Abstract
A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)–fluorouracil (FU)–folinic acid (FA) combination and by CPT11–FU–FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU–FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC50) of the double association without that drug divided by the IC50of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU–FA. http://www.bjcancer.com © 2001 Cancer Research Campaign
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References
Advanced Colorectal Cancer Meta-analysis Project (1992) Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 10: 896–903
Baisch H (1975) Analysis of PCP-data to determine the fraction of cells in the various phases of cell cycle. Rad Environ Biophys 12: 31–39
Carmichael J, De Graff WG, Gazdar AF, Minna JD and Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47: 936–940
Chou T and Talalay P (1984) Quantitative analysis of dose-effects relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27–55
Cunningham D, Pyrhönen S, James RD, Lunt CJA, Hickish TF, Heikkila R, Johannesen TB, Starkhammer H, Topham CA, Award L, Jacques C and Herait P (1998) Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352: 1413–1418
De Gramont A, Vignoud J and Tournigand C (1997) Oxaliplatin with high-dose leucovorin and 5 fluorouracil 48 hour continuous infusion in pretreated metastastic colorectal cancer. Eur J Cancer 33: 214–219
De Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, le Bail N, Louret C, Hendler D, de Brand F, Wilson C, Morran F and Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938–2947
Dauillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandi KP, Ireson T, Carmichael J, Alakl M, Gruia G, Awad L and Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355: 1041–1047
Fischel JL, Etienne MC, Formento P and Milano G (1998) Search for the optimal schedule for the oxaliplatin/5 fluorouracil association modulated or not by folinic acid: preclinical data. Clin Cancer Res 4: 2529–2535
Gamelin E, Boisdnon-Cell M, Allain P, Tureau A, Brienza S, Krikrian A, Cvitkovic E and Larra F (1997) Pharmacokinetic interference between oxaliplatin (LOHP) and fluorouracil (5-FU) delayed 5-FU metabolism + inhibition by LOHP. Proc Am Soc Clin Oncol 38: 223
Goldwasser F, Shimizu T, Jackman J, Hoki Y, O’Connor PM, Kohn KW and Pommier Y (1996) Correlations between S and G2 arrest and the cytotoxicity of camptothecin in human colon carcinoma cells. Cancer Res 56: 4430–4437
Guichard S, Cussac D, Hennebelle I, Bugat R and Camal P (1997) Sequence-dependent activity of the irinotecan-5Fu combination in human colon-cancer model HT-2g in vitro and in vitro. Int J Cancer 73: 729–734
Houghton JA, Schmidt C and Houghton PJ (1982) The effect of derivatives of folic acid on the fluorodeoxyuridylate-thymidylate synthase covalent complex in human colon xenografts. Eur J Cancer Clin Oncol 18: 347–351
Kones R (1990) Folic acid. An update with new recommended daily allowances. South Med J 83: 1454–1458
Kressner U, Inganas M, Byding S, Blikstad I, Pahlman L, Glimelius B and Lindmark G (1999) Prognostic value of p53 genetic changes in colorectal cancer. J Clin Oncol 17: 593–599
Lokiec F and Wasserman E (1997) Pharmacokinetics of the irinotecan/oxaliplatin combination: preliminary data of an ongoing phase I trial. Proc Am Assoc Cancer Res 38: 76
Milano G and Etienne MC (1994) Potential importance of dihydropyrimidine dehydrogenase (DPD) in cancer chemotherapy. Pharmacogenetics 4: 301–306
O’Reilly S and Rowinsky ER (1996) The clinical status of irinotecan (CPT 11), a novel water-soluble camptothecin analogue. Critic Rev Oncol Hematol 24: 47–70
Pavillard V, Formento P, Rostagno P, Formento JL, Fischel JL, Francoual M, Etienne MC and Milano G (1998) Combination of irinotecan (CPT 11) and 5-fluorouracil with an analysis of cellular determinants of drug activity. Biochem Pharmacol 56: 1315–1322
Ratain MJ (1999) Drug combinations: dangerous liaisons or great expectations? Annals Oncol 10: 375–376
Raymond E, Buquet-Fagot C, Djelloul S, Mester J, Cvitkovic E, Allain P, Louvet C and Gespach C (1997) Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG 337 in human colon, breast and ovarian cancers. Anticancer Drugs 8: 876–885
Raymond E, Chaney SG, Taamma A and Cvitkovic E (1998) Oxaliplatin: a review of preclinical and clinical studies. Annals Oncol 9: 1053–1071
Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Award L, Herait P and Jacques C (1998) Randomized trial of irinotecan versus fluorouracil by continuous infusion after fluororacil failure in patients with metastatic colorectal cancer. Lancet 352: 1407–1412
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrembacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL and Miller LL (2000) Irinotecan plus fluorouracil and leucovorin in metastatic colorectal cancer. Irinotecan study group. N Engl J Med 343: 905–914
Scanlon KJ, Newman EM, Lu Y and Priest DG (1986) Biochemical basis of cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci USA 83: 8923–8925
Scheithauer W, Kornek GV, Raderer M, Valencak J, Weinlander G, Hejna M Haider K, Kwasny and W Depisch D (1999) Combined irinotecan and oxaliplatin plus granulocyte colong-stimulating factor in patients with advanced fluororpyrimdine/leucovorinpretreated colorectal cancer. J Clin Oncol 17: 902–906
Shirasaka T, Shimamoto Y, Ohshimo H, Saito H and Fukushima M (1993) Metabolic basis of the synergistic antitumor activities of 5-fluorouracil and cisplatin in rodent models in vivo. Cancer Chemother Pharmacol 32: 167–172
Valencak J, Raderer M, Kornek GV, Henja MLH and Scheithauer W (1998) Irinotecanrelated cholinergic syndrome induced by coadministration of oxaliplatin. J Natl Cancer Inst 90: 160
Vindelov LL, Christensen ID and Nissen NI (1983) A detergent trypsin method for the preparation of nuclei for flow cytometry DNA analysis. Cytometry 3: 323–327
Wasserman E, Cuvier C, Lokiec F, Goldwasser F, Kalla S, Mery-Mignard D, Ouldkaci M, Besmaine A, Dupont-André G, Mahjovbi M, Marty M, Misset JL and Critkorie E (1999) Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics. J Clin Oncol 17: 1751–1759
Zeghari – Squalli N, Raymond E, Cvitkovic E and Goldwasser F (1999) Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN – 38 and diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res 5: 1189–1196
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Fischel, JL., Rostagno, P., Formento, P. et al. Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines. Br J Cancer 84, 579–585 (2001). https://doi.org/10.1054/bjoc.2000.1600
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DOI: https://doi.org/10.1054/bjoc.2000.1600
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