Amplification of Carcinogenesis by Non-Carcinogens — Diterpene Type Promoters and Models of Environmental Exposure

Summary

In the last 15 years the cocarcinogens of the polyfunctional di- terpene ester type originating from plants were established molecularly and biologically as non-carcinogenic amplifiers of carcinogenesis. Thus the long suspected concept of amplification of carcinogenesis by non- carcinogens was finally verified. In addition the new principle of “cryptic” cocarcinogens was detected in the form of higher esters of diterpenes. Besides for investigations in molecular cytology and molecular mechanisms of carcinogenesis, cocarcinogens of this type may be used in models of environmental exposure to investigate the role of cocarcinogens in general as possible carcinogenic risk factors of the human environment. Three model situations are devised and investigated: (i) Several polyfunctional diterpenes were detected to be present in roots of Croton flavens L. and identified as highly active irritants and cocarcinogens of the promoter type. The utilization of parts of this plant according to local habits may be suspected therefore to be responsible for the unusually high incidence of esophageal cancer on Curacao, (ii) Many but not all species of the Euphorbiaceae and Thyme- laeaceae families utilized as ornamentals were shown to contain irritant and cocarcinogenic diterpene esters. Provided intensive contacts are avoided with skin and/or by ingestion of plant parts, it is concluded that most likely an actual carcinogenic risk does not exist by maintenance of single species. However, it is called for epidemiological investigations of a possible risk in persons involved professionally in raising and handling of mass cultures of species of Euphorbiaceae and Thymelaeaceae containing irritants, (iii) It was shown that nectar collected by honey bees from certain species of Euphorbiaceae may contain irritant polyfunctional diterpenes of the promoter type. - The actual new findings i - iii suggest that in the etiology of human tumors besides solitary carcinogens, the classical first order carcinogenic risk factors, diterpene ester type co-carcinogens of the promoter type - non-carcinogenic amplifiers of carcinogenesis - may contribute. As compared to solitary carcinogens cocarcinogens of whatever type may be classified as second order carcinogenic risk factors.