrazole salt in live cells is reduced (oxidoreductive activity of the mitochondria) to water-insoluble dark-blue formazan.
  • the assay was performed in 96-well plates.
  • Apoptosis induction in the cells was assessed by determining the degree of binding of FITC-conjugated annexin to phosphatidylserine in the surface of the cell membrane.
  • the apoptotic index was determined by addition to 100 ⁇ l of cell suspension (IxIO 5 ) of 5 ⁇ l annexin and 5 ⁇ l propidium iodide from an Annexin V Kit (Becton Dickinson, USA) . Before the cytometric measurements, cells were incubated for 15 minutes in the dark.
  • the cell cycle was analysed in cells fixed in 80% ethanol.
  • the cells (at least IxIO 6 ) were thawed, rinsed with PBS buffer and stained with the solution of 50 ⁇ g/ml PI and 100 ⁇ g/ml TNase in 0.1% PBST (phosphate buffer, Triton) . After incubation for 30 minutes at room temperature, fluorescence was measured with a BDFACSCalibure flow cytometer BD Bioscences, San Jose, CA, USA) .
  • DNA histograms were analysed using the ModFit LT V.3.0 software (BD Biosciences, San Jose, CA, USA) .
  • the isobolograms were determined based on the IC 50 values obtained experimentally for the cytostatic drugs and for sulindac sulfide given alone or in combination.
  • the doses determined for each drug given alone were recorded on the x and y axes respectively and the line connecting the two points formed the so-called "theoretical addition line".
  • the IC 50 dose for a drug combination located close to or on the addition line identified an additive drug-drug interaction while the IC 50 values located below or above the addition line identified synergism and antagonism respectively.
  • the median effect method was used to determine the Combination Index (CI) depending on the percentage of dead cells (Fa) .
  • CI values ⁇ 1 identified a synergistic effect
  • DRI Dose Reduction Index
  • Fig. 2 The results of the study are given in Fig. 2.
  • the synergism between sulindac sulfide and oxaliplatin and 5- fluorouracil (5-FU) was demonstrated in human colon cancer cell lines (Colo-205 and SW48) .
  • y axis sulindac sulfide concentration
  • x axis oxaliplatin or 5-FU concentration
  • circles drug concentrations which cause death of 50% cells.
  • Colo-205 y axis: sulindac sulfide at ' a concentration of approximately 70 ⁇ M (oxaliplatin 0 ⁇ M) caused death of 50% cells; x axis: oxaliplatin at a concentration of approximately 33 ⁇ M (sulindac sulfide 0 ⁇ M) caused death of 50% cells.
  • additional line i.e. the concentrations of the two drugs are located which are required to produce the same effect assuming that their actions are addititive.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation du sulindac et/ou son métabolite en combinaison avec des médicaments cytostatiques en tant que traitement adjuvant pour le cancer du côlon chez les humains. L'agent cytostatique est choisi dans un groupe comprenant : le 5-fluorouracile, la capécitabine, l'oxaliplatine, la leucovorine et l'irinotécan et/ou leurs combinaisons.
PCT/PL2010/000015 2009-02-19 2010-02-18 Utilisation du sulindac et/ou son métabolite en tant que traitement adjuvant pour le cancer du côlon chez des humains Ceased WO2010095965A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP387312 2009-02-19
PL387312A PL387312A1 (pl) 2009-02-19 2009-02-19 Zastosowanie sulindaku i/lub jego metabolitu we wspomagającym leczeniu raka jelita grubego u ludzi

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WO2010095965A1 true WO2010095965A1 (fr) 2010-08-26

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2478407C1 (ru) * 2011-09-05 2013-04-10 Федеральное государственное бюджетное учреждение Министерства здравоохранения и социального развития Российской Федерации "Медицинский радиологический научный центр" (ФГБУ МРНЦ Минздравсоцразвития России) Способ комбинированного лечения местно-распространенного рака желудка
JP2019535824A (ja) * 2016-11-11 2019-12-12 セリックス バイオ プライベート リミティッド 胃腸ポリープの処置のための組成物及び方法
RU2725079C2 (ru) * 2020-02-25 2020-06-29 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр радиологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ радиологии" Минздрава России) Способ комбинированного лечения местно-распространенного рака желудка
RU2765845C1 (ru) * 2021-02-24 2022-02-03 Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) Способ комбинированного лечения местнораспространённого кардиоэзофагельного рака

