Suppression of tumor promotion by inhibitors of poly(ADP)ribose formation.

Tumor promoters, such as phorbol esters or hormones, cause many biological effects which may contribute to the expression of cancer. The mechanism of cancer expression may have a common theme. One method of learning about this common mechanism is the identification of chemicals that interfere with tumor development. That there is actually a common theme between very different substances, such as inflammatory skin tumor promoters and estradiol causing breast cancer, was shown by the fact that both skin and breast cancers are suppressed by the same agents, e.g., protease inhibitors and retinoids. In addition to skin and breast, protease inhibitors suppress colon, bladder, and liver cancers. The substances that crossed over in suppressing many varieties of cancer were found to inhibit oxygen radical formation by tumor promoter-activated neutrophils and ras oncogene expression in NIH 3T3 cells. Poly(ADP)ribose polymerase (PADPR polymerase) may serve as the connecting link between oxygen radicals that cause its activation and oncogene expression. PADPR polymerase is inhibited by retinoids, antioxidants, and some protease inhibitors. Benzamide, an inhibitor of PADPR polymerase, is also a chymotrypsin inhibitor which suppresses oxygen radical formation by tumor promoter-activated neutrophils. The inhibition of PADPR polymerase causes the expulsion of some oncogenes from NIH 3T3 cells at definite times after oncogene transfection. Further work is required to find what are the contributions of PADPR polymerase to tumor promotion and of its inhibitors to suppression of oncogene expression.