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The antitumor ribonucleoside analogues 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil (EUrd), first synthesized in 1995, have strong antitumor activity against human cancer xenografts without severe side effects. Here, we studied the antitumor mechanisms of ECyd and EUrd using mouse mammary tumor FM3A cells in vitro and the mechanism of selective cytotoxicity of ECyd using human tumor xenografts in nude rats in vivo. In FM3A cells, ECyd and EUrd were rapidly phosphorylated to ECyd 5'-triphosphate (ECTP) and EUrd 5'-triphosphate (EUTP), which strongly inhibiting RNA synthesis. Cells treated with EUrd were later found to contain both EUTP and ECTP, and ECTP accumulated as the final product. Probably the uracil moieties of EUrd derivatives were efficiently converted to cytosine moieties in the cells. EUrd and its derivatives were minor metabolites in the cells treated with ECyd, so cytidine forms probably were not converted to uridine forms at the nucleoside or nucleotide stage. The ultimate metabolite of ECyd and EUrd, ECTP, is stable in cultured cells with a half-life of at least 3 days, so ECyd and EUrd are on a "closed" metabolic pathway to ECTP. These characteristics of ECyd and EUrd may be important for their antitumor activity. ECyd had strong and selective antitumor activity against the human tumor xenografts. ECyd-phosphorylating activity (uridine/cytidine kinase) in the xenografts was higher than that in the organs of the rats. This finding may account for the strong activity with mild side effects. ECyd and EUrd may be a new kind of antitumor nucleoside analogue for clinical use. [ABSTRACT FROM AUTHOR]

Techniques for assay of in vitro lymphocyte transformation (LTF) were used with varicella-zoster virus (VZV) as the antigen to study the temporal characteristics of the VZV-specific cellular immune response in children with varicella and in normal subjects with a history of the illness. The LTF response in children with only vesicular eruptions was prompt, and individual peak activity was detected within one to two weeks after the onset of illness, followed by a gradual decrease of the activity to lower levels. Patients with a complication of meningoencephalitis showed a marked delay in the development of peak activity. No consistent difference in the development of complement-fixing antibody to VZV was observed in these patients with different clinical manifestations. The LTF response of normal subjects with remote clinical evidence of varicella was characterized by occasional high activity, a finding that suggests reinfection with VZV. These observations provide additional evidence that the specific cellular immune response is heavily involved in the pathogenesis of VZV infection. [ABSTRACT FROM PUBLISHER]

5-Trifluoromethyl-2'-deoxyuridine (CF3dUrd), an antitumor agent, is known to be short-lived in human plasma. Since its rapid elimination from the bloodstream seems to have descouraged the clinical evaluation of this drug, we explored the potential use of masked derivatives of CF3dUrd as "depot" forms of the parent compound. First, we observed that the toxicity of CF3dUrd against HeLA cells in culture was 10(4) times greater for a 24-h treatment as compared with a 1-h treatment at identical concentrations of the drug, which suggests the importance of using a prolonged treatment period. In fact, the divided dosing of CF3dUrd to L1210-bearing mice was markedly more effective than its single administration. 5'-O-Hexanoyl-, N3-p-butylbenzoyl-, 5'-O-benzyloxy-methyl-, and 3'-O-benzyl-CF3dUrd were found to be effective in maintaining the CF3dUrd concentration in plasma. The oral doses of these agents required to achieve 50% growth inhibition (ED50) in mice bearing sarcoma 180 tumors were 19, 34, 10, and 13 mg kg-1 day-1, respectively, whereas that of CF3dUrd was 63 mg kg-1 day-1. The ED50 values for these compounds were inversely correlated with the residence time of CF3dUrd in plasma. The therapeutic indices of these compounds, calculated as the dose producing a 50% inhibition of body-weight gain (IB50) divided by the ED50 value (1.89, 1.21, 1.40, and 2.15, respectively), were significantly higher than that of CF3dUrd (0.78). Consequently, these depot forms of CF3dUrd, particularly 3'-O-benzyl-CF3dUrd, are expected to be more useful than the parent compound as antitumor agents. [ABSTRACT FROM AUTHOR]

1-(3-O-Benzyl-2-deoxy-beta-D-ribofuranosyl)-5-trifluoromethyl-2,4(1H,3)- pyrimidinedione (FTC-092), a fluorinated pyrimidine derivative, appeared to be effective against various transplantable tumors in mice following oral administration, and its activity was superior to that of several other antitumor fluorinated pyrimidines. The ED50 value for FTC-092 the dose effective in achieving 50% inhibition of tumor growth against the solid form of sarcoma 180 was 13.3 mg/kg daily, whereas those for 5-trifluoromethyl-2'-deoxyuridine (CF3dUrd), the parent compound of FTC-092, for 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), the prodrug of 5-fluorouracil (FUra), and for FUra were 64.1, 122, and 28 mg/kg daily, respectively. The therapeutic indices (LD10/ED50) of FTC-092, CF3dUrd, FT, and FUra were 4.39, 1.7, 1.35, and 1.65, respectively. FTC-092 itself is not an active agent. After it has been absorbed from the gastrointestinal tract, FTC-092 undergoes a gradual biotransformation, mainly via the action of liver microsomes, releasing CF3dUrd over a long period. The levels of CF3dUrd in the stomach and small intestine of mice after the oral administration of FTC-092 were undetectable, whereas those following the administration of CF3dUrd at the same dose were high for a period of several hours. In contrast, the CF3dUrd level generated in plasma after the administration of FTC-092 remained at a high level for a longer period than did that observed on the administration of CF3dUrd. The low levels of CF3dUrd measured in stomach and small-intestine tissues and the maintenance of CF3dUrd in blood over long periods after the administration of FTC-092 are features that favor the possible clinical application of FTC-092. [ABSTRACT FROM AUTHOR]