Kazuya Ooi

Sequence-dependent antitumor effect of VP-16 and 1-β-d-arabinofuranosylcytosine in L1210 ascites tumor

The sequence-dependence of the antitumor effect of etoposide (VP-16) and 1-beta-D-arabinofuranosylcytosine (ara-C) was investigated against the L1210 ascites tumor in BDF1 mice. Treatment with VP16 (7.5 or 15 mg/kg) and ara-C (25 or 500 mg/kg) was administered intraperitoneally on days 1, 4 and 7 after tumor inoculation. Six hour pretreatment with 15 mg/kg VP16 followed by 500 mg/kg ara-C yielded a 100% cure rate, but only a 20% cure rate was obtained with the reverse sequence. Simultaneous administration of 15 mg/kg of VP-16 and 500 mg/kg ara-C interacted synergistically, producing a 70% cure rate. In contrast with the results obtained with VP-16 and 500 mg/kg ara-C, simultaneous administration of 25 mg/kg ara-C neither antagonized nor potentiated the antitumor effect of VP-16. Twenty-five mg/kg ara-C was too low to produce any antitumor effect with VP-16 in simultaneous administration. At every dose investigated, pretreatment with VP-16 followed by ara-C was the most effective antitumor schedule in L1210 leukemia. This sequence of drug administration did not cause greater toxicity as measured by weight loss or toxic death.

ENHANCED INCORPORATION OF 1-BETA -D-ARABINOFURANOSYLCYTOSINE BY PRETREATMENT WITH ETOPOSIDE

We examined the effects of timing of administration of etoposide on cytosine arabinoside (ara-C) incorporation into DNA in L1210 ascites tumor. At 1 hr after injection of ara-C, 3-hr and 6-hr pretreatments with 15 mg/kg of etoposide increased ara-C incorporation to more than 200% as compared to that of ara-C given alone. Simultaneous administration of etoposide, however, decreased ara-C incorporation to 33% of that of ara-C alone. These results might explain the previously reported sequence dependency of the antitumor effect of etoposide and ara-C.

Effects of UFT (Mixed Compound of Tegafur and Uracil) on Cell Kinetics and Inhibition of Thymidylate Synthase in L1210 Ascites Tumor

Previous work in our laboratory showed that UFT (mixed compound of tegafur and uracil, molar ratio 1:4, respectively) caused the prolonged reduction of dTTP in L1210 leukemia cells in comparison with 5-fluorouracil (5-FU). The purpose of this study was to assess the effect of UFT on cell cycle distribution and thymidylate synthase activity of a leukemia cell line as compared with 5-FU. UFT and 5-FU were orally given to BDF1 mice bearing L1210 ascites tumor on day 3 after the tumor inoculation. Cell cycle distribution patterns at 24 hr after the drug administration showed a higher percentage of S phase in tumor cells treated with UFT than in those treated with 5-FU. Until 6 hr after the oral administration of the drugs, UFT inhibited the incorporation of [3H] deoxyuridine into DNA more long than 5-FU did. These results indicated that UFT has longer and stronger inhibitory effects on DNA replication than 5-FU in vivo under the employed experimental conditions (i.e., low and single doses of these fluorinated pyrimidines).

Effects of 5-fluorouracil and a combination of tegafur and uracil (UFT) on nucleotide metabolism in L1210 ascites tumor.

Changes in the deoxyribonucleotide pools following a single oral administration of 13 mg/kg of 5-fluorouracil (5-FU) or of 64.8 mg/kg of UFT (a mixed compound of tegafur and uracil) were investigated. We compared their pharmacodynamics and effects on nucleotide metabolism in L1210 ascites tumor on day 3 after intraperitoneal tumor inoculation. The intracellular dTTP pool decreased to half the control level 1-6 hr after the administration of 5-FU. The dTTP pools rapidly recovered after 6 hr. In contrast, UFT kept the intracellular dTTP level to 1/3 to 1/2 of the control level for 24 hr. Either drug elevated the intracellular dATP pools, but decreased dCTP pools. UFT influenced the intracellular dATP and dCTP levels longer than 5-FU. Orally administered UFT seemed to exert a longer and more potent inhibitory effect on thymidylate synthetase than equimolar 5-FU. In view of these results, we suggest that UFT could be a more potent chemotherapeutic drug than 5-FU in oral administration.