Isoflavone genistein is a specific inhibitor of protein tyrosine kinase (PTK) and has been shown to have a variety of anticancer activities in cultured cells and animal models. We report here that genistein significantly inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-promoted skin tumorigenesis in a two-stage carcinogenesis model. In an initiation study, 10 micromol genistein was applied daily to female SENCAR mouse skin for 1 week, followed by initiation with 10 nmol DMBA. Mice were then treated with twice weekly 4 microg TPA. Genistein was shown to reduce tumor incidence and multiplicity in DMBA-initiated skin tumors by approximately 20% (P < 0.05) and 50% (P < 0.01), respectively. Two promotion studies were conducted using CD-1 and SENCAR mice. In experiment 1, CD-1 mice were initiated with 100 nmol DMBA and followed by a twice weekly regimen of 1 and 5 micromol genistein/4 microg TPA. In experiment 2, SENCAR mice were initiated with 10 nmol DMBA and followed by a regimen of 5, 10 and 20 micromol genistein/2 microg TPA.Both studies consistently showed that genistein substantially inhibited TPA-promoted skin tumorigenesis by reducing the tumor multiplicity by approximately 60 and 75%, respectively (P < 0.01). However, the tumor incidence appeared to be less affected. Mechanistic studies showed that genistein inhibited DMBA-induced bulky DNA adduct formation and substantially suppressed TPA-stimulated H2O2 and inflammatory responses in mouse skin by >60% (P < 0.01). In contrast, genistein only exhibited a moderate inhibition of TPA-induced ornithine decarboxylase activity (P > 0.05). Our results suggest that genistein exerts its anti-initiational and anti-promotional effects on skin carcinogenesis probably through blockage of DNA adduct formation and inhibition of oxidative and inflammatory events in vivo.

金雀异黄素是一种蛋白酪氨酸激酶(PTK)特异性抑制剂，它已被证明对各种培养的细胞模型和动物模型都有抗癌活性。在这里，我们研究金雀异黄素对7,12二甲[a]蒽苯并蒽(DMBA)-诱导的和12-O十四酰氟波醇- 13 -醋酸酯（TPA）诱导的皮肤癌Ⅱ期模型的显著抑制作用。 
雌性SENCAR小鼠的皮肤每日先被给予10微摩尔的金雀异黄素1周，随后给予10纳摩尔NMDA，然后半周给一次4微克TPA。结果显示金雀异黄素可降低肿瘤发病率和DMBA-诱导的皮肤癌多样性大约为20%（P< 0.05）和50％（P < 0.01）。两项研究可延伸到CD - 1和SENCAR小鼠试验。在实验1，CD - 1小鼠，先给100 纳摩尔 DMBA随后给5微摩尔金雀异黄素/ 4微克TPA，每周两次为1疗程。实验2，SENCAR小鼠，先给予10 纳摩尔NMDA，再分别给予5, 10 和20微摩尔金雀异黄素/ 2微克TPA。这两项研究一致表明，金雀异黄素可大大抑制TPA促进的皮肤癌，使其分别减少约60%和75％（P <0.01）。然而，它对肿瘤的发病率似乎影响较小。 
机理研究表明，金雀异黄素对DMBA诱发的DNA大量加合物的形成和TPA刺激的H2O2和小鼠皮肤炎症反应的抑制率大于60% (P < 0.01)。与此相反，金雀异黄素只显示对TPA诱导的鸟氨酸脱羧酶活性（P> 0.05）中度抑制作用。 
我们的研究结果显示，金雀异黄素可能通过阻止DNA加合物的形成与抑制体内氧化刺激的和炎症反应发挥对皮肤癌的发生和发展的对抗作用。