title: Intracellular pharmacodynamics of ara-C and flowcytometric analysis of cell cycle progression in leukemia chemotherapy.
abstract: To establish the most effective and reasonable mode of combining and administrering ara-C with other antileukemic agents in chemotherapy for acute leukemia, the action mechanisms of ara-C was investigated in terms of intracellular pharmacodynamics and the biochemical action mechanism of ara-C was investigated in leukemic cell. Rensonable methods of administering the agent was considered as follows. 1. A low level of ara-C in the incubation medium induced a higher concentration of ara-CTP in leukemic cells. Therefore, maintenance of even a low plasma ara-C level after ara-C therapy could enhance the antileukemic effect of the agent. 2. Ara-C activation was increased in the presence of 6MP by suppressing elevation of deaminase activity in the cell suspection medium. Therefore, administration of 6MP prior to ara-C therapy could enhance the antileukemic effect of the agent. 3. Ten micrograms/ml of ara-C, corresponding to intermediate dose ara-C therapy, induced rapid endonuclease activation, DNA ladder fragmentation and subsequent apoptosis in large numbers of leukemic cells, suggesting that intermediate dose ara-C therapy is effective in reducing residual leukemic cells after therapy. 4. Blood transfusion for patients with high grade anemia prior to bebenoyl ara-C therapy prolonged higher and longer plasma drug maintenance. 5. Flowcytometry of cell cycle progression of L1210 cells treated by ara-C and daunorubicin revealed that a combination of ara-C first and daunorubicin second was superior to the reverse sequential combination. These improvements in the mode of administering ara-C could provide better results following chemotherapy for leukemia.
authors.affiliation: First Dept Med, Fukui Medical School, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: R
authors.initials: R
authors.lastname: Takauji
authors.forename: K
authors.initials: K
authors.lastname: Kamiya
authors.forename: Y
authors.initials: Y
authors.lastname: Kawai
authors.forename: H
authors.initials: H
authors.lastname: Iwasaki
authors.forename: K
authors.initials: K
authors.lastname: Tohyama
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.forename: T
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D001711:Biotransformation; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000493:pharmacokinetics* / Q000633:toxicity; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003630:Daunorubicin / Q000633:toxicity; D005434:Flow Cytometry / Q000379:methods; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism / Q000473:pathology*; D015122:Mercaptopurine / Q000633:toxicity; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015122:Mercaptopurine; D003630:Daunorubicin