ENHANCEMENT OF CHLORAMBUCIL CYTOTOXICITY BY COMBINATION WITH FLAVONE ACETIC-ACID IN A MURINE TUMOR

Previous studies using murine tumours have shown enhanced action of ce rtain chemotherapeutic compounds when combined with agents that reduce tumour blood flow. In the majority of cases the compounds used were c ytotoxic to the induced hypoxic cells but in this study we have invest igated the relative importance of changes in tumour pH following blood flow reductions. The tale of tumour pH was investigated by using comb inations of the cytotoxic alkylating agent Chlorambucil (CHL) with the vascular occluding agent Flavone Acetic Acid (FAA). Chlorambucil is a weak acid (pKa = 3.7) and is concentrated within cells exposed to cul ture media at low pH or to the acidic microenvironment in vivo. In vit ro incubations showed that greater cytotoxicity was obtained when cell s were incubated at low pH and that the cytotoxicity was independent o f the level of oxygenation at the time of the drug incubation. Combina tion of both CHL and FAA in vivo resulted in greater reductions in cel l survival and growth delay than when either agent was given alone. Si multaneous administration of the two agents were very effective, poten tially due to two factors; firstly, that the pH of the tumour changes during ischaemia and secondly, that the reduced blood flow potentially alters the pharmacokinetic distribution of CHL resulting in 'drug-tra pping' within the tumour. Since the action of CHL is independent of th e induced hypoxia which results from blood flow reduction it is sugges ted that the increased in vivo action is due in part to the changes in tumour pH.