Homologous recombination is a highly conserved determinant of the synergistic cytotoxicity between cisplatin and DNA topoisomerase I poisons.
Phase I and II clinical trails are currently investigating the antitumor activity of cisplatin and camptothecins (CPTs; DNA topoisomerase I poisons), based on the dramatic synergistic cytotoxicity of these agents in some preclinical models. However, the mechanistic basis for this synergism is poorly understood. By exploiting the evolutionary conservation of DNA repair pathways from genetically tractable organisms such as budding and fission yeasts to mammalian cells, we demonstrate that the synergism of CPT and cisplatin requires homologous recombination. In yeast and mammalian cell lines defective for RAD52 and XRCC2/3, respectively, the combination of these agents proved antagonistic, while greater than additive activity was evident in isogenic wild-type cells. Homologous recombination appears to mediate a similar interaction of X-rays and CPT, but antagonizes the synergism of cytarabine (Ara-C) with CPT. These findings suggest that homologous recombination comprises an evolutionarily conserved determinant of cellular sensitivity when CPTs are used in combination with other therapeutics.
van Waardenburg
Robert C A M
RC
Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
de Jong
Laurina A
LA
van Delft
Foke
F
van Eijndhoven
Maria A J
MA
Bohlander
Melanie
M
Bjornsti
Mary-Ann
MA
Brouwer
Jaap
J
Schellens
Jan H M
JH
D000818:Animals; D016466:CHO Cells; D002166:Camptothecin / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000633:toxicity*; D006224:Cricetinae; D003412:Cricetulus; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D051721:Rad52 DNA Repair and Recombination Protein; D011995:Recombination, Genetic / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D059004:Topoisomerase I Inhibitors; D014965:X-Rays
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497197:RAD52 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D029701:Saccharomyces cerevisiae Proteins; D059004:Topoisomerase I Inhibitors; C113187:XRCC2 protein, human; D003561:Cytarabine; D004264:DNA Topoisomerases, Type I; D002945:Cisplatin; D002166:Camptothecin