THE IN-SITU TUMOR RESPONSE TO COMBINATIONS OF CYCLOPHOSPHAMIDE AND TIRAPAZAMINE

The potential of tirapazamine to enhance the in situ efficacy of the a nticancer drug cyclophosphamide (CP) was evaluated in two rodent tumou rs (KHT sarcoma, 16C mammary carcinoma) and one human ovarian tumour x enograft (MLS) using end points of in vivo to in vitro cell survival o r in situ tumour growth delay. For comparison, bone marrow toxicity un der similar treatment conditions was determined using a CFU-GM stem ce ll survival assay. The results showed that a 0.27 mmol kg(-1) dose of tirapazamine alone had little anti-tumour effect. However, when given prior to a range of CP doses, tirapazamine increased the efficacy of t his chemotherapeutic agent in all three tumour models investigated. CF U-GM stem cell toxicity, assessed under similar treatment conditions, demonstrated that this dose of tirapazamine (1) led to some bone marro w toxicity on its own; and (2) increased the toxicity of CP beyond tha t seen with CP alone. The present findings demonstrate that the biored uctive agent tirapazamine can potentiate the in situ anti-tumour effic acy of the alkylating agent CP. However, in the preclinical models inv estigated, the enhanced anti-tumour effect did not translate into a th erapeutic benefit because a similar increase in bone marrow toxicity a lso resulted from this treatment combination.