Cocarcinogenesis and tumor promoters of the diterpene Ester type as possible carcinogenic risk factors

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Abstract
In the last 15 years the hypothetical concept of cocarcinogenesis has been substantiated by chemical, biochemical, and biologic investigation of the polyfunctional, diterpene mono- and diester type promoters (and stimulators) of initiation, originating from plant species. Thus, the long suspected concept of amplification of carcinogenesis by non-carcinogens was finally established. In addition, the new principle of “cryptic” cocarcinogens was detected in the form of low activity 20-esters of corresponding highly active polyfunctional diterpene mono- and diesters. Cryptic cocarcinogens require metabolic activation by esterases or lipases to become directly acting promoters and/or stimulators of initiation. It is suspected that cocarcinogens of the diterpene ester type may play a role as possible carcinogenic risk factors of the human environment, especially as environmental promoters. Apart from certain officinal or folk medical drugs derived from Euphorbiaceae and Thymelaeaceae, three etiologic models of possible human exposure to polyfunctional diterpenes are presently investigated: (i) The utilization according to local habits of roots and other parts of Croton flavens L. Such utilization was suspected to be responsible for the unusually high incidence of esophageal cancer on the island of Curacao. Several polyfunctional diterpenes of the tigliane type were detected to be present in the roots of the plant. They were identified as highly active irritants and as cocarcinogens of the promoter type in mouse skin. (ii) It was shown that many, but not all, species of the Euphorbiaceae and Thymelaeceae families utilized as ornamental plants in family homes, gardens, and parks contain irritant and cocarcinogenic diterpene esters. Provided intensive contacts are avoided with skin and/or by ingestion of plant parts, it appears most likely that an actual carcinogenic risk does not exist by raising and maintenance of single species of such plants. However, it is suggested that the existence of a possible occupational risk in persons involved professionally in raising and maintaining of mass cultures of species of Euphorbiaceae and/or Thymelaeaceae be clarified by epidemiologic investigations. (iii) It was shown that nectar collected by honey bees from species of Euphorbiaceae growing abundantly in certain locations contain irritant polyfunctional diterpenes of the promoter type. The results presented demonstrate for the first time that in the etiology of human cancer, besides well defined environmental solitary carcinogens also well defined and highly active environmental cocarcinogens, i.e., non-carcinogenic amplifiers of carcinogenesis, may play an important role. Environmental cocarcinogens of the diterpene ester type are capable to amplify initiation in prototype processes of cocarcinogenesis, such as initiation/promotion and stimulated initiation/promotion, and therefore may be considered complete cocarcinogens. As compared to environmental solitary carcinogens, the classical first order carcinogenic risk factors, environmental cocarcinogens may be considered second order carcinogenic risk factors. In this way the risk of cancer by envionmental carcinogens of whatever origin and nature may be graded to allow for more refined risk/benefit evaluations and thus for more appropriate preventive legislation.
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