COMBINATION THERAPY WITH NUCLEOSIDE ANALOGS AND ALKYLATING-AGENTS

The nucleoside analog, 2'-deoxycoformycin (dCF), and the alkylating ag ents, chlorambucil (CLB) and cyclophosphamide, are effective agents in the treatment of chronic B cell leukemias and lymphomas. The cyclopho sphamide analog, 4-hydroperoxycyclophosphamide (4-HC), generates the s ame active metabolite as cyclophosphamide in cells and has been used e xtensively for bone marrow purging in vitro. We have observed that deo xyadenosine (dAdo) plus dCF (dAdo/dCF) inhibit the repair of x-irradia tion-induced and bleomycin-induced DNA damage in vitro, and that this results in either synergistic or additive cytotoxicity, respectively. In the present study we examined whether dAdo/dCF, can enhance the ant itumor activity of CLB and 4 HC in chronic lymphocytic leukemia (CLL) cells in vitro. CLL cells were treated with CLB for 6 hr and then with dAdo/dCF for 18 hr and cytotoxicity was measured by the MTT assay. Sy nergy was observed between CLB and dAdo/dCF in CLL cells from 2 patien ts, with synergy increasing as the CLB dose was raised. In contrast, s imilar treatment of human bone marrow cells resulted in little or no s ynergistic cell kill. Treatment of CLL cells from 2 patients with 4 HC for 30 min followed by dAdo/dCF for 18 hr resulted in little synergis tic cytotoxicity, although this drug combination did produce an additi ve cell kill. Thus, combination therapy with nucleoside analogs and al kylating agents may be useful for improving treatment of CLL