ISOTHIOCYANATES AND PLANT POLYPHENOLS AS INHIBITORS OF LUNG AND ESOPHAGEAL CANCER

A group of arylalkyl isothiocyanates were tested for their abilities t o inhibit tumorigenicity and DNA methylation induced by both the tobac co-specific nitrosamine, NNK, in A/J mouse lung and the esophageal-spe cific carcinogen, NMBA, in F344 rat esophagus. In addition, ellagic ac id was tested for its ability to inhibit NMBA-induced esophageal tumor igenesis. In the strain A lung tumor model, PEITC effectively inhibite d NNK-induced lung tumors at a dose of 5 mu mol, but was not inhibitor y at lower doses. PPITC, PBITC, PPeITC, and PHITC were all considerabl y more potent inhibitors of NNK lung tumorigenesis than PEITC, and PHI TC was the most potent inhibitor of all. Thus, in the strain A lung tu mor model, there was a trend of increased inhibitory efficacy among ar ylalkyl isothiocyanates with increased alkyl chain length. In the F344 rat esophageal tumor model, PPITC was clearly more potent than PEITC, BITC and PBITC had little inhibitory effect on esophageal tumorigenes is, and in a separate experiment, PHITC actually enhanced esophageal t umorigenesis. Thus, the structure-activity relationships for inhibitio n of tumorigenesis by arylalkyl isothiocyanates were considerably diff erent in the two animal models. However, the effects of the isothiocya nates on tumorigenesis were well-correlated to their effects on DNA ad duct formation in either model. The most likely mechanism of inhibitio n of tumorigenesis by these isothiocyanates is via inhibition of the c ytochrome p450 enzymes responsible for activation of NNK in mouse lung or NMBA in rat esophagus. Ellagic acid was an effective inhibitor of esophageal tumorigenesis, although not as potent as PEITC or PPITC. Li ke the isothiocyanates, ellagic acid inhibits cytochrome p450-mediated activation of NMBA. (C) 1997 Elsevier Science Ireland Ltd.