Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP099) Mechanism of sensitization of hypoxic cells to cisplatin by tirapazamine.

Chernikova, Sophia*,1, Peters, Katherine1, Kovacs, Mary1, Brown, J. Martin1, 1 Radiation Oncology, Stanford, CA, USA

ABSTRACT- Tirapazamine (TPZ) is an anticancer drug that under hypoxic conditions is activated into a highly damaging free radical, thus taking advantage of the hypoxic environment of solid tumors. Under hypoxic conditions the TPZ radical generates multiple types of damage to DNA including base damage, single-strand breaks, and double-strand breaks. We and others have previously shown that TPZ has a unique schedule-dependent synergy with cisplatin such that pretreatment with TPZ before cisplatin produces synergistic cell killing, while simultaneous treatment with TPZ and cisplatin leads to only additive cytotoxicity. Despite ample evidence that the TPZ potentiation of cisplatin cytotoxicity in tumors is the result of hypoxia, the nature of the interaction between cisplatin and TPZ is still unclear. However, we have shown that this interaction is absent in CHO UV41 cells deficient in the nucleotide-excision repair (NER) protein, XPF, and that TPZ pretreatment results in decreased (or delayed) repair of interstrand and intrastrand cross-links produced by cisplatin. Taking together these data suggest that the ERCC1/XPF complex, which is the only NER factor required for the repair of DNA interstrand cross-links, is involved in the TPZ potentiation of cisplatin effect. At present we are exploring the hypothesis that the potentiation of cisplatin cytotoxicity by TPZ is due to sequestering of ERCC1/XPF by TPZ-induced damage.

Key words: tirapazamine, hypoxia, cisplatin, ERCC1/XPF

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2005 RRS