Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy.
The primary focus of chemoprevention research is the prevention of cancer using pharmacological, biological, and nutritional interventions. Chemotherapeutic approaches that have been used successfully for both the prevention and treatment of a number of human malignancies have arisen from the identification of specific agents and appropriate molecular targets. Although drug-metabolizing enzymes have historically been targeted in attempts to block the initial, genotoxic events associated with the carcinogenic process, emerging evidence supports the idea that manipulating drug-metabolizing enzymes may also be an effective strategy to be used for treating tumor progression, invasion, and, perhaps, metastasis. This report summarizes a symposium that presents some recent progress in this area. One area of emphasis is the development of a CYP17 inhibitor for treatment of prostate cancer that may also have androgen-independent anticancer activity at higher concentrations. A second focus is the use of a mouse model to investigate the effects of aryl hydrocarbon receptor and Cyp1b1 status and chemopreventative agents on transplacental cancer. A third area of focus is the phytochemical manipulation of not only cytochrome P450 (P450) enzymes but also phase II inflammatory and antioxidant enzymes via the nuclear factor-erythroid 2-related factor 2 pathway to block tumor progression. A final highlight is the use of prodrugs activated by P450 enzymes to halt tumor growth and considerations of dosing schedule and targeted delivery of the P450 transgene to tumor tissue. In addition to highlighting recent successes in these areas, limitations and areas that should be targeted for further investigation are discussed.
Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, USA.
Hollie I
HI
Swanson
Vincent C O
VC
Njar
Zhen
Z
Yu
David J
DJ
Castro
Frank J
FJ
Gonzalez
David E
DE
Williams
Ying
Y
Huang
Ah-Ng T
AN
Kong
Joshua C
JC
Doloff
Jie
J
Ma
David J
DJ
Waxman
Emily E
EE
Scott
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D002273:Carcinogens / Q000037:antagonists & inhibitors; D065633:Cytochrome P-450 CYP1B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004798:Enzymes / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000037:antagonists & inhibitors / Q000633:toxicity; D011247:Pregnancy; D011355:Prodrugs / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004798:Enzymes; D051267:NF-E2-Related Factor 2; D004364:Pharmaceutical Preparations; D011084:Polycyclic Aromatic Hydrocarbons; D011355:Prodrugs; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D013254:Steroid 17-alpha-Hydroxylase