Identification of non-cross-resistant platinum compounds with novel cytotoxicity profiles using the NCI anticancer...

The widespread clinical use of platinum compounds in cancer chemotherapy has prompted a search for new platinum agents. To search for platinum agents with novel profiles of activity, we used clustered image maps, the COMPARE algorithm, and other numerical methods to analyze platinum compounds submitted to the National Cancer Institute's anticancer drug screen and tested against the screen's 60 diverse human cancer cell lines (the NCI-60). A total of 107 platinum compounds for which the data were adequate could be clustered into 12 groups, 11 of which were characterized by distinctive activity profiles against the cell lines. Each group (except the mixed one) was then found to have a characteristic chemical structure as well. Four of the groups were subjected to further analysis. Mean graph representations of the averaged activity profiles of the different groups served to highlight their similarities and differences. To identify compounds that might retain activity in the setting of resistance to clinically used platinum compounds, we determined the activity levels of 38 of the compounds (representative of the different activity-structure groups) against cisplatin and oxaliplatin-resistant ovarian cancer cell lines. Many of the compounds retained activity against the resistant cells, providing evidence that they differ from cisplatin and oxaliplatin, not only in their selective activity against the various NCI-60 cell types, but are also in their susceptibility to mechanisms of resistance. Since platinum compounds have generally been classified as alkylating agents, we also compared their patterns of activity with those of representative alkylating agents, with NCI-60 growth rates, and with the profiles of 1582 molecular markers in the NCI-60 cells. Much more analysis remains to be done, but the absence of any definitive, biologically interpretable molecular predictor of activity is consistent with the idea that platinum compounds have multiple intracellular targets and that cells can have multiple mechanisms of resistance.