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Structure-activity relationships for epidermal ornithine decarboxylase induction and skin tumor promotion by
J DiGiovanni1, F H Kruszewski, M M Coombs
1University of Texas System Cancer Center, Smithville 78957.
Abstract:
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.
Insights
This study compared skin tumor promotion by anthralin and chrysarobin derivatives. Certain anthralin derivatives showed significant tumor-promoting activity, correlating with epidermal ornithine decarboxylase (ODC) induction.
Area of Science:
- Chemical carcinogenesis
- Dermatology
- Enzymology
Background:
- Anthralin and chrysarobin are known skin irritants and potential tumor promoters.
- The mechanism of skin tumor promotion by anthrone derivatives is not fully understood.
- Epidermal ornithine decarboxylase (ODC) is a key enzyme implicated in skin carcinogenesis.
Purpose of the Study:
- To compare the skin tumor promoting and epidermal ODC inducing activities of structural analogs of anthralin and chrysarobin.
- To investigate the relationship between chemical structure and biological activity of these compounds.
- To elucidate the role of ODC in the mechanism of skin tumor promotion by anthrones.
Main Methods:
- SENCAR mice were initiated with 7,12-dimethylbenz[a]anthracene and promoted with various doses of anthrone derivatives.
- Skin tumor promotion was assessed by papilloma response.
- Epidermal ODC induction was measured after topical application of the compounds.
- In vitro base-catalyzed oxidation and in vivo inhibition studies were performed.
Main Results:
- Carbon-10 (C10)-acyl derivatives of anthralin demonstrated significant skin tumor promoting activity, with 10-acetylanthralin being more potent than 10-myristoyl-anthralin at lower doses.
- C6-substituted chrysarobin derivatives showed varied activities; 6-methoxychrysarobin (physcion anthrone) was highly active, while 6-hydroxychrysarobin (emodin anthrone) and chrysophanic acid were inactive.
- Tumor promoting activities strongly correlated with epidermal ODC induction, suggesting ODC's role in anthrone-mediated skin tumor promotion.
- Oxidation at the C10 position of anthralin derivatives correlated with their ODC-inducing and tumor-promoting effects.
- Copper(II)bis(diisopropylsalicylate) inhibited both ODC induction and skin tumor promotion by chrysarobin.
Conclusions:
- The tumor promoting and ODC-inducing activities of anthralin and chrysarobin derivatives are structure-dependent.
- Oxidation at the C10 position appears crucial for the biological activity of these compounds.
- ODC induction is a key event in the mechanism of skin tumor promotion by anthrones.
- Further research into the role of oxidation and ODC in skin carcinogenesis is warranted.