Oxaliplatin-Induced Damage of Cellular DNA

• DOI: 10.1124/mol.58.5.920
• Publication Date: 2018-01-08T20:40:21Z
• Authors: Jan M. Woynarowski; Sandrine Faivre; Maryanne C.S. Herzig; Brenda Arnett; William G. Chapman; Alex V. Trevino; Eric Raymond; Stephen G. Chaney; Alexandra Vaisman; Maria Varchenko; Paul E. Juniewicz
• Keywords: DNA adduct

Damage to cellular DNA is believed determine the antiproliferative properties of platinum (Pt) drugs. This study characterized damage by oxaliplatin, a diaminocyclohexane Pt drug with clinical antitumor activity. Compared cisplatin, oxaliplatin formed significantly fewer Pt-DNA adducts (e.g., 0.86 ± 0.04 versus 1.36 0.01 adducts/10⁶ base pairs/10 μM drug/1 h, respectively, in CEM cells, <i>P</i> &lt; .01). Oxaliplatin was found induce potentially lethal bifunctional lesions, such as interstrand cross-links (ISC) and DNA-protein (DPC) cells. As total adducts, however, produced (<i>P</i> .05) lesions than did cisplatin: 0.7 0.2 1.8 0.3 ISC 0.8 0.1 1.5 DPC/10⁶ drug, after 4-h treatment. Extended postincubation (up 12 h) not compensate lower DPC levels oxaliplatin. determinations isolated nuclei unequivocally verified that inherently less able cisplatin form these lesions. Reactivation drug-treated plasmids, observed four cell lines, suggests are repaired similar kinetics adducts. Oxaliplatin, more efficient per equal number inhibiting chain elongation (∼7-fold cells). Despite reactivity, exhibited or greater cytotoxicity several other human tumor lines (50% growth inhibition cells at 1.1/1.2 μM, respectively). The results demonstrate oxaliplatin-induced including DPC, likely contribute drug9s biological properties. However, requires does achieve inhibition.