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

Abstract

Inhibition of human fibroblasts, granulocyte-monocyte progenitor cells, and lymphocytes was observed at (E)-5-(2-bromovinyl)-2'-deoxyuridine concentrations ranging from 21 to 197 p.g/ml. These concentrations were 10-to 100-fold above usual serum concentrations after oral administration. (E)-5-(2-Bromovinyl)-2'-deoxyuridine compares favorably with currently used antivirals in terms of in vitro myelotoxicity and immunotoxicity.(E) -5 -(2-Bromovinyl)-2' -deoxyuridine (BVdU) is a synthetic pyrimidine deoxynucleoside which has demonstrated significant in vitro activity against herpes simplex virus type 1 and varicella-zoster virus (4,5).The drug has proven beneficial in herpesvirus infections in several animal models (4,6,7,11,16,18). In the only published human trial, oral BVdU limited the severity of herpes zoster in four patients, three of whom had underlying malignancy (3).The selective antiviral activity of BVdU is at least partially attributed to its phosphorylation by virus-induced thymidine kinase and its relatively low affinity for cellular phosphorylases. BVdU, therefore, should be relatively nontoxic for animal cells (1, 2). Minimal toxicity has been suggested by in vitro studies in which a number of mammalian cell lines were used (4,5,15), but there have been few studies of the effects of BVdU on human cell lines (20).To investigate the possible toxicity of BVdU for human cells, we studied its effect on the growth of human foreskin fibroblasts (HFF) and granulocyte-monocyte colony-forming cells (CFU-C) and its effect on the proliferation of stimulated peripheral blood mononuclear cells (PBM) (Fig. 1)

Selection of L Cell Sublines Resistant to (E)-5-(2-Bromovinyl)-2′-Deoxyuridine

“…As an inhibitor of virus replication, we decided to employ (E)-5-(2-bromovinyI)-2'-deoxyuridine (BVDU) which had been successfully utilized to develop an efficient in vitro lat ency system in human embryo lung (HEL) cells [3], In agreement with the recent obser vation of Bubley et al [4], both the TK and T K + (HSV-1) L cell sublines (LTK and LTK+) were found to be highly susceptible to the toxic effects of BVDU at concentrations 100-1,000 times lower than those tolerated by other cell systems [5,6], This prompted us to select BVDU-resistant cell lines from both LTK and LTK+ cells. These cell lines would answer the questions of the mode of action of BVDU in the naturally susceptible cell lines and of the effects of BVDU on L cells carry ing the HSV-TK gene.…”

Oral BVDU treatment of varicella and zoster in children with cancer

“…killer (K) cell or natural killer (NK) cell activities or proliferative responses to mitogens or specific antigens, unless it is present at high or very high concentrations (40-200 pg/ml) [34,35], that is 20000-100000-fold higher than its minimum inhibitory concentration for VZV [26].…”