The cell cycle is regulated by a number of key proteins that appear to be frequently inactivated or aberrantly expressed in human cancer. The cyclin D and E family of proteins, together with their cyclin-dependent kinase (cdk) partners (cdk4 and -6) phosphorylate the retinoblastoma (Rb) tumor suppressor protein, which regulates G^S transition and commitment to cell-cycle transition (Figure 5.2). Cyclin/cdk activity is restrained by cdk inhibitors (CKIs) of the p16mk4a and the p21clp1 family of proteins. The appropriate interaction of the cyclin/cdk families and the CKIs regulate the cell-cycle checkpoints at the G^S and G2/M transitions, ensuring faithful chromosome replication and separation to preserve genetic stability. Failure of these checkpoints to arrest cells in response to certain stimuli is characteristic of cancer cells and is due to the frequent genetic aberration in expression and function of cell-cycle regulatory proteins in transformed cells.
The greater understanding of the cell cycle has led to the development of a number of compounds that might restore the control of cell division in cancer cells. In particular, two strategies are now being explored in the clinic. First, compounds have been developed to mimic the action of CKIs by interfering with action of the cdk molecules.61 Second, phar-macologic agents have been developed to target the proteo-some or histone deacetylases, thereby interfering with the degradation and expression of key molecules that regulate the cell-cycle checkpoint.
Flavopiridol targets the ATP-binding pocket of cdk2 and arrest cells at either the G^S or G2/M checkpoints and may inhibit other cdks including cdk1, cdk7, and cdk9. The initial Phase I trial explored a 72-hour continuous infusion of flavopiridol, but dose-limiting toxicities included secretory diarrhea and symptomatic hypotension62 (Table 5.6). In three separate phase II studies with this schedule, objective tumor responses were rare, although disease stabilization was seen in a number of patients.63-65 Previous preclinical studies had shown synergy and induction of apoptosis when flavopiridol was combined with standard cytotoxic therapies,66 and clinical activity using combination therapy has been seen in patients previously resistant to the given cytotoxic drug alone.67,68 Preclinical evidence of synergism with paclitaxel therapy followed by flavopiridol in animal models further supported clinical studies of this combination,69 and Phase I combination studies have demonstrated promising activity in lung, esophagus, and prostate cancer.70 Thus, although cdk
inhibitors alone may only have a cytostatic effect, combined therapy may prove more promising in enhancing their anticancer mode of action.
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