Purine analogs (fludarabine and 2-chlorodeoxyadenosine) as apoptosis-inducing drugs in CML therapy.

Fludarabine (Flu) and 2-chlorodeoxyadenosine (2-CdA) are purine analogs with antineoplastic activity in lymphoproliferative malignancies. We recently showed in vitro the effective role of Flu and 2-CdA in the activation of apoptosis. We observed a dramatic induction of apoptosis in vitro by Flu (Figure 1) and 2-CdA on fresh CML cells, with or without the association of IFN-a. The mechanism behind this is at present unknown, but in vivo studies have also suggested therapeutic roles for Flu and 2-CdA in CML patients. We think that programmed cell death may be suppressed in cells carrying the bcr-abl transcript and that Flu and 2-CdA might remove this suppression effect in the neoplastic cell cycle. McGahon et al. reported that K562, a chronic myelogenous leukemia (CML) cell line expressing the BCR-ABL fusion protein, is resistant to the induction of apoptosis by a number of agents and conditions. They indicate that BCRABL acts as an anti-apoptosis gene in CML and suggest that the effect is dependent on this chimeric protein. CML cells may also resist the effects of cytotoxic agents by overexpression of apoptosis-suppressing genes such as bcl-2 or ras. These observations indicate that the myeloid expansion in CML may occur via prolongation of cell survival and that the elevated expression of BCR-ABL tyrosine kinase activity may act to suppress apoptosis. They conclude that an antisense approach to inhibit the expression of the apoptosis-suppressing gene in combination with standard chemotherapy may offer a new therapeutic strategy in conditions in which suppression of apoptosis contributes to the development of the malignancy. In CML cells such as the K562 cell line, due to