Enhancement of antitumor effects in vivo by the combination therapy with S-1 and Oxaliplatin in combination with radiation on a 5-FU resistant human colon cancer xenografts.

Abstract

S-1 is a novel 5-fuorouracil derivative chemotherapeutic agent composed of tegafur (a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine that inhibits degradation of 5-FU, and oxonate that regulates the phosphorelation of 5-FU in the gastrointestinal tract to redue the adverse effects. Oxaliplatin (trans-1-diaminocyclohexane-oxalatoplatinum; L-OHP), a third-generation platinum compound, has shown promising antitumor activity in the many types of cancer. The purpose of the present study is to investigate whether combined S-1 and Oxaliplatin and radiation are effective in the treatment of 5-FU resitant tumors. The study was performed using a human colon cancer cell line, designated DLD-1/FU, which is resistant to 5-FU. The cells were implanted into the leg of nude mice. When tumor volume reached 80-100mm3, treatments were begun: treated with a vehicle (control), treated with a single dose of 5Gy local tumor irradiation, 8mg/kg of S-1 or 5mg/kg of Oxaliplatin, and combination treatments. Tumor growth was measured every 2 to 3 days, and the effects of the treatments were expressed by tumor growth delay. The results showed that the combined treatment with S-1 and Oxaliplatin plus tumor irradiation 5Gy was effective in delaying tumor growth compared to the drug only, or drug plus irradiation. Current experiments explore cellular and molecular mechanisms underlying the interaction between S-1, Oxaliplatin and radiation.