Premium
Cellular models of altered base excision repair reveal a differential contribution of reactive oxygen species‐induced 7,8‐dihydro‐8‐oxo‐2′‐deoxyguanosine to the cytotoxic mechanisms of platinum anticancer drugs cisplatin and oxaliplatin
Author(s) -
Preston Thomas J,
Henderson Jeffrey T,
McCallum Gordon P,
Wells Peter G
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1191-a
Subject(s) - oxaliplatin , cisplatin , dna damage , reactive oxygen species , pharmacology , dna repair , cytotoxicity , dna glycosylase , chemistry , cancer research , carboplatin , base excision repair , oxidative stress , deoxyguanosine , biochemistry , cancer , medicine , chemotherapy , dna , in vitro , colorectal cancer
Cisplatin anticancer therapy is limited by toxicity and onset of tumor resistance. The platinum analog oxaliplatin exhibits increased activity against cisplatin‐resistant cancers, but the mechanisms for this potency remain to be identified. Both drugs form platinum‐DNA crosslinked adducts, and cisplatin causes oxidative DNA damage such as the 7,8‐dihydro‐8‐oxo‐2′‐deoxyguanosine (8‐oxodG) lesion. To assess oxidative DNA damage as a mechanism of platinum compound cytotoxicity, 8‐oxodG‐directed base excision repair (BER) was stably enhanced in human cells by expression of human oxoguanine glycosylase 1 (α ‐ogg1 ) or E. coli formamidopyrimidine glycosylase ( fpg ). Cisplatin and oxaliplatin increased reactive oxygen species (ROS) and 8‐oxodG levels, and cytotoxicity was decreased by antioxidant therapy. Ectopic expression of α ‐ogg1 or fpg induced 8‐oxodG repair and reduced death by ROS initiators (H 2 O 2 , menadione) and both platinum drugs, although protection against cisplatin exceeded that for oxaliplatin. Oxaliplatin also caused an increased proliferative block independent of 8‐oxodG‐mediated effects. We conclude that the 8‐oxodG lesion is cytotoxic, and BER a likely determinant of risk. The greater antitumor efficacy of oxaliplatin appears unrelated to oxidative DNA damage, suggesting a novel strategy for improving the therapeutic index in cancer therapy. (Support: NIEHS grant no. ES013848, CIHR)