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. Although the total level of liver microsomal P450s does not vary considerably among humans, genetic polymorphism and inducibility of a given P-450 isoenzymes gives the interindividual variations in the levels of P450 isoforms (CYPs). 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.

Considering all above, investigations on P-450 mediated metabolic transformations of antitumor agents are concentrated on several aspects. 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: (i) cyclophosphamide was metabolized by CYP2B6, whereas transformation of tamoxifen occurred with CYP3A7 and CYP3A5 giving rise different products in each case. (ii) 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. (iii) the selective mechanism-based inactivation of P-450 was observed for antitumor drug thio-tepa and other antitumor agents.

Studies on metabolic transformations of acridine antitumor compounds which are under I and II Phase of clinical trials are carrying out in our group. We are involved in the identification of metabolic products as well as in the mechanism of P450 level modulation. The transformations are performed with human liver microsomes of individual CYP overexpression and with selected human E.coli recombinant CYPs. The results in the field of CYP mechanism-based inhibition by our compounds in comparison with other antitumor drugs will be presented.

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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. Specific metabolism of antitumor agents with cytochrome P-450 isoenzymes
5. 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
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.