Potentiation of the anti-tumour effect of melphalan by the vasoactive agent, hydralazine.
The vaso-active drug hydralazine causes a considerable increase in the cytotoxic effect of melphalan towards the KHT tumour in mice. The enhancement in response, measured as the concentration of melphalan required to achieve a given tumour response, is 3.0 and 2.35 when determined using the regrowth delay assay and the technique for determining surviving fraction in vitro following treatment in vivo respectively. In contrast, measurement of systemic toxicity shows that the addition of hydralazine only causes a small increase (ER = 1.15) in melphalan damage. This suggests that the drug combination may have some therapeutic benefit. The tumour specificity for the action of hydralazine is supported by the finding that binding of 3H-misonidazole is increased in tumours but not in other tissues when mice are treated with hydralazine. Increased binding of labelled misonidazole is associated with an increase in the level and duration of hypoxia, which will occur as a consequence of changes in tumour blood flow brought about by hydralazine. However, hypoxia per se is not responsible for the enhanced effect of melphalan, since the agent BW12C, which also induces substantial tumour hypoxia as a result of changing the O2 affinity of haemoglobin, has no effect on melphalan tumour cytotoxicity.
Stratford
I J
IJ
MRC Radiobiology Unit, Oxon, UK.
Adams
G E
GE
Godden
J
J
Nolan
J
J
Howells
N
N
Timpson
N
N
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006830:Hydralazine / Q000494:pharmacology*; D008297:Male; D008558:Melphalan / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors
D006830:Hydralazine; D008920:Misonidazole; D008558:Melphalan