Yoshiyuki Kagawa

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.

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.

Combined oral administration of etoposide and arabinofuranosylcytosine-5'-stearylphosphate enhances the antitumor effect against P388 ascites tumors.

We investigated the antitumor effect of oral administration of etoposide and arabinofuranosylcytosine-5′-stearylphosphate (C18PCA) against P388 ascites tumors in B6D2F1 mice. Etoposide (25 mg/kg) and C18PCA (5 mg/kg) were given orally on days 1–5 after tumor inoculation. The median life span of the mice treated with etoposide or C18PCA alone was 19.5 and 18 days, respectively. The combination of both drugs significantly extended the median life span to 33 days. To clarify this enhancement of the increase in median life span, we examined intracellular deoxyribonucleoside triphosphate (dNTP) pools, cell-cycle distribution, DNA fragmentation, and the time course of the plasma drug concentration. Etoposide had no effect on intracellular dNTP pools in this experimental system, whereas treatment of cells with C18PCA or with the combination of both drugs resulted in a significant increase in dTTP pools to values ranging from 1.8-to 2.0-fold higher than the control levels. There was a significant increase in cells in the S+G2/M phase when cells had been treated with both etoposide and C18PCA. Agarose-gel electrophoresis of the extracted DNA revealed that C18PCA enhanced the fragmentation of DNA, with a length of about 180 bp being induced by etoposide. The plasma peak levels of etoposide (100 nM) and ara-C (50 nM) were observed at 20 and 30 min after the simultaneous administration of both drugs, respectively. The plasma etoposide level gradually decreased to 10% of the peak level at 240 min after administration. On the other hand, the plasma concentration of ara-C was maintained at above 20 nM at 240 min. These observations suggest that C18PCA and etoposide act on P388 murine leukemic cells by accumulating cells in the S+G2/M phase. Even if the plasma concentration of ara-C is low, the repair of DNA damage by etoposide may be hindered in the presence of ara-C following an increase in DNA fragmentation.