Evaluation of nitrobenzimidazoles as hypoxic cell radiosensitizers.
Radiobiological and pharmacokinetic assays were performed to determine the potential of 2-nitrobenzimidazole (NBI) as a hypoxic cell radiosensitizing agent. As judged by comparing survival curve slopes of Serratia marcescens irradiated under aerated and hypoxic conditions, the NBI enhancement ratio (ER) at 2 mM concentration was 2.4 +/- 0.2, compared with an oxygen enhancement ratio of 3.3 +/- 0.3. 2,5-Dinitrobenzimidazole (DNBI) was investigated in vitro; its ER was 3.0 +/- 0.3 at 4 mM concentration. Very poor tissue penetration of DNBI precluded further testing in vivo. Acute toxic signs appeared in C3H/HeJ mice following ip injection of NBI at 100 mg/kg. These would be partly attributable to the stress caused by the high pH of the injection vehicle. The LD50 was estimated to be 125-150 mg/kg. Mammary adenocarcinoma tumors grown in the flanks of these mice exhibited maximum NBI levels at 5 min postinjection (ip). Peak tumor radiosensitization occurred in the interval between 5 and 10 min postinjection. The ER for tumor regrowth delay was 2.1 +/- 0.3 following 50 mg/kg injected into mice 5 min before irradiation. Functional evaluation up to 40 days after treatment revealed no evidence of neurological deficit.
D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D004307:Dose-Response Relationship, Radiation; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D009368:Neoplasm Transplantation; D010100:Oxygen; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D012706:Serratia marcescens / Q000187:drug effects / Q000528:radiation effects*
D001562:Benzimidazoles; D011838:Radiation-Sensitizing Agents; C038747:2-nitrobenzimidazole; C038748:2,5-dinitrobenzimidazole; D010100:Oxygen