THE PROCARCINOGEN HYPOTHESIS FOR BLADDER-CANCER - ACTIVITIES OF INDIVIDUAL-DRUG METABOLIZING ENZYMES AS RISK-FACTORS

Bladder cancer provides the most definitive example for an association between environmental agents and cancer, However, in the absence of i ndustrial occupational exposure, the primary carcinogen is rarely iden tified, and the mechanisms involved in cancer formation are poorly und erstood. The environmental procarcinogen hypothesis of tumour pathogen esis proposes that many carcinogens require metabolic activation by dr ug metabolizing enzymes to form the proximate carcinogen, A balance of exposure to the carcinogen, the activity of the enzymes involved in e ither formation of proximate carcinogen, or production of non-toxic me tabolites, will determine tumour risk. We have used mephenytoin, debri soquine and dapsone as selective probes for the phenotypic measures of activity of CYP2C19, CYP2D6, and CYP3A4, respectively, Within subject reproducibility of phenotypic measures, and the lack of cross-inhibit ion when the three drugs are given in a concurrent cocktail, have been confirmed. We have applied the cocktail drug approach in two, non-ove rlapping series of cases with bladder cancer and matched controls. In both series, patients with aggressive bladder cancer (GIII histopathol ogy) had a history of excess alcohol intake, an under-representation o f poor metabolizers of debrisoquine, a significant mean reduction in d apsone recovery ratio, but no difference metabolism support the procar cinogen environmental hypothesis for bladder cancer and suggest that m easurement of activity of selected individual drug metabolizing enzyme s involved in the pathogenesis of this tumour can be used to identify subjects at high risk of developing bladder cancer.