Properties of intraepithelial neoplasia relevant to cancer chemoprevention and to the development of surrogate end points for clinical trials.
Cancer chemoprevention is defined as the prevention of cancer by the administration of diet supplements or drugs. A drug discovery effort should therefore focus on finding agents that will avert the process of intraepithelial neoplasia which precedes invasive cancer. Over 30 agents developed by the chemoprevention program at the National Cancer Institute are being tested against intraepithelial neoplasia of many organ sites in more than 80 clinical trials. Two basic mechanisms underlie the onset and development of intraepithelial neoplasia. First is the development of the two precursor lesions of chronic diffuse epithelial hyperplasia and genomic instability, the latter being produced by "mutator" mutations in genes responsible for genomic stability, by gene copy amplification or loss from DNA breakage-fusion-anaphase-bridge cycles, by unequal sister chromatid exchange, and by accumulation of double minutes. Second is the development of multicentric intraepithelial neoplastic lesions which independently progress through each of the following processes at a continuously accelerating rate: clonal evolution, hyperproliferation, production of genomic structural variants, and apoptosis. Recommended chemoprevention strategies based on these mechanisms are (i) the development of better technology for early diagnosis, (ii) the development of multiple agents that block intralesional proliferation at steps along the signal pathway of mitotic signal transduction and along the signal pathway of synthesis of daughter cell components, (iii) the development of nontoxic anti-inflammatory agents, anitoxidants, antimutagens, and proapoptotics, (iv) the avoidance of "clonal escape" through use of drug combinations, and (v) the use of computer-assisted quantitative image analysis to assay modulation of surrogate end points in chemoprevention clinical trials.
Boone
C W
CW
Division of Cancer Prevention and Control, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Bacus
J W
JW
Bacus
J V
JV
Steele
V E
VE
Kelloff
G J
GJ
D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D018890:Chemoprevention; D002986:Clinical Trials as Topic; D018450:Disease Progression; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000517:prevention & control*; D015398:Signal Transduction
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor