Antiproliferative effect of D-aspartic acid beta-hydroxamate (DAH) on Friend virus-infected erythropoietic progenitor cells.
D-aspartic beta-hydroxamate (DAH), an aspartic acid analog, exerts antitumoral activity on murine leukemia L5178Y, both in vitro and in vivo. In this study, we show that DAH is also active in vivo against Friend virus (FV-P)-induced erythroleukemia, and we report the effects of DAH in vivo an in vitro on FV-P target cells, i.e. the mature erythroid colony-forming cells (CFU-E). 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 days 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 treated 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 treatments. DAH treatment initiated 3 days after viral infection inhibits 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 cells 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 number of nucleated spleen cells and the hematocrit of infected mice. DAH treatment initiated 3 days after viral infection prevents the tremendous increase of CFU-E in the spleen of infected mice: on day 11, the spleen 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 spleen CFU-E numbers were 45.4 x 10(6) and 1.5 x 10(6) in untreated and treated infected mice, respectively. In control uninfected mice, DAH treatment induced a transient decrease in spleen CFU-E followed by a rebound phenomenon. In vitro, preincubation with DAH inhibits colony formation 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 proliferation of infected target cells (CFU-E) in vivo.
Tournaire
R
R
INSERM U. 218, Centre Léon Bérard, Lyon, France.
Arnaud
S
S
Hamedi-Sangsari
F
F
Malley
S
S
Grange
J
J
Blanchet
J P
JP
Doré
J F
JF
Vila
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001216:Asparagine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003864:Depression, Chemical; D004354:Drug Screening Assays, Antitumor; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects; D005622:Friend murine leukemia virus; D004915:Leukemia, Erythroblastic, Acute / Q000150:complications / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011086:Polycythemia / Q000209:etiology / Q000517:prevention & control; D012192:Retroviridae Infections / Q000150:complications / Q000401:mortality / Q000473:pathology*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013163:Splenomegaly / Q000209:etiology / Q000517:prevention & control; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014412:Tumor Virus Infections / Q000150:complications / Q000401:mortality / Q000473:pathology*
D000970:Antineoplastic Agents; C024848:beta-aspartylhydroxamic acid; D001216:Asparagine