Chen L C, Sly L, De Luca L M
Differentiation Control Section, National Cancer Institute, Bethesda, MD 20892.
Carcinogenesis. 1994 Oct;15(10):2383-6. doi: 10.1093/carcin/15.10.2383.
We have previously reported that high dietary retinoic acid (RA; 30 micrograms/g diet) inhibits carcinoma formation in a two-stage skin carcinogenesis protocol, using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiator and 12-O-tetradecanoyl phorbol-13-acetate (TPA) as the tumor-promoter in female SENCAR mice. We next asked whether switching the diets from high to control levels of RA and vice versa would influence carcinoma formation. Mice at 3 weeks of age were initiated with DMBA (20 micrograms) once, followed by 20 weekly applications of TPA (2 micrograms). At 3 weeks of age mice were weaned onto a diet containing either 3 (control) or 30 (high) micrograms RA/g diet. Half of the mice from either dietary group were switched to the other diet at 20 weeks of age, when papilloma formation was at its peak. These four groups are designated RA 3 micrograms, RA 30 micrograms, RA 3/30 micrograms and RA 30/3 micrograms groups. As previously found, papilloma formation (including incidence and yield) was not significantly affected by dietary treatment. However, high dietary RA inhibited carcinoma formation; specifically cumulative carcinoma incidence (18.5-23.1% versus 50%) and yield (0.19-0.23 versus 0.68) were significantly lower (P < 0.05) in the high dietary RA treatment groups than the RA 3 micrograms control group, as was the carcinoma conversion efficiency (2.1-3.8% versus 9.4%). The beneficial effect on carcinoma formation was still evident when excess RA was given late during the carcinogenesis process (i.e. the RA 3/30 micrograms group). Moreover, a residual effect of excess RA was also seen after the dietary RA was switched to the control level at 20 weeks of age, when papilloma yield was highest (i.e. the RA 30/3 micrograms group). It is therefore concluded that the chemopreventive effect of high dietary RA on skin carcinogenesis induced by a two-stage carcinogenesis protocol with DMBA and TPA resides mainly at the step of conversion from benign papillomas to malignant carcinomas.
我们之前报道过，在雌性SENCAR小鼠的两阶段皮肤致癌实验中，高剂量膳食视黄酸（RA；30微克/克饮食）可抑制癌形成，该实验以7,12-二甲基苯并[a]蒽（DMBA）作为启动剂，12-O-十四烷酰佛波醇-13-乙酸酯（TPA）作为肿瘤促进剂。接下来我们探究了将饮食中RA的水平从高剂量切换至对照剂量以及反之切换是否会影响癌形成。3周龄的小鼠一次性给予DMBA（20微克），随后每周给予20次TPA（2微克）。3周龄时，将小鼠断奶并给予含3（对照）或30（高剂量）微克RA/克饮食的饲料。在20周龄时，当乳头状瘤形成达到高峰时，将每个饮食组中的一半小鼠切换至另一种饮食。这四组分别命名为RA 3微克组、RA 30微克组、RA 3/30微克组和RA 30/3微克组。如之前所发现的，饮食处理对乳头状瘤形成（包括发生率和数量）没有显著影响。然而，高剂量膳食RA抑制癌形成；具体而言，高剂量膳食RA处理组的累积癌发生率（18.5 - 23.1%对50%）和数量（0.19 - 0.23对0.68）显著低于RA 3微克对照组（P < 0.05），癌转化效率也是如此（2.1 - 3.8%对9.4%）。当在致癌过程后期给予过量RA时（即RA 3/30微克组），对癌形成的有益作用仍然明显。此外，在20周龄时，当乳头状瘤数量最高时，将膳食RA切换至对照水平后，仍可看到过量RA的残留效应（即RA 30/3微克组）。因此得出结论，高剂量膳食RA对由DMBA和TPA的两阶段致癌方案诱导的皮肤癌发生的化学预防作用主要存在于从良性乳头状瘤向恶性癌转化的步骤中。
