Colorectal cancer is a major public health problem throughout the world and the tumor frequently shows mutations in repetitive DNA sequences resulting in microsatellite instability (MSI).  MSI is caused by genetic and epigenetic changes in the DNA mismatch repair (MMR) genes.  Cancers with MSI such as colorectal, endometrial, lung and several melanomas present a genetically-resistant 'mutator' phenotype with DNA mismatch repair (MMR) gene deficiencies, resulting in such tumors being refractory to several anticancer agents.  Novel noncrosslinking DNA minor groove binders from the pyrrolo-benzodiazepine dimers (PBDs) class have shown cell cycle arrest and cytotoxicity in genetically-resistant cancer cells that have deficiencies in DNA MMR as well as other apoptosis and DNA repair genes such as p53 or REV3.  These novel PBDs are also active in colorectal cancer cells with Kras mutations.  Novel PBDs activate the ATM/ATR effector kinase pathway causing cell cycle arrest and apoptosis through both, p53-dependent and p53-independent mechanisms, and are highly synergistic with other anticancer agents.

Novel strategies for the treatment of genetically-resistant colorectal cancer

240th National Meeting (2010)

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