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.