Potentiation of EO9 anti-tumour activity by hydralazine

EO9[3-hydroxy-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione)prop-bet a-en-alpha-ol] has been selected for phase I evaluation in Europe. Activity has been seen previously in a highly refractory, necrotic mouse adenocarcinoma (MAC 16) but EO9 is shown here to be inactive against early tumours (MAC 15A and MAC 13) and a well vascularised, well-differentiated established adenocarcinoma (MAC 26). EO9 becomes active against MAC 26 tumours when hydralazine (10 mg/kg) is administered 1 min after EO9. Co-administration of hydralazine decreases EO9 plasma clearance and increases plasma area under the curve values (0.053 to 0.115 micrograms h/ml). These pharmacokinetic changes are accompanied by anti-tumour activity but no increase in bone marrow toxicity so this therapeutic gain may be due, at least in part, to microenvironmental changes resulting from hydralazine induced tumour vascular shutdown.