Determining efficacy of cancer chemopreventive agents using a cell-free system concomitant with DNA adduction

Mutat Res. 1999 Mar 10;425(1):143-52. doi: 10.1016/s0027-5107(98)00244-9.

Abstract

The large (>2000) and expanding number of natural and synthetic agents with potential cancer chemopreventive properties renders it economically and physically impossible to test each of these agents for their efficacy in the widely accepted 2-year animal bioassay and clinical trials. Therefore, there is a growing need for relevant short-term screening tests to study these compounds such that only the most efficacious ones undergo extensive long-term studies. We have previously reported in a pilot study that the use of a microsome-mediated test system concomitant with DNA adduction is a pertinent and relevant model for rapidly studying the efficacy and mechanisms of cancer chemopreventive agents. We have extended this study to investigate 26 additional agents for their potential chemopreventive abilities by studying their effects on microsome-mediated benzo[a]pyrene (BP)-DNA adduction. These agents had differential effects on the two major adducts of BP-DNA, i.e., BP-7,8-diol-9,10-epoxide (BPDE)-deoxyguanosine (dG) and 9-OH-BP-dG-derived adducts. These agents were therefore categorized into five classes. Three test agents (ellagic acid, genistein and oltipraz) were strong inhibitors of both adducts. These agents diminished BP-DNA adduction by 65-95% and were categorized as Class I agents. Six other agents (benzyl isocyanate, R(+)-1-phenylethyl isocyanate, linoleic acid ethyl ester, (+)-biotin, indole-3-carboxylic acid and beta-carotene) moderately inhibited both BP-DNA adducts (25-64%); these compounds were identified as Class II agents. Six additional test agents inhibited only one adduct selectively and nine others were ineffective; these agents were categorized as Class III and Class IV, respectively. Interestingly, seven test agents enhanced BPDE-dG or 9-OH-BP-dG or both adducts and were categorized as Class V agents. Four of these Class V agents concomitantly inhibited BPDE-dG while enhancing 9-OH-BP-dG. This emphasizes the importance of studying individual DNA adducts in contrast to total DNA binding. In conclusion, Class I and Class II agents may be good candidates for further chemoprevention studies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Biotransformation
  • Cell-Free System
  • DNA Adducts*
  • Drug Screening Assays, Antitumor
  • Microsomes, Liver / metabolism
  • Rats

Substances

  • Antineoplastic Agents
  • DNA Adducts