Over the last decade, the
Chemoprevention Branch, Division of
Cancer Prevention and Control, National Cancer Institute, USA, has been developing drugs that will slow or stop the progression to invasive
cancer of precancerous (pre-invasive) lesions generally termed 'intraepithelial dysplasia' or 'dysplasia'. Over 40 short-term clinical trials are in progress, testing the following classes of agents on precancerous lesions in the different major organ systems:
antimutagens (
N-acetylcysteine,
oltipraz), antiproliferatives (
difluoromethylornithine,
dehydroepiandrosterone,
selenomethionine),
antioxidants (
vitamin E,
curcumin),
anti-inflammatories (
aspirin,
piroxicam,
ibuprofen,
sulindac sulfone) and hormonally active agents (
tamoxifen in
breast ductal carcinoma in situ and
finasteride in
prostatic intraepithelial neoplasia). Because of the strong practical need to keep so many clinical trials as short-term as possible, certain tissue changes known to be associated with high
cancer risk were selected for use as
biomarker end-points in the trials, such changes being quantitatively assayed by computer-assisted image analysis. These '
surrogate end-point biomarkers' (SEBs) are based on the individual cellular morphological and functional changes universally used by histopathologists to diagnose the lesion of intraepithelial
neoplasia (Riddell, 1984; Boone et al., 1992; Wright et al., 1994). High grades of this lesion precede invasive
cancer in the great majority of cases, and therefore SEBs based on them are linked to high
cancer risk. Table 1 summarizes some of the short-term clinical trials now being monitored by the
Chemoprevention Branch. The SEBs abbreviated 'PPNN' in the figure are: proliferative index (P); ploidy (
DNA histogram) (P); nuclear morphometry and
chromatin texture (N); and nucleolar size and frequency (N). Computer-assisted image analysis is used to assay these features quantitatively, which gives the SEBs increased objectivity, reproducibility and sensitivity. Further details concerned with
cancer chemoprevention trials using SEBs, and their relation to the field of
cancer epidemiology, are given below.