COMPARISON OF ANTITUMOR ACTIVITIES OF 2-CHLORODEOXYADENOSINE AND 9-BETA-AVABINOSYL-2-FLUOROADENINE IN CHRONIC LYMPHOCYTIC-LEUKEMIA AND MARROW-CELLS IN-VITRO

The in vitro antitumor activities of the nucleoside analogs, 2-chlorod eoxyadenosine (CdA) and 9-beta-arabinosyl-5-fluoroadenine monophosphat e (Flu), and the alkylating agent, chlorambucil (CLB), were compared i n leukemic cells from 28 patients with chronic lymphocytic leukemia (C LL). On a molar basis, the median sensitivities of the cells to these agents were CLB > CdA > Flu. CLL cells from 90% of the patients had si milar relative orders of sensitivities to CdA and Flu, while cells fro m 10% of the patients showed differential sensitivities to these agent s. There was no relationship between the sensitivities of the cells to the nucleoside analogs and sensitivity to CLB. CdA and CLB produced s imilar toxicities to human marrow progenitor cells in vitro, while Flu was less toxic to these cells. An 18 h exposure to CdA produced signi ficantly greater cell kill of both CLL and marrow progenitor cells tha n an equivalent 2 h treatment; however, the difference in cytotoxicity was greater for the tumor cells resulting in a higher therapeutic ind ex with the 18 h treatment. The intracellular accumulation of drug var ied 5-fold for CdA, with the major metabolite being CdAMP, and 15-fold for Flu, with the major metabolite being F-ara-ATP. However, the accu mulation of CdA, Flu or their metabolites did not predict for drug sen sitivity. These studies suggest that CdA and Flu cross-resistance cann ot be assumed in all CLL patients. The therapeutic effectiveness of Cd A may be enhanced by use of a prolonged, low-dose drug regimen.