The Relevance of the Mouse Papilloma Test as a Predictor of Retinoid Activity in Human Psoriasis

Abstract

The combination of the results of mouse antipapilloma tests with those from hypervitaminosis A tests in mice as the basis for calculating a therapeutic index has been used for more than 20 years in the search for retinoids as useful drugs in human dermatology. A number of retinoids identified as active or inactive when administered systemically in these mouse systems have gone into clinical trials; clinical results on 11 retinoids were available for a retrospective analysis on the predictive relevance of the mouse models for retinoid activity in human psoriasis. This analysis revealed that the therapeutic index in mice correctly identified eleven compounds and differentiated them into markedly active moderately active or inactive retinoids when subsequently used clinically in the treatment of various forms of psoriasis. Acidic retinoids were more difficult to assess than nonacidic ones and the therapeutic index appeared to underestimate their potency in humans. One retinoid, motretinide, showed a favorable therapeutic index but failed to demonstrate antipsoriatic activity in the clinic. The reason for this discrepancy is that humans and mice metabolize this compound differently. Thus, although chemically induced skin papillomas in mice reflect only certain analogies to human psoriasis and other keratinizing dermatoses, they may be considered a useful tool in the search for retinoids for the treatment of keratinization disorders.

v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: effects of phorbol esters and retinoic acid.

“…1B) (33). Indeed, mutagenized mouse skin has been used for many years to identify vitamin A derivatives with antikeratinizing properties (35). More recent evidence (for review, see ref.…”

Inhibition of Papilloma Formation by Analogues of 7,8-Dihydroretinoic Acid

“…The dose−response pattern was consistent, and significant numbers of treated mice were without tumors. At the highest dose (135.7 nmol) of 6b , its activity was similar to that of RA at 15.3 nmol, and its ED 50 (Table ) was about 4-fold of that of etretinate, the well-known and highly active analogue of ethyl retinoate. ,, The 2,4,6-trimethylphenoxy analogue ( 6a ) was modestly active (ED 50 , 60 nmol), and the 2-methyl-4-fluorophenoxy analogue ( 6f ) appeared to have modest activity at the only dose (45.9 nmol) at which it was tested (Table ). None of the three 7-aza-8-oxo-dihydro-RA analogues ( 13b − d ) inhibited papilloma development at the tested doses.…”

“…Replacement of the trimethylcyclohexenyl group of the vitamin-A family of compounds with a substituted-benzene group relates the retinoids of this report to the aromatic retinoids, ,,, many of which have high activity in the mouse-skin papilloma assay and in other retinoid assays. Methyl and methoxy groups on the benzene ring of the 7-hetero-7,8-dihydroretinoids were chosen to resemble the pattern of substituents on some of the aromatic retinoids (e.g., the TMMP analogues) and the cyclohexenyl group of RA; also, the tert -butyl group was selected because of its important influence on the activity of the “retinobenzoic acids” of Shudo and co-workers. , …”

“…of that of etretinate, the well-known and highly active analogue of ethyl retinoate. 3,4,19 The 2,4,6-trimethylphenoxy analogue (6a) was modestly active (ED 50 , 60 nmol), and the 2-methyl-4-fluorophenoxy analogue (6f) appeared to have modest activity at the only dose (45.9 nmol) at which it was tested (Table 2). None of the three 7-aza-8-oxo-dihydro-RA analogues (13b-d) inhibited papilloma development at the tested doses.…”

“…However, an alternative route was postulated and brought to fruition. The route consists of treatment of 7 with trimethylsilyl cyanide to produce a trimethylsilyl cyanohydrin [15][16][17] compound proved to be sufficiently reactive to acylate most of the aromatic amines (19), but acylation of some of the representatives of 19 proceeded slowly. Therefore, some of the 7-aza-8-oxo-7,8-dihydroretinoates (12) were prepared by employing the acyl bromide (18), which was obtained by hydrolyzing 17 and converting the resulting 14 to 18.…”