DiGiovanni J, Kruszewski F H, Coombs M M, Bhatt T S, Pezeshk A
University of Texas System Cancer Center, Smithville 78957.
Carcinogenesis. 1988 Aug;9(8):1437-43. doi: 10.1093/carcin/9.8.1437.
The present study was designed to compare the skin tumor promoting and epidermal ornithine decarboxylase (ODC) inducing activities of various structural analogs of anthralin (1,8-dihydroxy-9-anthrone) and chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone). Groups of 30 SENCAR mice each were initiated with 7,12-dimethylbenz[a]anthracene and 2 weeks later promoted with once- or twice-weekly applications of various doses of these anthrone derivatives. Carbon-10 (C10)-acyl derivatives of anthralin were active skin tumor promoters in the range of 25-440 nmol per mouse. 10-Acetylanthralin was significantly more active than 10-myristoyl-anthralin at low doses (e.g. 25 and 50 nmol per mouse) and nearly as potent as the unsubstituted compound. Higher doses (greater than or equal to 100 nmol per mouse) of this derivative were toxic, hence, reducing the final papilloma response. On a relative activity scale where anthralin is 1.0, these derivatives had activities that were approximately 0.7 and 0.2, respectively. 10,10-Dipropylanthralin was totally inactive at the doses tested. C6-Substituted derivatives of chrysarobin demonstrated diverse tumor promoting activities when tested in the range of 25-440 nmol per mouse. On a relative activity scale where chrysarobin is 1.0, 6-methoxychrysarobin (physcion anthrone) was approximately 0.9, whereas 6-hydroxychrysarobin (emodin anthrone) had no activity. Chrysophanic acid (1,8-dihydroxy-3-methyl-9,10-anthraquinone) was also inactive as a tumor promoter at the doses tested. In general, the tumor promoting activities of these anthrone derivatives correlated very well with their ability to induce epidermal ODC after a single topical application indicating an important role for this enzyme in skin tumor promotion by anthones. The ability of C10-substituted derivatives of anthralin to undergo base catalyzed oxidation in vitro correlated with both ODC inducing and tumor promoting activities. In addition, copper(II)bis(diisopropylsalicylate) was found to inhibit both ODC induction and skin tumor promotion by chrysarobin. These latter data, when taken together, suggest a role for oxidation at C10 in skin tumor promotion by anthrone derivatives.
本研究旨在比较蒽林（1,8 - 二羟基 - 9 - 蒽酮）和柯桠素（1,8 - 二羟基 - 3 - 甲基 - 9 - 蒽酮）各种结构类似物的皮肤肿瘤促进活性以及对表皮鸟氨酸脱羧酶（ODC）的诱导活性。每组30只SENCAR小鼠用7,12 - 二甲基苯并[a]蒽进行启动，2周后每周一次或两次涂抹不同剂量的这些蒽酮衍生物进行促进。蒽林的碳 - 10（C10） - 酰基衍生物在每只小鼠25 - 440 nmol的范围内是活跃的皮肤肿瘤促进剂。在低剂量（例如每只小鼠25和50 nmol）时，10 - 乙酰蒽林比10 - 肉豆蔻酰蒽林活性显著更高，并且几乎与未取代的化合物一样有效。该衍生物的更高剂量（大于或等于每只小鼠100 nmol）具有毒性，因此降低了最终的乳头瘤反应。在以蒽林为1.0的相对活性尺度上，这些衍生物的活性分别约为0.7和0.2。10,10 - 二丙基蒽林在测试剂量下完全无活性。柯桠素的C6 - 取代衍生物在每只小鼠25 - 440 nmol的范围内测试时表现出不同的肿瘤促进活性。在以柯桠素为1.0的相对活性尺度上，6 - 甲氧基柯桠素（大黄素蒽酮）约为0.9，而6 - 羟基柯桠素（大黄素蒽酮）无活性。大黄酚（1,8 - 二羟基 - 3 - 甲基 - 9, ten - 蒽醌）在测试剂量下作为肿瘤促进剂也无活性。一般来说，这些蒽酮衍生物的肿瘤促进活性与其单次局部应用后诱导表皮ODC的能力非常相关，表明该酶在蒽酮促进皮肤肿瘤中起重要作用。蒽林的C10 - 取代衍生物在体外进行碱催化氧化的能力与ODC诱导和肿瘤促进活性均相关。此外，发现双（二异丙基水杨酸）铜（II）可抑制柯桠素诱导的ODC和皮肤肿瘤促进作用。综合这些后一组数据表明，C10处的氧化在蒽酮衍生物促进皮肤肿瘤中起作用。
