Lack of chemopreventive activity of beta-carotene and alpha-tocopherol dietary supplementation on spontaneous tumorigenesis in p53-deficient mice

Randomized clinical trials that tested the efficacy of supplemental antioxidants showed no benefit toward cancer, and the ATBC Trial and CARET suggested that such supplements may cause harm in individuals at high risk for lung cancer. The p53-deficient mouse, with p53 tumor suppressor activity eliminated by gene targeting, has proven useful for studying interactions between genetic susceptibility to tumors and potentially salutary dietary interventions. We have previously shown the rapid and spontaneous tumorigenesis seen in these mice to be responsive to dietary modulation. To determine the activity of antioxidant vitamins in this model, male nullizygous p53-deficient mice (10-12 weeks old) were fed either AIN-76A (a semi purified diet) or NIH-07 (an open formula with dietary sources of carotenoids) with or without combined beta-carotene (4 mmol/kg diet) and alpha-tocopherol (300 mg/kg diet) supplementation (17-20/group). During the 27-week study 90% of the mice developed tumors (most commonly lymphoma); vitamin treatment had no effect on tumor-related mortality (Cox proportional hazards model) or on mean survival time on study for all mice (88 to 90 days for AIN-76A diet and 78 to 81 days for NIH-07 diet). These results suggest that dietary administration of antioxidant vitamins cannot overcome a pre-existing genetic defect that predisposes to tumor development.

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