Cell Cycle Checkpoints and Cancer Chemotherapy
The majority of anticancer agents in current clinical practice arrest cell cycle progression at one or more definable points (Table 1). The DNA damaging agents including, bleomycin, adriamycin, etoposide, nitrogen mustards and cisplatin, arrest cell cycle progression in G1 and/or G2 phases. These agents can also prolong S phase progression. The antimetabolites including, methotrexate, 5-fluorouracil and 6-mercaptopurine, arrest cell cycle progression at the G1/S phase border and in S phase. The microtubule inhibitors including, vincristine, vinblastine and taxol, arrest cells primarily in mitosis and more specifically in a pseudometaphase state. Arrest at these stages in the cell cycle is dependent on the integrity of a series of negative feedback control systems that have become commonly termed checkpoints (1, 2). These checkpoints could protect cells from cytotoxicity by extending the time for drug-induced perturbations to be corrected before cell division. This possibility is supported by findings from yeast genetics, which have shown that inactivating mutations in checkpoint control genes sensitized cells to DNA damaging agents, antimetabolites or antimitotic agents (1, 2). Furthermore, the findings by Pardee and colleagues, that chemical agents like pentoxifylline, can abrogate G2 checkpoint control and synergise with DNA damaging agents (3), also supports the protective role of cell cycle checkpoints. Based on such observations, we have suggested that the integrity of checkpoint control systems in cancer cells may in large part determine chemosensitivity (1). Our thinking here is that uncontrolled progression through one or more of these checkpoints in the presence of damage will predispose cells to killing. We discuss below recent observations we and other workers have made in investigating the role of the G1 and G2 cell cycle checkpoints in chemosensitivity. We focus on attempts to determine whether the G1 and G2 cell cycle checkpoints are commonly defective in cancer cells, whether such checkpoint alterations affect chemosensitivity and whether checkpoint alterations in cancer cells could provide new opportunities for drug discovery.
KeywordsCell Cycle Checkpoint Ataxia Telangiectasia Nitrogen Mustard Arrest Cell Cycle Progression Negative Feedback Control System
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