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WO2001012227A1 (fr) * 1999-08-12 2001-02-22 American Cyanamid Company Composition contenant un ains et un inhibiteur de kinase du regf destinee au traitement ou a l'inhibition de polypes du colon et du cancer colorectal
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EP1428528A1 (fr) 2002-09-27 2004-06-16 Tiense Suikerraffinaderij N.V. Composées synergiques contenant des fibres alimentaires et du NSAID destinées au traitement du cancer
JP2005247807A (ja) * 2004-03-08 2005-09-15 Japan Science & Technology Agency Ｎｓａｉｄを利用した癌治療用組成物
US20080119559A1 (en) 2005-03-23 2008-05-22 Florida Atlantic University Treatment or prevention of cancer and precancerous disorders
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PL353267A1 (en) 1999-08-12 2003-11-03 American Cyanamid Company Nsaid and efgr kinase inhibitor containing composition for the treatment or inhibition of colonic polyps and colorectal cancer
WO2001035956A1 (fr) * 1999-11-15 2001-05-25 Advanced Research And Technology Institute, Inc. Utilisation des ains dans le traitement du cancer du pancreas
EP1428528A1 (fr) 2002-09-27 2004-06-16 Tiense Suikerraffinaderij N.V. Composées synergiques contenant des fibres alimentaires et du NSAID destinées au traitement du cancer
JP2005247807A (ja) * 2004-03-08 2005-09-15 Japan Science & Technology Agency Ｎｓａｉｄを利用した癌治療用組成物
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ANDRE T ET AL.: "Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer", N ENGL J MED, vol. 350, 2004, pages 2342 - 2351
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FLIS SYLWIA ET AL: "Inhibitory effects of 5-fluorouracil and oxaliplatin on human colorectal cancer cell survival are synergistically enhanced by sulindac sulfide.", ANTICANCER RESEARCH JAN 2009 LNKD- PUBMED:19331183, vol. 29, no. 1, January 2009 (2009-01-01), pages 435 - 441, XP009133151, ISSN: 0250-7005 *
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PARKIN ET AL.: "Global cancer statistics, 2002", CA CANCER J CLIN, vol. 55, 2005, pages 74 - 108
SINICROPE F A ET AL: "Sulindac plus 5-fluorouracil and levamisole: Potential adjuvant treatment for colon cancer", GASTROENTEROLOGY, vol. 108, no. 4 SUPPL., 1995, & 95TH ANNUAL MEETING OF THE AMERICAN GASTROENTEROLOGICAL ASSOCIATION AND DIGESTIVE DISEASE WEEK; SAN DIEGO, CALIFORNIA, USA; MAY 14-17, 1995, pages A539, XP009133142, ISSN: 0016-5085 *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2478407C1 (ru) * 2011-09-05 2013-04-10 Федеральное государственное бюджетное учреждение Министерства здравоохранения и социального развития Российской Федерации "Медицинский радиологический научный центр" (ФГБУ МРНЦ Минздравсоцразвития России) Способ комбинированного лечения местно-распространенного рака желудка
JP2019535824A (ja) * 2016-11-11 2019-12-12 セリックス バイオ プライベート リミティッド 胃腸ポリープの処置のための組成物及び方法
EP3538086A4 (fr) * 2016-11-11 2021-01-20 Cellix Bio Private Limited Compositions et méthodes pour le traitement de polypes gastro-intestinaux
JP7118449B2 (ja) 2016-11-11 2022-08-16 セリックス バイオ プライヴェート リミテッド 胃腸ポリープの処置のための組成物及び方法
RU2725079C2 (ru) * 2020-02-25 2020-06-29 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр радиологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ радиологии" Минздрава России) Способ комбинированного лечения местно-распространенного рака желудка
RU2765845C1 (ru) * 2021-02-24 2022-02-03 Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) Способ комбинированного лечения местнораспространённого кардиоэзофагельного рака

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