The in situ tumour response to combinations of cyclophosphamide and tirapazamine.

The potential of tirapazamine to enhance the in situ efficacy of the anti-cancer drug cyclophosphamide (CP) was evaluated in two rodent tumours (KHT sarcoma, 16C mammary carcinoma) and one human ovarian tumour xenograft (MLS) using end points of in vivo to in vitro cell survival or in situ tumour growth delay. For comparison, bone marrow toxicity under similar treatment conditions was determined using a CFU-GM stem cell 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 this chemotherapeutic agent in all three tumour models investigated. CFU-GM stem cell toxicity, assessed under similar treatment conditions, demonstrated that this dose of tirapazamine (1) led to some bone marrow toxicity on its own; and (2) increased the toxicity of CP beyond that seen with CP alone. The present findings demonstrate that the bioreductive agent tirapazamine can potentiate the in situ anti-tumour efficacy of the alkylating agent CP. However, in the preclinical models investigated, the enhanced anti-tumour effect did not translate into a therapeutic benefit because a similar increase in bone marrow toxicity also resulted from this treatment combination.