The
tumor-producing and skin-irritating activity of the antipsoriatic
drug dithranol and its 10-acyl analogues
butantrone (10-butyryl dithranol),
10-isobutyryl dithranol and
10-valeryl dithranol were studied in 650 SENCAR mice using a two-stage skin
carcinogenesis assay. An initiation with 20 micrograms of 7,12-dimethylbenz(alpha)anthracene (DMBA) was followed 2 weeks later by three applications per week of the test compounds in 50 microliter of
acetone for 21 weeks. In addition the compounds were studied without DMBA pre-treatment using application periods of 21 and 36 weeks. The concentration of
dithranol was the maximum tolerated, 3.5 mM. For the less irritating 10-acyl analogues 30 mM solutions were used. The first signs of skin irritation were observed after an application period of 1-2 weeks and the irritation continued to the end of the experiment in all groups except the
acetone controls.
Dithranol caused the most severe irritation although the differences between the groups were not pronounced. On histopathology, the majority of animals had
hyperplasia and other inflammatory changes of the skin. The first
papillomas appeared 8-11 weeks after initiation and the incidences of
papillomas at the end of the experiment were 85% (
dithranol 3.5 mM), 16% (
butantrone 30
mM), 36% (10-isobutyryl
dithranol 30 mM) and 50% (10-valeryl
dithranol 30 mM). Without initiation the incidences were 6 and 2% (
dithranol), 2 and 2% (
butantrone) and 2 and 0% (10-valeryl dithranol) in the 21- and 36-week studies, respectively. Histologically, the
papillomas were mostly squamous
papillomas and only a few
keratoacanthomas were found. It is concluded that the
tumor-producing and skin-irritating activity of
dithranol is clearly greater than that of
butantrone,
10-isobutyryl dithranol and
10-valeryl dithranol.