Effect of chemopreventive agents on DNA adduction induced by the potent mammary carcinogen dibenzo[a,l]pyrene in the human breast cells MCF-7.
Over 1500 structurally diverse chemicals have been identified which have potential cancer chemopreventive properties. The efficacy and mechanisms of this growing list of chemoprotective agents may be studied using short-term bioassays that employ relevant end-points of the carcinogenic process. In this study, we have examined the effects of eight potential chemopreventive agents, N-acetylcysteine (NAC), benzylisocyanate (BIC), chlorophyllin, curcumin, 1,2-dithiole-3-thione (D3T), ellagic acid, genistein, and oltipraz, on DNA adduction of the potent mammary carcinogen dibenzo[a,l]pyrene (DBP) using the human breast cell line MCF-7. Bioactivation of DBP by MCF-7 cells resulted in the formation of one predominant (55%) dA-derived and several other dA- or dG-derived DNA adducts. Three test agents, oltipraz, D3T, and chlorophyllin substantially (>65%) inhibited DBP-DNA adduction at the highest dose tested (30 microM). These agents also significantly inhibited DBP adduct levels at a lower dose of 15 microM, while oltipraz was effective even at the lowest dose of 5 microM. Two other agents, genistein and ellagic acid were moderate (45%) DBP-DNA adduct inhibitors at the highest dose tested, while NAC, curcumin, and BIC were ineffective. These studies indicate that the MCF-7 cell line is an applicable model to study the efficacy of cancer chemopreventive agents in a human setting. Moreover, this model may also provide information regarding the effect of the test agents on carcinogen bioactivation and detoxification enzymes.
Smith
W A
WA
Graduate Center for Toxicology, 354 Health Sciences Research Building, University of Kentucky Medical Center, Lexington, KY 40536-0305, USA.
Freeman
J W
JW
Gupta
R C
RC
D016588:Anticarcinogenic Agents / Q000494:pharmacology; D016587:Antimutagenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001580:Benzopyrenes / Q000633:toxicity*; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D018890:Chemoprevention / Q000379:methods*; D002735:Chlorophyllides / Q000494:pharmacology; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D011719:Pyrazines / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D016587:Antimutagenic Agents; D000970:Antineoplastic Agents; D001580:Benzopyrenes; D002273:Carcinogens; D002735:Chlorophyllides; D018736:DNA Adducts; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; C007020:chlorophyllin; C041517:dibenzo(a,l)pyrene; C049325:1,2-dithiol-3-thione