Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors.
The hypoxic cytotoxin tirapazamine (TPZ) is currently in phase III clinical trial and appears to have clinical activity. One hypothesis as to why TPZ has been used more successfully in the clinic than most other bioreductive drugs is that its unusual O(2) dependence allows killing of radioresistant cells at "intermediate" O(2) concentrations. We have determined the O(2) dependence of the metabolism of TPZ to its reduction product SR 4317, and its cytotoxicity, in stirred suspensions of HT29 colon carcinoma cells while monitoring O(2) in solution with an Oxylite trade mark probe. The O(2) dependence of the cytotoxicity of TPZ is entirely accounted for by its inhibition of the metabolism of TPZ, with a K(O(2)) value (O(2) concentration for 50% inhibition) of 1.21 +/- 0.09 (SEM) microM. We used this experimental O(2) dependence to extend a recent (Hicks et al., Cancer Res. 63, 5970-5977, 2003) pharmacokinetic/pharmacodynamic model for the cytotoxicity of TPZ in anoxic HT29 multicellular layers to model cell killing in tumors. The model indicates that the O(2) dependence of killing by TPZ complements that of radiation well during fractionated radiotherapy. It predicts that lowering K(O(2)) would decrease killing in radioresistant cells at intermediate O(2) concentrations, while higher K(O(2)) values would exacerbate metabolic consumption of TPZ and thus further impede its penetration into hypoxic regions. Raising K(O(2)) would also increase metabolic activation at physiological O(2) concentrations, thereby compromising hypoxic selectivity. We conclude that the K(O(2)) value of TPZ is indeed close to the optimum for a bioreductive drug of this class (i.e. one that kills only cells in which it is reduced).
Hicks
Kevin O
KO
Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand. k.hicks@auckland.ac.nz
Siim
Bronwyn G
BG
Pruijn
Frederik B
FB
Wilson
William R
WR
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D003110:Colonic Neoplasms / Q000378:metabolism*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000633:toxicity; D000077704:Tirapazamine; D014227:Triazines / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D010100:Oxygen