Protection against 12-O-tetradecanoylphorbol-13-acetate induced skin-hyperplasia and tumor promotion, in a two-stage carcinogenesis mouse model, by the 2,3-dimethyl-6 (2-dimethylaminoethyl)-6H-indolo-[2,3-b]quinoxaline analogue of ellipticine

The effects of topical applications of 2,3-dimethyl-6(2-dimethylaminoethyl) -6H-indolo-[2,3-b]quinoxaline (B-220), on 12-O-tetradecanoylphorbol-13-acet ate (TPA) or benzoylperoxide (BPO) induced promotion of skin tumors and hyp erplasia were studied in female SENCAR mice. Papillomas were induced by ini tiation with 7,12-dimethylbenz[a]anthracene (DMBA), followed by promotion b iweekly with TPA or BPO. Administration of B-220 1 h before TPA promotion r esulted in a prolonged latency period of tumor appearance and a significant ly reduced (up to 15% of positive controls) papilloma yield at 20 weeks. Mo reover, if B-220 treatment was terminated after 20 weeks and TPA treatment continued, papilloma development resumed indicating that initiated tumor ce lls were still present but were unable to grow with B-220 present. If B-220 pretreatment was not given during the first 10 weeks of TPA promotion, inc idence at 20 weeks was not reduced but tumor multiplicity was still decreas ed. In addition a marked reduction of the TPA induced sustained epidermal h yperplasia was observed in the long term experiment. Neither the inflammato ry response nor the increase in the number of apoptotic cells seen in short term experiment after a single TPA treatment were inhibited by B-220. B-22 0 administration before BPO promotion had no effect on the appearance of BP O induced papillomas or epidermal hyperplasia, suggesting that TPA and BPO promote tumor formation via at least partially different mechanisms. In exp eriments where B-220 was applied topically 1 h before DMBA initiation, litt le or no effect was seen. No morphological changes in mouse skin due to lon g term exposure (two times/week, 39 weeks) to B-220 were found. In conclusi on, we present evidence that B-220 is a potent inhibitor of mouse skin tumo r promotion by TPA, but has little effect on the initiation step or the sur vival of initiated cells. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.