• Masakazu Fukushima, Kazuki Sakamoto, Hideyuki Ohshimo, Fumio Nakagawa, and Tetsuo Taguchi.
• Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi, Tokushima 771-0194, Japan. fukusima@taiho.co.jp
• Oncol. Rep. 2010 Oct 1; 24 (4): 835-42.

AbstractTo clarify the molecular interaction of irinotecan (CPT-11) and oxaliplatin (l-OHP) in combination with 5-fluorouracil (5-FU), the antitumor effects of CPT-11 and l-OHP combined with the oral 5-FU prodrug, S-1 composed by tegafur, gimeracil and potassium oteracil, were investigated on human colon cancer KM12C xenografts sensitive or resistant to 5-FU in nude mice. In parental KM12C tumor xenografts, combined treatment of CPT-11 with oral S-1 significantly augmented the antitumor activity compared with those of CPT-11 and S-1 alone. Interestingly, combined therapy of CPT-11 with S-1 was markedly effective with almost 90% of inhibition of tumor growth on 5-FU-resistant tumors (KM12C/ 5-FU), and its potency likely corresponded to that in parental tumors. In contrast, combined administration of l-OHP with S-1 did not shown an effect on KM12C/5-FU tumor xenografts. To investigate why only CPT-11 potentiated the anti-tumor activity in combination with 5-FU pro-drugs against 5-FU-resistant colon tumors, the activities or expression levels of thymidylate synthase (TS), ribonucleotide reductase (RNR) and other enzymes in 5-FU-metabolism in both tumors were measured following administration of CPT-11 and/or l-OHP. CPT-11, but not l-OHP, induced a decrease in activities and protein levels of TS and an increase in those of RNR in KM12C/5-FU tumors only, which was likely related to decreased expressions of several proteins in G1/S phase of the cells including CDK4, pRB, and E2F1 in these tumors. These findings suggest that CPT-11, but not l-OHP, would overcome the resistance to 5-FU in combination with 5-FU pro-drugs on 5-FU-resistant colon tumors.

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