CHLORAMBUCIL IN CHRONIC LYMPHOCYTIC-LEUKEMIA - MECHANISM OF ACTION

Chronic lymphocytic leukemia (CLL) is the most common leukemia in West ern countries but the clinical presentation and rate of disease progre ssion are highly variable. When treatment is required the most commonl y used therapy is the nitrogen mustard alkylating agent, chlorambucil (CLB), with or without prednisone. Although CLB has been used in the t reatment of CLL for forty years the exact mechanism of action of this agent in CLL is still unclear. Studies in proliferating model tumor sy stems have demonstrated that CLB can bind to a variety of cellular str uctures such as membranes, RNA, proteins and DNA; however, DNA crossli nking appears to be most important for antitumor activity in these sys tems. In addition, a number of different mechanisms can contribute to CLB resistance in these tumor models including increased drug metaboli sm, DNA repair and CLB detoxification resulting from elevated levels o f glutathione (GSH) and glutathione S-transferase (GST) activity. Howe ver, unlike tumor models in vitro, CLL cells are generally not prolife rating and studies in CLL cells have raised questions about the hypoth esis that DNA crosslinking is the major mechanism of antitumor action for CLB in this disease. CLB induces apoptosis in CLL cells and this a ppears to correlate with the clinical effects of this agent. Thus, alk ylation of cellular targets other than DNA, which can also induce apop tosis, may contribute to the activity of CLB. Alterations in genes suc h as p53, mdm-2, bcl-2 and bar which control entry into apoptosis may cause drug resistance. Loss of wild-type p53 by mutation or deletion o ccurs in 10 to 15% of CLL patients and appears to correlate strongly w ith poor clinical response to CLB. The induction of apoptosis by CLB i s paralleled by an increase in P53 and Mdm-2 but this increase is not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pat hways. The level of Mdm-2 mRNA in the CLL cells is not a useful predic tor of drug sensitivity. In addition, although Fax and Bcl-2 are impor tant regulators of apoptosis and the levels of these proteins are elev ated in CLL cells compared with normal B cells, the levels of Fax and Bcl-2, or the Bax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside anal ogs may produce cell death in CLL by a P53 dependent pathway other age nts, such as dexamethasone or vincristine, may act through P53-indepen dent pathways.