ANTIPROLIFERATIVE EFFECT OF D-ASPARTIC ACID BETA-HYDROXAMATE (DAH) ONFRIEND VIRUS-INFECTED ERYTHROPOIETIC PROGENITOR CELLS

D-aspartic beta-hydroxamate (DAH), an aspartic acid analog, exerts ant itumoral activity on murine leukemia L5178Y, both in vitro and in vivo . In this study, we show that DAH is also active in vivo against Frien d virus (FV-P)-induced erythroleukemia, and we report the effects of D AH in vivo and in vitro on FV-P target cells, i.e. the mature erythroi d colony-forming cells (CFUE). DAH treatment (2 g/kg/day) given for 95 days as a single daily i.p. injection to DBA/2 mice either 3 or 12 da ys following inoculation with a high dose (10(3) plaque-forming units) of FV-P resulted in a marked increase in the mean survival time of tr eated animals (212 and 191%, respectively). Since FV-P elicits spleen enlargement and polycythemia, we examined the effects of DAH on spleen size, spleen-nucleated cell number, and hematocrit, in normal and FV- P infected mice, at different times in the course of continuous DAH tr eatments. DAH treatment initiated 3 days after viral infection inhibit s the virus-induced splenomegaly, with at day 26 p.i. 1.15 x 10(8) and 12.6 x 10(8) nucleated cells per spleen observed in DAH-treated mice and untreated mice respectively, whereas only 1.03 x 10(8) nucleated c ells were observed in uninfected mice. Furthermore, DAH prevents virus -induced polycythemia: on day 26, an hematocrit of 39% was measured in DAH-treated mice as compared to 60% in untreated mice. DAH treatment initiated 12 days after viral infection reduces splenomegaly, the numb er of nucleated spleen cells and the hematocrit of infected mice. DAH treatment initiated 3 days after viral infection prevents the tremendo us increase of CFU-E in the spleen of infected mice: on day 11, the sp leen of infected mice contained 4.6 x 10(6) CFU-E, while the spleen of treated mice only contained 26 x 10(3) CFU-E, and on day 26 the splee n CFU-E numbers were 45.4 x 10(6) and 1.5 x 10(6) in untreated and tre ated infected mice, respectively. In control uninfected mice, DAH trea tment induced a transient decrease in spleen CFU-E followed by a rebou nd phenomenon. In vitro, preincubation with DAH inhibits colony format ion by FV-P infected CFU-E, at doses starting at 3 mM, as compared to uninfected CFU-E. These data show that DAH inhibits the expression of the retroviral infection, and appears to preferentially inhibit the pr oliferation of infected target cells (CFU-E) in vivo.