Effect of acyclovir and interferon on human hematopoietic progenitor cells

Abstract

Continuous in vitro exposure of human bone marrow cells to acyclovir (-200 ,uM) or human leukocyte interferon (-250 U/ml) caused 50% inhibition of granulocyte colony-forming cell differentiation. Colonies expressed in the presence of either agent were reduced both in size and number. Erythroid progenitors were more resistant than granulocyte progenitors to the antiproliferative effects of acyclovir. Progenitor cells of patients recovering from cytotoxic chemotherapy were no more sensitive to the effects of acyclovir or interferon than were cells obtained from patients before chemotherapy.Acyclovir (ACV) [9-(2-hydroxyethoxymethyl)guanine] is being evaluated as topical or systemic therapy in local and disseminated herpesvirus infection. ACV inhibits herpes simplex virus types I and II and varicella-zoster virus at concentrations that have little effect on the division of mammalian fibroblasts (1,4,6,19,24) or lymphocytes (25). In mice, rabbits, and guinea pigs infected with herpes simplex virus types I and II ACV is both effective and nontoxic (7,12,20,24). The favorable therapeutic effect of ACV is explained by its efficient phosphorylation to an active form by cells which contain virusspecified kinases (6, 8) and the high affinity of herpesvirus-specified DNA polymerase for this active ACV triphosphate (6). Although ACV is highly selective in comparison with other antimetabolites, we previously found that human fibroblasts and mitogen-and antigen-stimulated human lymphocytes can be inhibited by higher levels (100 to 200 ,uM) of ACV (14). McGuffin et al. (15) recently reported -20% inhibition of human granulocyte colony-forming unit (CFU-C) differentiation at ACV concentrations of 100 puM. Because higher doses of ACV may be required to treat more resistant herpesviruses in patients myelosuppressed by chemotherapy, we have measured the effect of higher doses of ACV on human CFU-Cs. The myelosuppression caused by ACV was compared with that of human leukocyte interferon which is known to be myelosuppressive in man. To determine whether the kinetic state of the marrow altered the susceptibility of myeloid precursors we studied samples obtained before and after chemotherapy. We also determined possible effects of ACV on the immature erythroid progenitor, the erythroid burst-forming unit (BFU-E), and its progeny, the erythroid colony-forming unit (CFU-E).MATERIALS AND METHODS Patient samples. Bone marrow cells were obtained from seven patients (five with glioblastoma, one with melanoma, one with oat-cell carcinoma) before treatment with intensive chemotherapy and autologous bone marrow infusion. Marrow cells were also obtained from three patients with oat-cell carcinoma after combination chemotherapy, from one patient with acute lymphocytic leukemia in remission, and from two normal donors. Peripheral blood cells enriched for granulocyte progenitors during the period of leukocyte recovery after chemotherapy (23) were obtained from two patients with oat-cell carcinoma. Peripheral blood cells were also obtained from...

Effect of several antiviral agents on human lymphocyte functions and marrow progenitor cell proliferation

“…Thus, uninfected cells escape toxicity of the activated ACV and BVdU at concentrations far in excess of those demonstrating antiviral activity. The effects of ACV on CFU-c in our study are similar to those described in previous reports (18,20). We observed inhibition of ConA and PHA stimulation by ACV at concentrations somewhat lower than those described in earlier reports (17,27), which is probably attributable to variability of responsiveness between different donors (17) or to technical differences in these assays.…”

Effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine on proliferation of human fibroblasts, peripheral blood mononuclear cells, and granulocyte-monocyte progenitor cells in vitro

“…In contrast, these investigators reported that the ID50 of BVdU for CFU-C was 120 FtM (40 ,ug/ml) compared with 197 ,ug/ml determined by our assay. Such variability between in vitro assays for antiviral toxicity has been observed previously (12,13) (19) demonstrated no consistent suppression of antigen-or mitogen-induced lymphocyte blastogenesis by acyclovir (ACV) below concentrations of 50 ,ug/ml (11.5 F.M). Levin et al (9) demonstrated suppression of blastogenesis only at ACV concentrations of 100 ,uM (23 ,ug/ml).…”

Effect of in vitro Acyclovir Treatment on Selected Functions of Blood-Derived Macrophages

“…A wide range of ACV con centrations had no effect on the viability of Mp and increased rather than reduced the surviving cell numbers and their protein con tent. Previous reports [6,7,18] indicated that ver)' high concentrations of ACV may inhibit cell growth and DNA synthesis of normal cells. In contrast, cells which were transfected with ultraviolet-irradiated HSV and ex pressed a thymidine-kinase-positive pheno type, were significantly more sensitive to inhi bition by ACV [18].…”

“…In uninfected cells, the uptake of ACV is poor, little phosphorylation takes place and the af finity of the phosphorylated drug for cellular a-DNA polymerase is low. However, some studies [6,7] indicate that higher concentra tions may inhibit cell division and synthesis of cellular DNA. Studies on the in vitro devel opment of hematopoietic progenitor cells and on the immune response of in vitro-stimulated peripheral blood mononuclear cells also indi cate that high, but not therapeutic, concentra tions of ACV may influence these functions [4][5][6][7].…”