In vivo efficacy and pharmacokinetics of a new hypoxic cell radiosensitizer doranidazole in SUIT-2 human pancreatic cancer xenografted in mouse pancreas

A new 2-nitroimidazole radiosensitizer doranidazole is now undergoing clini cal evaluation in combination with intraoperative radiotherapy for unresect able pancreatic cancer. However, there have been no laboratory data on its effect against pancreatic cancer. This study was undertaken to clarify the efficacy and pharmacokinetics of doranidazole in a human pancreatic cancer SUIT-2 xenografted in the pancreas of nude mice. The tumor-bearing mice wer e irradiated to the upper abdomen using electron beams with or without prio r administration of doranidazole. The tumors were excised 3-6 days later an d their weight was measured. Doranidazole given alone had no antitumor effe ct, but it had radiosensitizing effects when 100, 150, or 200 mg/kg of the drug was combined with single 5 Gy irradiation. The tumor/serum ratios for doranidazole concentration were 0.3-0.4, but the concentrations in the tumo r were similar to those in the surrounding normal pancreas. At doses of 100 mg/kg or higher, concentrations of doranidazole in the pancreatic tumor ap peared to be sufficient to obtain definite radiosensitization.