Inhibitory effects of oxaliplatin in experimental radiation treatment of colorectal carcinoma: does oxaliplatin improve 5-fluorouracil-dependent radiosensitivity?

摘要

BACKGROUND AND PURPOSE: New chemoradiotherapy regimens for rectal cancer with integration of oxaliplatin with 5-fluorouracil-based therapy are being actively investigated. However, only limited preclinical data are available on oxaliplatin as radiosensitizer in colorectal carcinoma. MATERIALS AND METHODS: A human colorectal carcinoma cell line (HT29) was exposed to ionizing radiation with or without oxaliplatin and/or 5-fluorouracil, upon which clonogenicity and cell cycle profiles were analyzed. HT29 xenografts were treated for two weeks with daily radiation and/or the oral 5-fluorouracil analog capecitabine with or without oxaliplatin once weekly, and tumor volumes were followed for up to 60 days. RESULTS: Pretreatment of HT29 cells with oxaliplatin for 2h, followed by radiation and a 48-h exposure to 5-fluorouracil, resulted in increased radiocytotoxicity, and combination index analysis indicated synergistic effects. Ionizing radiation and oxaliplatin induced cell cycle G(2)/M phase arrest in HT29 cells at distinctly different time points. Growth of HT29 xenografts was clearly inhibited by radiation. Capecitabine and oxaliplatin together significantly improved the inhibitory effect, but oxaliplatin did not add to the growth inhibitory response induced by radiation plus capecitabine. CONCLUSIONS: The combination of oxaliplatin and 5-fluorouracil sensitized colorectal carcinoma cells to ionizing radiation in vitro. In vivo, however, oxaliplatin did not convincingly improve the increased radiocytotoxicity conferred by capecitabine treatment. In the absence of conclusive clinical evidence, the integration of OXA into combined-modality treatment of rectal cancer must remain controversial.