MODULATION OF CHEMOSENSITIVITY THROUGH ALTERED EXPRESSION OF CELL-CYCLE REGULATORY GENES IN CANCER

Alterations in the expression of genes affecting cell cycle progressio n occur in all human cancers. These may occur either by overexpression of genes such as cyclin D1, mutation of regulatory genes such as p16, or abrogation of checkpoints following DNA damage as in the cases of mutation or deletion of the p53 gene. Perturbation of the normal funct ions of these genes has a profound effect on cellular proliferation, d ifferentiation and apoptosis. There is increasing evidence that such a lterations may modulate the cellular response to treatment with chemot herapeutic agents. In many cases genetic alterations may induce resist ance to drug treatment as in the case of mutations of the p53 gene. Ho wever, the deregulated expression of cell cycle genes may also increas e sensitivity to treatment by directly altering the expression of the target for chemotherapeutic drugs as in the case of deletion of the re tinoblastoma gene. It is crucial to understand the interactions betwee n drug mechanisms of action and the genetic alterations in cancer to e xploit potential areas in which the alterations found in tumors may co nstitute potential vulnerability.