Cytochrome P-450 refers to a family of heme proteins present in mammalian cells as well as in plants and prokaryotes. Substrates for mammalian P-450 enzymes (P-450) comprise endogenously synthesized compounds as well as xenobiotic compounds including medicines, food additives and environmental pollutants. The total level of liver microsomal P450s does not vary considerably among humans, however, the interindividual variations in the levels of P450 isoforms (CYPs) are shown. What is more, the variability in expression of CYPs was observed between various tissues and between tumor and normal cells. Such differences indicate the opportunities for the development of prodrugs, which are nontoxic to normal cells and are activated to cytotoxic agents only within the tumor tissue. Gene directed therapy may be also included in this respect. On the other hand, P-450 are capable of deactivating of anticancer drugs, thus, inhibitors of the specific isoenzymes in tumor cells would be developed as modulators of antitumor activity.

In view of all above, investigations on P-450 mediated metabolic transformations of antitumor agents are concentrated on several aspects in many laboratories. Firstly, the studies on the molecular mechanism of metabolic pathways allow to design chemical modification leading to less toxic or more active analogs. Secondly, finding out the contributions of specific human liver CYP enzymes to the activation of antitumor prodrugs will help to modulate the rate of metabolism in patients with various CYP levels and to predict drug selectivity towards normal and tumor cells. Furthermore, the analysis of the individual CYP induction or inhibition allows to predict the drug-drug interactions and helps to design the directed individual therapy in clinical trials.

The following metabolic issues of selected antitumor drugs will be presented: 1. cyclophosphamide was metabolized by CYP2B6, CYP3A4 and tumors with overexpressions of these enzymes were more sensitive to clinical trials, 2. transformation of tamoxifen occurred with CYP3A7 and CYP3A5, whereas this drug was also an inhibitor of recombinant CYP2B6, 3. product of 6a-hydroxylation of taxol was formed with CYP 2C8 and 3A4 and is competitively inhibited by quercetin, however, the pretreatment of taxol with corticoids increased the rate of metabolite formation. 4. the selective mechanism-based inactivation of P-450 was observed for antitumor drug thio-tepa and for other antitumor agents.

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1. Glucuronidation of antitumor agents - detoxification, mechanism of drug resistance or the prodrug design? Studies on acridine antitumor agents in the light of clinical therapeutics
2. Polymorphism and the level of P450 gene expression in drug metabolism
3. Metabolism of antitumor 9-amino-1-nitroacridine derivative C-1748 (Capridine-beta) in human hepatoma HepG2 cells
4. The role of hepatic cytochrome P-450 enzymes in metabolism of imidazoacridinone antitumor agent, C1311 (Symadex^R): studies with the hepatic NADPH:cytochrome P450 reductase null mice
5. Metabolic transformations of antitumor agents with cytochrome P-450 isoenzymes
6. Imidazoacridinone antitumor agent, C-1311, as a selective mechanism-based inactivator of human recombinant cytochrome P450 1A2.
7. The role of Cytochrome P450 Reductase in metabolism of potent nitroacridine antitumor agent, C‑1748.
8. METABOLIC TRANSFORMATIONS OF ANTITUMOR AGENTS WITH CYTOCHROME P-450 ISOENZYMES.