Hypoxic cell cytotoxin tirapazamine induces acute changes in tumor energy metabolism and pH: a 31P magnetic resonance spectroscopy study.

Abstract

Tirapazamine is a hypoxic cell cytotoxin in phase II/III trials. To further understand its mechanism of action in vivo, we examined the effect of tirapazamine on tumor energy metabolism and pH. RIF-1 and SCCVII tumors were grown subcutaneously in the flanks of C3H mice. Tumor energy metabolism, expressed as the ratio of inorganic phosphate to nucleotide triphosphate (Pi/NTP), and intracellular pH (pHi), were measured by 31P magnetic resonance spectroscopy (MRS). In RIF-1 and SCCVII tumors, tirapazamine increased the Pi/NTP ratio by 2.6-fold and 3-fold, respectively, within the first hour after an intraperitoneal dose of 0.3 mmol/kg. A corresponding decrease in pHi from 7.05+/-0.07 to 6.48+/-0.06, and 7.21+/-0.09 to 6.45+/-0.02 in RIF-1 and SCCVII tumors, respectively, was observed. The decrease in tumor 31P bioenergetics and pH was reversible, as exemplified by RIF-1 tumors, which showed a further increase in Pi/NTP ratio of 3.5-fold by 5-8 hr, returning to normal range at 24 hr. Corresponding pHi of RIF-1 tumors was 6.88+/-0.05 at 5-8 hr and 7.16+/-0.05 at 24 hr. We concluded that tirapazamine induces acute changes in tumor energy metabolism and pHi. These findings are relevant to the rational selection and optimal timing of coadministered therapy.