Chlorophyllin (CHL), a clinically used water-soluble salt of chlorophyll, exhibits antimutagenic activity in vitro by a mechanism that involves complex formation with the carcinogen. Co-administration of CHL and 2- amino-3-methylimidazo[4,5-f]quinoline (IQ) to rats inhibited IQ-DNA binding in target organs for tumorigenesis and protected in the colon aberrant crypt focus (ACF) assay. However, post-initiation exposure to 0.1% CHL in the drinking water increased the number of IQ-induced ACF/colon. This proposal seeks to better define the relative risks versus benefits of CHL treatment in colon cancer.
AIM 1 employs the ACF assay to determine the relationships between IQ dose, CHL dose, and timing of CHL and IQ treatment. The assays examine the dose-response for inhibition and promotion, down to CHL doses used in humans, to seek a threshold for promotion below which CHL will protect. Dose-fractionation studies will provide insight into the relationship between IQ dose and rate of cell proliferation under the influence of continuous CHL exposure. The relative potency of six heterocyclic amines will be studied in the ACF assay and a correlation sought between Kb's of CHL-carcinogen complexes and inhibition of ACF.
AIM 2 examines the progression of ACF to adenomas and carcinomas in rats given IQ in the diet, and determines whether CHL operates as an anticarcinogen in the colon and other primary target organs.
AIM 3 investigates loss of mutant K-ras alleles in the progression of IQ- induced ACF to adenomas and carcinomas, and tests the hypothesis that high dose IQ treatment is proliferative and favors a population of ACF less dependent on ras-mediated oncogenic pathways.
AIM 4 examines factors responsible for the promotional activity of CHL. In addition to dose-response studies (aim 1), structure-activity experiments will compare the post-initiation effects of different chlorophylls. Finally, several intermediate biomarkers associated with the post-initiation phase of colon carcinogenesis will be examined to provide insight into the possible mechanisms of tumor promotion by CHL.
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