A NEW TUMOR PROMOTION PATHWAY AND ITS INHIBITORS

Tumor promotion is a critical point in multistage carcinogenesis in hu mans. We have identified a common biochemical and molecular tumor prom otion mechanism, the okadaic acid pathway, applicable in various organ s. Tumor promotion by the okadaic acid class of compounds is mediated through inhibition of protein phosphatases 1 and 2A, resulting in an i ncrease of protein phosphorylation and a subsequent expression of cell proliferation genes. Recently, we demonstrated that okadaic acid indu ced the release of mouse tumor necrosis factor-alpha (mTNF-alpha) from BALB/3T3 cells. The first part of this review discusses the link betw een the okadaic acid pathway and TNF-alpha as endogenous tumor promote rs in vivo. Inhibitors of tumor promotion are varied. For the purpose of cancer chemoprevention in humans, the inhibitors sarcophytol A, can ventol, and (-)-epigallocatechin gallate (EGCG) were studied and the r esults are presented. The inhibitory mechanisms also were varied: sarc ophytol A inhibited H2O2 formation by TPA-activated human polymorphonu clear leukocytes; canventol inhibited protein isoprenylation in the ce lls; and EGCG, which is a main constituent of Japanese green tea, is a n antioxidant. These inhibitors are promising cancer chemopreventive a gents. Study of the essential tumor promotion mechanisms will facilita te the development of cancer chemopreventive agents.