URINARY BLADDER CANCER PROMOTION BY DIETARY L-TRYPTOPHAN

过量促进膀胱癌发生的研究

Studies on the promotion of urinary bladder carcinogenesis by excess dietary L-tryptophan and a Vitamin B6 deficiency will be conducted using N-(4-(5-nitro-2-furyl)-2-thiazolyl)formamide (FANFT) as the initiator. The role of dietary L-tryptophan and its metabolites in urinary bladder cancer is unclear. Early studies reported DL-tryptophan as a co-carcinogen in animal models but failed to show carcinogenicity of tryptophan fed alone. Dr. S. M. Cohen has demonstrated DL-tryptophan as an enhancer of bladder cancer initiated by feeding 0.2% FANFT for 6 weeks. Bladder tumor yields were 20% in the FANFT alone group and 50-53% in the FANFT plus 2% DL-tryptophan group. Further studies used a lower dose of carcinogen (4 weeks) and 2% L-tryptophan to evaluate a promotional role of tryptophan. Although the tumor yield was low in the FANFT alone group (4%) the increase in the FANFT plus tryptophan group (19%) was not significant. Vitamin B6 (pyridoxal phosphate) is intimately involved in tryptophan metabolism and has corrected abnormal tryptophan metabolite patterns in urinary bladder cancer patients. An early animal study suggested that Vitamin B6 deficiency enhanced the bladder tumor yield. We propose to use the 4-week treatment with FANFT as the initiator of urinary bladder cancer in male Fischer rats and to study L-tryptophan excess and Vitamin B6 (pyridoxine) deficiency as promoters. 1) The earlier study will be repeated using larger numbers of animals to secure statistically significant results. 2) Vitamin B6 deficiency, which causes abnormal tryptophan metabolite excretion patterns, will be evaluated alone in this model. 3) Vitamin B6 deficiency combined with L-tryptophan excess will be assessed to determine if these two conditions potentiate each other in bladder cancer promotion. 4) Urinary tryptophan metabolites will be measured by high pressure liquid chromatography in all bioassays to indicate which evaluations are best correlated with bladder cancer promotion. 5) Autoradiographic and scanning electron microscopic studies will evaluate the effects of these dietary manipulations on urinary bladder hyperplasia. The proposed studies are important because L-tryptophan and its metabolites are endogenous substances in normal urine and could contribute significant promoting activity in human urinary bladder cancer.