COMBINATION OF IRINOTECAN (CPT11) AND 5-FLUOROURACIL WITH AN ANALYSISOF CELLULAR DETERMINANTS OF DRUG ACTIVITY

We evaluated the combination SN38 (7-ethyl-10-hydroxycamptothecin) -5f luorouracil (5FU) +/- folinic acid (FA) on six human colon cancer cell lines expressing spontaneous sensitivity to both drugs. Tumoral param eters potentially related to drug sensitivity were investigated: topoi somerase I (topo I) cleavable complexes formed with SN38, thymidylate synthase (TS) activity, folylpolyglutamate synthetase activity and dih ydropyrimidine dehydrogenase activity. Drugs (SN38 and/or 5FU +/- FA) were applied for 72 hr, either sequentially or together. The concentra tion ratio between SN38 and 5FU was 100. Cytotoxicity (MTT [3-(4,5-dim ethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] test), DNA flow cy tometry and isobologram analysis (Chou and Talalay) were performed. Ba sed on 5FU IC,, values and isobologram analyses, the most cytotoxic sc hedule was SN38 followed by 5FU - FA, with high synergistic effects. F low cytometry indicated that SN38 induced a more or less marked S-G2 b lock in all cell lines. Sensitivity to SN38, 5FU +/- FA, or combinatio ns were not linked to the potential above-cited tumoral parameters. In terestingly, an inverse correlation was demonstrated between TS activi ty and topo I cleavable complexes (r(2) = 0.78, P = 0.019). These data emphasize the critical importance of the irinotecan-5FU schedule and strongly support this association for the treatment of potentially 5FU -sensitive tumors. BIOCHEM PHARMACOL 56;10: 1315-1322, 1998. (C) 1998 Elsevier Science Inc.