Growth-inhibitory effect of 2-CdA on myeloid CFU-GM progenitors in normal human long-term bone marrow cultures and its compensation by G-CSF or IL-3.

As neutropenia is a common side effect of treatment with 2-chlorodeoxyadenosine (2-CdA), we investigated the myelosuppressive action of 2-CdA in Dexter-type human long-term bone marrow cultures (LTBMCs). LTBMCs were incubated with varying doses of 2-CdA (5 to 20 nM/L) during the first week. At 20 and 10 nM/L 2-CdA, we found a marked reduction in colony-forming unit-granulocyte/macrophage (CFU-GM) production throughout the culture period of 7 weeks (maximum reduction to 3.

Effect of deoxycytidine on 2-chloro-deoxyadenosine-mediated growth inhibition of normal human erythroid and myeloid progenitor cells.

The cytotoxic effect of chlorodeoxyadenosine (CdA) on lymphocytes and monocytes requires phosphorylation by the enzyme deoxycytidine kinase and can be antagonized by coadministration of deoxycytidine (dCyt), a competitive substrate of deoxycytidine kinase. It has also been shown for lymphocytes that coadministration of 3-aminobenzamide (3-ABA), an inhibitor of the enzyme poly-(ADP ribose) synthetase, is activated by CdA-mediated DNA strand breaks, consumes intracellular nicotinamide-dinucleotide (NAD) and can antagonize the lethal effect of CdA. Recent in vitro studies have shown that not only growth of lymphocytes and monocytes, but also colony formation by erythroid and myeloid progenitors derived from normal human bone marrow, is inhibited by CdA in a dose-dependent manner.

Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth.

Previous studies have shown that 2-chloro-2'-deoxyadenosine (CdA) is markedly toxic to normal and malignant human lymphocytes in vitro and in vivo. Recent clinical trials have shown that CdA is a very promising drug for the treatment of lymphoid malignancies. The present investigations were designed to test the effect of CdA on the in vitro clonal growth of both myeloid progenitors and T-lymphocyte colony-forming cells (CFU-TL) obtained from normal human bone marrow and peripheral blood.