Enhancement of antitumor effects by the combination chemoradiotherapy with S-1, oxaliplatin on a 5-FU resistant human colon cancer xenografts

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Purpose: S-1 is a novel 5-fluorouracil (5-FU) 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 phosphorylation of 5-FU in the gastrointestinal tract to reduce the adverse effects. oxaliplatin (trans-l-diaminocyclohexane- oxalatoplatimum; 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 resistant tumors. Materials and Methods: 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 80–100 mm³, treatments were begun: treated with a vehicle (control), treated with a single dose of 5 Gy local tumor irradiation, 8 mg/kg of S-1 or 5 mg/kg 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. Results: 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. A weight decrease of the mouse was seen in the oxaliplatin and S-1 therapy groups (include combination therapy) . It seems that this weight decrease is closely related to the toxicity of S-1 and the toxicity of oxaliplatin. Western analysis showed that PCNA was decreased when combined with S-1, Pxaliplatin and radiaiton. Conclusion: In this experiment we found that S-1 and oxaliplatin chemoradiotherapy was very effective to human colorectal cancer which S-1, oxaliplatin and radiation doesn‘t work. This finding suggests that the colorectal cancer patient, whose treatment (S-1 chemothe rapy, radiation therapy) was not effective, can be treated by the S-1, oxaliplatin chemo raditoherapy.But there are some toxicity using S-1, oxaliplatin so we should investigate the mechanisms of this toxicity and find how to reduce these. Current experiments explore cellular and molecular mechanisms underlying the interaction between S-1, oxaliplatin and Radiation.