Induction of apoptosis by 2-chloro-2 ' deoxyadenosine (2-CdA) alone and incombination with other cytotoxic drugs: Synergistic effects on normal and neoplastic lymphocytes by addition of doxorubicin and mitoxantrone

2-CdA is active as a single agent in the treatment of low-grade lymphomas. We analyzed the induction of apoptosis by 2-CdA alone (n=5) and in combinat ion with other drugs in peripheral lymphocytes from 25 patients with leukem ic low-grade lymphomas and from 25 healthy volunteers. 2-CdA was tested in 4 escalating concentrations (0.05 mu g/ml to 0.4 mu g/ml). Linear regressio ns showed a dose dependant apoptosis rate of 0.29 x mu g 2-CdA/ml + 0.11 (r (2)=0.88, p=0.006) in normal cells and 0.41 x mu g 2-CdA/ml + 0.15 (r(2)=0. 88, p=0.005) in leukemic cells. Intracellular metabolization of 2-CdA into 2-CdA-5'mono-, -di- and the active metabolite -triphosphate was analyzed by HPLC and paralleled the dose dependent increase of apoptosis. The combinat ion of 2-CdA with doxorubicin or mitoxantrone had a synergistic effect on t he induction of apoptosis (p<0.001) in both normal and neoplastic lymphocyt es, whereas 2-CdA plus etoposide or cytosine arabinoside were only additive . Due to the flat slope of the dose response of 2-CdA concentration on apop tosis we assume that higher in vivo dosages of 2-CdA in the treatment of lo w-grade lymphomas may not result in a higher clinical efficacy. The synergi stic lymphocytotoxic effect of 2-CdA combined with doxorubicin or mitoxantr one may be relevant for new treatment approaches.