INITIATING ACTIVITY OF 8 PYROLYSATES OF CARBOHYDRATES IN A 2-STAGE MOUSE SKIN TUMORIGENESIS MODEL

Tumor initiating potential was tested for eight pyrolysates of carbohydrates in a two-stage mouse skin carcinogenesis model using 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The pyrolysates were levoglucosan (LG-I), levoglucosenone (LG-II), furfural (FF), 5-(hydroxymethyl)-2-furfural (HMF), glyoxal (GL), methylglyoxal (MGL), 3-deoxy-D-glucosone (DG) and thiazolidine (TZ). The total initiating doses were 200-mu-mol for LG-I and DG, 25-mu-mol for LG-II and 500-mu-mol for FF, HMF, GL, MGL and TZ. 7,12-Dimethylbenz[a]anthracene (DMBA) was used as a positive control agent applied to a total dose of 100-mu-g. All compounds were topically administered to the dorsal skin twice weekly for 5 weeks with or without TPA treatment for the following 47 weeks. In conjunction with promotion TZ induced skin tumors in 40% of the mice (average 0.65 tumors/mouse), FF in 25% (0.40/mouse), LG-I in 25% (0.35/mouse) and LG-II, HMF, DG and GL in 10-20% (0.11-0.25/mouse) respectively whereas DMBA induced skin tumors in 100% of the animals (6.7/mouse). MGL did not induce any tumors during the experiment and no tumors appeared in any of the groups treated with test chemicals alone. As assessed by Fisher's exact test, tumor incidences were significant in the TZ (0.01 < P < 0.05) and DMBA (P < 0.01) groups as compared with the dimethylsulfoxide (DMSO) followed by TPA groups (5%, 0.05/mouse). Statistical analyses with Peto's trend test revealed significant tumor development in the LG-I (P < 0.01), LG-II (0.05 < P < 0.01), FF (0.01 < P < 0.05) and TZ (P < 0.01) followed by TPA groups (compared with DMSO + TPA). The results indicate that LG-I, LG-II, FF and TZ potentially possess tumor initiating activity, while HMF, GL, MGL and DG do not, as judged by the statistical analysis based on the incidences and development of the skin papillomas and/or carcinomas. A positive correlation between tumor initiating potential and clastogenic activity based on calculated ID50 (50% initiating dose) and published CD20 (20% clastogenic dose) values was evident for LG-II, FF and TZ, while LG-I was an exception.