Enhancement of chemotherapy and nitroimidazole-induced chemopotentiation by the vasoactive agent hydralazine

摘要

Nitroimidazoles have been shown to be potent sensitisers of certain clinically active chemotherapeutic agents. This process of chemopotentiation has been shown to be hypoxia-mediated. The present studies evaluated whether increasing the level of hypoxia in the tumour tissue, by treatment with the vasoactive agent hydralazine, could modify the chemosensitising ability of nitroheterocyclics. Administering either misonidazole or RSU 1164 before, or hydralazine after, the chemotherapeutic agents melphalan, cyclophosphamide or the nitrosourea CCNU, increased the extent of cell kill in both the KHT sarcoma and RIF-1 tumour. However, even greater enhancements could be achieved when hydralazine was used in treatment protocols in which a nitroimidazole was combined with chemotherapy. For example, a 5.0 mg kg-1 dose of hydralazine given 30 min after melphalan, or a 2.5 mmol kg-1 dose of misonidazole administered 30 min before melphalan, increased, compared to melphalan alone, the resultant tumour cell kill by factors of approximately 1.9 and approximately 1.3, respectively. By comparison, when hydralazine was given after the melphalan plus misonidazole combination, treatment efficacy was enhanced approximately 3-fold compared to melphalan alone. Yet in contrast to the results of the tumour response studies, the inclusion of hydralazine did not increase the bone marrow toxicity associated with the chemotherapeutic agent when used alone or in conjunction with a nitroimidazole. The results, therefore, imply that the addition of hydralazine to the chemotherapy, or chemotherapy-sensitiser protocol, led to a therapeutic advantage.