Increased sensitivity of thymidine kinase-deficient (TK-) tumor cell lines to the cell growth inhibitory effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and related compounds

Abstract

Various established antiherpetic drugs, including 1-beta-D-arabinofuranosylthymine (araT), acyclovir (ACV), 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG), 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), and structurally related analogues thereof, i.e. (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU), (E)-5-(2-bromovinyl)-2'-deoxycytidine (BVDC), (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), and the carbocyclic analogues of BVDU (C-BVDU), IVDU (C-IVDU) and BVDC (C-BVDC), were evaluated for their inhibitory effects on the growth of murine mammary carcinoma (FM3A/0), murine leukemia (L1210/0) and murine fibroblast (LM/0) cells and the thymidine kinase-deficient (TK-) sublines derived from the FM3A/0, L1210/0 and LM/0 cells. BVDU, IVDU and BVDC showed a markedly increased cytostatic activity against the TK- cell lines. To determine the biochemical mechanism of the increased cytostatic action of these compounds toward TK- cell lines, BVDU and IVDU were further evaluated for their inhibitory effects on pyrimidine nucleotide metabolism, in particular thymidylate synthetase activity, their incorporation into DNA and into trichloroacetic acid (TCA)-insoluble material, and their effects on DNA, RNA and protein synthesis in both TK+ and TK- cells. No marked differences were noted in the interaction of BVDU and IVDU with these potential targets between TK+ and TK- cell lines. Furthermore, neither FM3A/0 nor FM3A/TK- cells expressed a significant phosphorylating activity for (125I) IVDU. However, BVDU and IVDU specifically inhibited the incorporation of (1-14C) mannose and (1-14C) glucose into glycoproteins of FM3A/TK- and L1210/TK- cells. To what extent the inhibition of the incorporation of these monosaccharides into glycoproteins may contribute to the increased cytostatic effects of BVDU and IVDU on TK- cells remains to be determined.