We have extended our previous studies regarding the cellular aspects of DNA damage and repair, as it relates to anti-cancer chemotherapeutic agents. Recent studies support previous findings that at low levels of resistance to DNA damaging agents (i.e., <15-fold over baseline), DNA repair is the most important mechanism of cellular resistance. This is true in every system studied to date, and can be demonstrated by the study of cellular DNA or transfected plasmid DNA. Recent findings suggest that gene specific repair is a very important component of the DNA repair competency phenotype. For example, in human ovarian cancer cells which differ in overall genomic repair by a factor of 2-3 fold; the difference in gene specific repair can be as high as >8- fold. This difference in gene specific repair more closely correlates with cell survival than overall repair measurements. Further, it appears that in human ovarian cancer cells, gene specific repair of the interstrand cross links of cisplatin may be more important than gene specific repair of intrastrand adducts. We also have investigated the role(s) of other agent(s) in the modulation of DNA damage and repair. Current data show that taxol slows the repair of cisplatin-DNA damage in a fashion that suggests that this is the primary mechanism for synergism between these two agents. This slowing in repair occurs in a setting where the cellular accumulation of cisplatin is not different from control.
