|Budget Amount *help
¥1,600,000 (Direct Cost : ¥1,600,000)
Fiscal Year 2001 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 2000 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1999 : ¥500,000 (Direct Cost : ¥500,000)
1. Pharmacokinetic study of ara-CTP, an intracellular active metabolite of ara-C.
ara-CTP was measured in leukemic cells by the newly established sensitive method in 25 leukemic patients receiving ara-C or log-acting ara-C, BHAC at low or conventional doses. The ara-CTP concentrations differed by the administration methods, doses, and patients, and were not predicted from the plasma ara-C concentrations. As the maintenance of the plasma ara-C was important for the retention of ara-CTP in the cell, continuous infusion of ara-C and BHAC produced ara-CTP efficiently. In BHAC therapy, patients with complete remission achieved greater ara-CTP amounts than those without remission, suggesting that ara-CTP would 6e a crucial parameter for the therapeutic efficacy of BHAC. Myelosuppression was correlated to the plasma ara-C level, suggesting that normal hematopoietic stem cells have similar sensitivity to ara-C among individuals.
2. Detection of ara-C incorporated into DNA.
The detection method fo
r ara-C incorporated into DNA was established. DNA was separated from acid insoluble fraction of leukemic cells after treatment with ara-C. The DNA was digested enzymatically to nucleosides that included ara-C. ara-C was isolated by high performance liquid chromatography, followed by liophilization. The recovery of each step was over 90 %. Radioimmunoassay will be applied to the isolated sample using anti-ara-C serum to confirm its ara-C concentration.
3. Cytotpxic effects evaluated by a new computer-controlled in vitro pharmacokinetic simulation system.
Cytotoxicity was compared between a pharmacokinetically simulated condition and a conventional culture system condition. The survival rates of the cell line K562 incubated with the simulated ara-C infusions for 2, 4, 8, and 16 h demonstrated that the cytotoxicity of ara-C was time-dependent. In contrast, under a conventional culture system, no time-dependent inhibition was observed. Similarly, the simulations of the infusion of daunorubicin for 0.5, 2, 4, and 8 h revealed that the cytotoxic effect of daunorubicin was concentration-dependent Less