The effect of hydralazine on the tumor cytotoxicity of the hypoxic cell cytotoxin RSU-1069: evidence for therapeutic gain.
The effect of the vasodilator hydralazine on both the tumor and systemic toxicity of RSU-1069 has been evaluated in C57B1 mice bearing Lewis lung tumors. The results obtained indicate that both hydralazine and RSU-1069 are cytotoxic to the Lewis lung tumor on their own. However, administration of hydralazine (5 mg/kg PO) at times up to either 3 hr before or 3 hr after RSU-1069 (0.1 mg/g IP) results in a level of cell killing greater than expected from additive effects. This potentiation by hydralazine was observed with doses of RSU-1069 from 0.01 to 0.1 mg/g. The results obtained using excision assays were confirmed using in situ growth delay as the endpoint. Growth delay (+/- s.e.m.) values for tumors to double in volume of 1.5 (+/- 1.2), 2.0 (+/- 1.3) and 6.0 (+/- 0.9) were obtained for hydralazine (5 mg/kg PO) alone, RSU-1069 (0.1 mg/g IP) alone and for hydralazine administered at the same time as RSU-1069 respectively. In contrast to the potentiating effect of hydralazine on the tumor cytotoxicity of RSU-1069, it had no significant effect on the systemic toxicity of RSU-1069 as measured by LD50/30d. No detailed studies to examine the mechanism responsible for the potentiation of tumor cytotoxicity have been performed in the present study. However, the results obtained would be consistent with previous reports that vasodilators such as hydralazine can selectively reduce tumor blood flow and thus oxygenation. Such reduced tumor oxygenation would increase the cytotoxic effects of RSU-1069 which is known to be more toxic to cells at reduced oxygen levels.
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D006830:Hydralazine / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
D011838:Radiation-Sensitizing Agents; D006830:Hydralazine; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole