Chrysarobin

Abstract: A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin decreased 125I-labeled epidermal growth factor (EGF) binding in epidermal membrane preparations within 1 h while 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) gradually reduced binding with maximum inhibition at 15 h. Subsequently, 125I-EGF binding increased to approximately 200% of control in epidermal membrane preparations from both TPA- and chrysarobin-treated mice. A single application of TPA but not chrysarobin resulted in a rapid translocation of protein kinase C (PKC) to the membrane; however, treatment with both promoters ultimately led to a time-dependent loss of PKC activity in both membrane and cytosol fractions. The initial inhibition of 125I-EGF binding was sustained for at least 24 h after single and multiple treatments with both promoting agents. Acid washing restored EGF binding to control levels in membrane preparations obtained 24 h after a single application, whereas acid washing of membrane preparations obtained 24 h after a second application of TPA or chrysarobin increased binding (2.5-fold and 1.5-fold that of the control, respectively). The presence of increased amounts of ligands for the EGF receptor in tumor promoter-treated epidermis was initially confirmed in 125I-EGF binding competition experiments using NRK-49F cells. A single topical application of TPA or chrysarobin induced elevated levels of transforming growth factor-alpha (TGF-alpha) mRNA at 6 h or 15-24 h, respectively. Elevated levels of a TGF-alpha precursor (21 kDa) were subsequently observed in cytosol and membrane preparations after single and multiple applications of TPA or chrysarobin. These results suggest that repeated topical application of tumor promoters may lead to sustained loss of a negative-feedback mechanism involving phosphorylation at Thr-654 of the EGF receptor by PKC. The concomitant elevation of ligands, such as TGF-alpha, may provide a mechanism for sustained cell proliferation essential for skin tumor promotion.

Abstract: The skin tumor-promoting ability of 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) was compared with that of 12- O -tetradecanoylphorbol-13-acetate (TPA) and 1,8-dihydroxy-9-anthrone (anthralin) in SENCAR mice Although dose-response comparisons indicated that chrysarobin was several orders of magnitude less potent than TPA for promoting papilloma formation, this anthrone was 15 to 2 times more potent than anthralin Maximal papilloma responses were achieved by 15 weeks of promotion with TPA whereas at least 25 weeks of promotion were necessary to achieve maximal papilloma responses with chrysarobin or anthralin indicating marked differences in tumor latency between the two classes of compounds Interestingly, at optimal promoting doses, chrysarobin gave a carcinoma response (22% with 03 carcinomas per mouse at 45 weeks) similar to that of TPA suggesting that this compound may be more efficient at promoting carcinomas than papillomas In two-stage promotion experiments, chrysarobin was incapable of functioning independently as a Stage I or II promoter despite its complete promoting activity Chrysarobin and TPA were compared at optimal promoting doses for their ability to induce: ( a ) skin edema, ( b ) epidermal hyperplasia, and ( c ) epidermal omithine decarboxylase In each case, distinct differences were noted between the two compounds When taken together, the data support the hypothesis that anthracene-derived skin tumor promoters work at least in part by a mechanism different from the phorbol esters

Abstract: This article reviews the history of selected therapeutic agents for psoriasis: arsenic (including Fowler's solution), ammoniated mercury, chrysarobin and anthralin, tars, aminopterin and methotrexate, and corticosteroids The developers of these drugs paved the way for the new and improved treatments available today for the treatment of psoriasis

Abstract: The characteristics of the skin tumor promotion response with anthrone derivatives has been further examined in SENCAR mice. Chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone) was an effective skin tumor promoter when applied twice weekly with dose-dependent increases in both papillomas and squamous cell carcinomas between 25 and 100 nmol/mouse. A similar dose-response relationship for papilloma and carcinoma formation was observed when chrysarobin was applied once weekly. Interestingly, chrysarobin was approximately twice as active as a skin tumor promoter when applied once weekly versus twice weekly. Doses of 25, 100, and 220 nmol/mouse gave maximal papilloma responses of 2.90, 8.15, and 9.38 versus 0.73, 4.70, and 5.42 papillomas/mouse, respectively, in mice initiated with 25 nmol 7,12-dimethylbenz(a)anthracene. Thus, unlike 12- O -tetradecanoylphorbol-13-acetate (TPA), where a twice weekly application frequency is optimal, application of anthrone promoters such as chrysarobin once weekly is a more optimal frequency for papilloma development. Chrysarobin was also a much more effective skin tumor promoter when the start of promotion was delayed by an additional 10 weeks. Thus, groups of mice initiated with 10 nmol 7,12-dimethylbenz(a)anthracene and having promotion started in either the 3rd or the 13th week after initiation had maximal responses of 5.6 or 11.0 papillomas/mouse, respectively. In addition, the rate of papilloma development was faster in the delayed promotion group. The progression of papillomas to carcinomas was examined in all chrysarobin-treated groups and compared with three groups of mice treated with 3.4 nmol TPA. After 60 weeks of promotion, the anthrone promoter-treated groups had carcinoma:papilloma ratios 2.5 to 5.0 times higher than the TPA-treated groups. This was due primarily to the fact that similar carcinoma responses were observed in both anthrone- and TPA-treated mice at optimal promoting doses whereas the papilloma responses were significantly lower in the former groups. The data suggest that anthrone derivatives are very efficient tumor promoters. The results are further discussed in terms of mechanisms of skin tumor promotion.