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.