Most antitumor agents exert their cytotoxic effect through the induction of apoptosis, and this process may be mediated through an elevation in p53 protein, with a subsequent increase in bax and decrease in bcl-2. p53 also increases mdm-2 expression and mdm-2 may then bind and inactivate p53. Cells from 31 patients with chronic lymphocytic leukemia (CLL) were treated in vitro with 2-chlorodeoxyadenosine (CdA), arabinosyl-2-fluoroadenine (F-ara-A), or chlorambucil (CLB) and drug sensitivity measured using the MTT assay. The protein levels of bax and bcl-2 were measured in CLL cells from 25 patients, and were found to be higher in leukemic cells than in normal B cells. The bcl-2 levels varied three-fold, the bax levels fifteen-fold, and the bax:bcl-2 ratios ranged from 0.44 to 2.91. The expression of mdm-2 mRNA was measured in CLL cells from 28 patients and was found to vary twenty-fold. However, no correlation was observed between drug sensitivity to CdA, F-ara-A, or CLB and the cellular levels of mdm-2 mRNA, or the protein levels of bax or bcl-2, or the bax:bcl-2 ratio. Treatment of CLL cells having wild type p53 with CdA, F-ara-A or CLB produced an increase in p53 protein and mdm-2 mRNA. This was not observed in cells having a p53 mutation, and these cells were highly resistant to both CLB and the nucleoside analogs. In contrast to the nucleoside analogs and CLB, dexamethasone and vincristine had no effect on mdm-2 mRNA levels. Treatment of CLL cells containing a wild type p53 gene with CdA, F-ara-A, or CLB, did not produce any consistent changes in bax or bcl-2. Thus, CdA, F-ara-A and CLB appear to act in CLL cells through a p53-dependent pathway, whereas this does not occur with dexamethasone or vincristine. The cellular levels of mdm-2, bcl-2, bax or the bax:bcl-2 ratios are not predictive indicators of clinical sensitivity in CLL, but an increase in mdm-2 levels after drug treatment is indicative of p53 function in these cells.

The Oncologist Fundamentals of Cancer MedicineThe cell cycle is a highly ordered process that results in the duplication and transmission of genetic information from one cell generation to the next. During the process DNA must be accurately replicated and identical chromosomal copies distributed to two daughter cells. The cell cycle is divided into discrete phases: G 1 (gap 1) is the interval or gap between mitosis (M phase) and DNA synthesis (S phase). During G 1 the cell is subject to stimulation by extracellular mitogens and growth factors; in response to these stimuli, the cell passes through G 1 and proceeds with DNA synthesis in S phase; G 2 (gap 2) is the interval between the completion of DNA synthesis (S) and mitosis; M phase is marked by the generation of bipolar mitotic spindles, segregation of sister chromatids and cell division. The regulation of the cell cycle must ensure that the events in each phase are complete before moving to the next. Thus checkpoints for monitoring the integrity of DNA are strategically placed in late G 1 and at the G 2 /M interface to prevent progression and propagation of mutated or damaged cells. G 0 refers to cells that are quiescent (temporarily or permanently out of cycle). The normal cell is dependent on external stimuli (mitogens or growth factors) to move it out of G 0 and through the early part of G 1 . The cell responds to these external stimuli, communicated through a cascade of intracellular phosphorylations, by upregulating expression of the cyclins which associate with the cyclin-dependent kinases (CDKs). The time periods shown in Figure 1 are generic and only indicate the relative duration of each phase.The cell cycle is propelled by a series of protein kinases; these CDKs complex with their respective cyclin and, subsequently, are phosphorylated by an activating kinase. Cyclin is the regulatory unit and CDK is its catalytic partner.Cyclins, with their bound and activated CDKs, function during distinct stages of the cell cycle. As the name suggests, the level of each cyclin independently increases or decreases within the phases of the cycle. Cyclin/CDK complexes phosphorylate specific protein substrates to move the cell through the cycle with activation of DNA synthesis (in late G 1 and S), and formation of the structural components associated with mitosis (in late G 2 and M). The periodicity of the cyclins, mediated by their synthesis and subsequent proteolytic degradation, ensure the well-delineated transitions between cell cycle stages. Because errors encoded in the genome may result in defective clones, close monitoring of the cell cycle for abnormal Figure 1. The Cell Cycle-Times are relative.

No abstract

No abstract