EVIDENCE FOR A NEW MODEL OF TUMOR PROGRESSION FROM CARCINOGENESIS AND TUMOR PROMOTION STUDIES WITH 7-BROMOMETHYLBENZ[A]ANTHRACENE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (5) , 2034-2041
Abstract
7-Bromomethylbenz[a]anthracene (BrMeBA) is a modest initiator of tumors in mouse skin and a powerful promoter. Evidence has also been presented that carcinomas and papillomas arising in mouse skin from a 2-stage induction regimen (initiation and promotion) originate in 2 separate populations, rather than representing progressive stages on a single pathway. Ten nmol of BrMeBA applied biweekly to female SENCAR mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA)is an effective promoting dose. The question of whether BrMeBA or its solvolysis product, 7-hydroxymethylbenz[a]anthracene, is the effective promoter was tested in Charles River CD-1 mice, in which 90 nmol, of BrMeBA appiled weekly following a single dose of 200 nmol of DMBA induced papillomas in 17 wk (median induction time) and carcinomas in 43 wk after beginning of promotion. Without DMBA initiation, papillomas appeared 11 wk later in much lower yield, while carcinomas appeared 14 wk later. Animals treated with 7-hydroxymethylbenz[a]anthracene for 82 wk had developed only 16 tumors in 8 animals (initiated) or 6 tumors in 5 animals (uninitiated), with survivals of 18 of 30 and 19 of 30, respectively. In SENCAR mice treated with 90, 30, or 10 nmol of BrMeBA biweekly, the ratio of total carcinomas to total papillomas in initiated mice was about half that in uninitiated mice, due primarily to a large reduction in papilloma incidence in uninitiated mice. When adjusted for the number of papillomas, the risk of developing the 1st carcinoma at any time was dependent only on the dose of BrMeBA and not on whether DMBA was given first. An attempt to inhibit BrMeBA promotion with the antiinflammatory steroid fluocinolone acetonide resulted in inhibition of DMBA-initiated papillomas but had no effect on the carcinoma latent period or incidence. The results are explained in terms of new models of tumor progression which suggest either that promoters with the capabilities of 12-O-tetradecanoylphorbol-13-acetate can divert cells at a minimum level of initiation from progression to cancer or that initiation can create at least 2 populations of altered cells, one (or more) of which is less likely to progress to cancer than normal cells.

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