柯桠素对皮肤肿瘤促癌作用的调节

DiGiovanni J, Kruszewski F H, Chenicek K J

University of Texas System Cancer Center, Smithville 78957.

Carcinogenesis. 1988 Aug;9(8):1445-50. doi: 10.1093/carcin/9.8.1445.

The present study examined the effect of several prototypic inhibitors of phorbol ester skin tumor promotion on skin tumor promotion by chrysarobin, an anthrone tumor promoter. Retinoic acid (RA) inhibited skin tumor promotion by chrysarobin; however, the degree of inhibition was dependent on the treatment protocol. When RA (10 micrograms/mouse) was given 1 h after each twice-weekly application of chrysarobin (220 nmol/mouse), a marked inhibition of papilloma formation was observed (78%). In additional experiments, using a once-weekly application of chrysarobin, RA also inhibited skin tumor promotion but the magnitude of inhibition was less. Interestingly, RA (10 micrograms/mouse), given 1 or 6 h after the promoter, did not inhibit the induction of epidermal ornithine decarboxylase (ODC) activity induced by a single topical application of chrysarobin (220 nmol). Fluocinolone acetonide (1 microgram/mouse), given 5 min before each twice-weekly application of chrysarobin (220 nmol/mouse) effectively inhibited skin tumor promotion (88%). A 0.5 or 0.25% supplement of alpha-difluoromethylornithine (alpha-DFMO) in the drinking water inhibited the induction of epidermal ODC following chrysarobin (220 nmol/mouse) treatment by 85 or 70%, respectively. Supplements of both 0.25 and 0.5% of alpha-DFMO also led to a 50 and 61% inhibition, respectively, in the number of papillomas per mouse after 25 weeks of promotion with chrysarobin. Interestingly, 0.25% alpha-DFMO in the drinking water did not reduce the number of papillomas per mouse after 20 weeks of promotion with 1.7 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the number of papillomas per mouse that were greater than or equal to 4 mm in diameter was significantly reduced in both chrysarobin- and TPA-treated mice. The data indicate that RA, FA and alpha-DFMO may be general inhibitors of tumor promoter regardless of the chemical class of tumor promoter. The ability of these inhibitors of phorbol ester promotion to inhibit anthrone promotion indicates that some common biochemical pathways may exist for both classes of skin tumor promoters.

本研究检测了几种佛波酯皮肤肿瘤促癌作用的原型抑制剂对蒽酮类肿瘤促癌剂柯桠素皮肤肿瘤促癌作用的影响。维甲酸（RA）可抑制柯桠素的皮肤肿瘤促癌作用；然而，抑制程度取决于治疗方案。当每周两次每次给予柯桠素（220 nmol/只小鼠）后1小时给予RA（10 μg/只小鼠）时，可观察到乳头状瘤形成受到显著抑制（78%）。在另外的实验中，采用每周一次给予柯桠素的方式，RA也能抑制皮肤肿瘤促癌作用，但抑制程度较小。有趣的是，在给予促癌剂后1小时或6小时给予RA（10 μg/只小鼠），并不抑制单次局部应用柯桠素（220 nmol）所诱导的表皮鸟氨酸脱羧酶（ODC）活性。在每周两次每次给予柯桠素（220 nmol/只小鼠）前5分钟给予醋酸氟轻松（1 μg/只小鼠），可有效抑制皮肤肿瘤促癌作用（88%）。饮用水中添加0.5%或0.25%的α-二氟甲基鸟氨酸（α-DFMO），分别可使柯桠素（220 nmol/只小鼠）处理后表皮ODC的诱导抑制85%或70%。添加0.25%和0.5%的α-DFMO，在用柯桠素促癌25周后，每只小鼠乳头状瘤的数量也分别减少了50%和61%。有趣的是，在用1.7 nmol 12-O-十四酰佛波醇-13-乙酸酯（TPA）促癌20周后，饮用水中0.25%的α-DFMO并没有减少每只小鼠乳头状瘤的数量。然而，在柯桠素和TPA处理的小鼠中，直径大于或等于4 mm的每只小鼠乳头状瘤的数量均显著减少。数据表明，无论肿瘤促癌剂的化学类别如何，RA、氟轻松和α-DFMO可能都是肿瘤促癌剂的通用抑制剂。这些佛波酯促癌作用抑制剂抑制蒽酮促癌作用的能力表明，这两类皮肤肿瘤促癌剂可能存在一些共同的生化途径。