Karyotypic "state" as a potential determinant for anticancer drug discovery

Cancer is a genetic disease caused by genomic instability. In many cancers, this instability is manifested by chromosomal reconfigurations and karyotypic complexity. These features are particular hallmarks of the epithelial cancers that are some of the malignancies most resistant to long term control by current chemotherapeutic agents. We have asked whether we could use karyotypic complexity and instability as determinants for the screening of potential anticancer compounds. Using a panel of well characterized cancer cell lines, we have been able to identify specific groups of chemical compounds that are more cytotoxic toward the relatively more karyotypically complex and unstable panel members. Thus, we delineate an approach for the identification of "lead compounds" for anticancer drug discovery complementary to those that are focused at the outset on a given gene or pathway.