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.