Comparison of Complete Carcinogenesis and Tumor Initiation and Promotion in Mouse Skin: The Induction of Papillomas by Tumor Initiation-Promotion a Reliable Short Term Assay

Abstract

Skin tumors can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase), followed by repetitive treatment with a weak or noncarcinogenic tumor promoter. Using a two-stage system to induce tumors in Senear mice there is a very good dose-response relationship between the induction of the number of papillomas per mouse at early times (10 to 20 weeks) and the final carcinoma incidence after longer latency (20 to 50 weeks). This system can be used not only to determine the tumor initiating and promoting activities of a compound but if the agent is given repeatedly by itself one can also determine if it is a complete carcinogen, i.e., if it has both tumor initiating and promoting activity. With the exception of a few pure tumor initiators, there is in general a good qualitative and quantitative correlation between the ability of a polycyclic aromatic hydrocarbon (PAH) to act as a complete carcinogen and to act as a tumor initiator in mouse skin. In addition, if the agent is given concurrently with a known complete carcinogen or a tumor initiator one can also determine if the agent has co-carcinogenic or co-tumor initiating activity or even possibly anticarcinogenic activity. Likewise, if the agent is given concurrently with a known tumor promoter one can determine if the agent has co-promoting or anti-pro-moting activity. There is a good correlation between the tumor-initiating activities of PAH and their abilities to bind covalently to DNA. In addition, various inhibitors of PAH tumor initiation show a strong correlation with their abilities to inhibit the binding of the PAH to DNA and their anti-tumor initiating activities. There is also a good correlation between the promoting abilities of phorbol esters to promote tumors and their abilities to induce ornithine decarboxylase (ODC), cell proliferation and dark basal keratinocytes. When other nonpromoting hyperplastic agents are used, only dark cell induction correlates with promotion. Certain polyamines and prostaglandins can enhance phorbol ester tumor promotion. Anti-inflammatory steroids, retinoids, and protease inhibitors are potent inhibitors of tumor promotion. They inhibit tumor promotion by inhibiting either the 12-0-tetradecanoylphorbol-13-acetate (TPA) induced cell proliferation, ODC and/or dark basal keratinocytes. Certain weak promoters such as mezerein which mimics TPA in many biochemical and morphological effects are potent second step promoters in a two-stage promotion regimen.