Hypoxic cell cytotoxin tirapazamine induces acute changes in tumor energy metabolism and pH: a 31P magnetic resonance spectroscopy study.
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.
Aboagye
E O
EO
Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Dillehay
L E
LE
Bhujwalla
Z M
ZM
Lee
D J
DJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009711:Nucleotides; D010710:Phosphates; D014227:Triazines; D000077704:Tirapazamine