[Pharmacodynamics and action mechanism of antitumor agents].
In the aspects of pharmacodynamics of antitumor agents, the blood level of administered drug is elevated first and maintained for a certain period of time. Then the drug reaches to tumor cells and is incorporated into the cells. After activated, it induces damage of DNA strands, inhibition of DNA synthesis and suppression of the cell proliferation. Each agent shows different behavior in each step of pharmacodynamics. 1) Blood drug level; distribution of antitumor agent in red and white blood cells, and plasma after administration is different among drugs. Lipophilic drug such as behenoyl ara-C is well absorbed and stored in red blood cell membrane, which is re-utilized effectively for the maintenance of plasma drug levels. Drugs having strong DNA binding affinity such as anthracycline, are accumulated in white blood cells and their blood levels are correlated with the white blood cells counts. 2) Incorporation of antitumor agents into the cells; especially incorporation of nucleoside analogs are correlated with the number of nucleoside transport sites of the cell membrane. Drug incorporation is also greatly influenced by activation and inactivation of drug in the cells. 3) Activation of the drugs in the cells; the activation reactions require the corresponding enzymes and cofactors. Activation of ara-C depended on deoxy cytidine kinase activity, whereas activation of 6-mercaptopurine required hypoxanthine guanine phosphoribosyl transferase and phosphoribosyl pyrophosphate. The latter is the limiting factor of the activation reaction. In a case of rapid activation of a certain drug, such as ara-C, in a cell suspension, intracellular concentration of its active form exceeded extracellular concentration of the drug within 10 min of the incubation time. 4) Effects of nucleotide pool changes by antitumor agent on activation of the other antitumor drug; inhibitors of riboside diphosphate reductase, such as fludarabine or hydroxyurea, reduced deoxynucleoside triphosphates pools, and the reduction resulted in the decrease of feedback inhibition of deoxy cytidine kinase. Subsequently, activation of ara-C to its nucleotides was increased. 5) DNA damage by antitumor agents and its repair; a part of DNA damages induced by labile DNA binder are repaired. Inhibition of the repair would be effective for increasing antitumor effects. 6) Suppression of drug inactivation; in a case of ara-C, inactivation is nearly 100 times higher than activation. A number of procedures for suppressing the drug inactivation have been investigated to increase production of intracellular active form of the drug.(ABSTRACT TRUNCATED AT 400 WORDS)
Nakamura
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First Dept. of Internal Medicine, Fukui Medical School, Japan.
Ueda
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T
D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001803:Blood Transfusion; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D003561:Cytarabine