A course of very small doses of DMBA, each of them allegedly with no promoting potency, acts with clear synergistic effect as a strong promoter of DMBA-initiated mouse skin carcinogenesis. A comparison of the tumorigenic and carcinogenic effects of DMBA (7,12-dimethylbenz-alpha-anthracene) and TPA (12-O-tetradecanoyl-phorbol-13-acetate) used as initiators and promoters in classical two-stage experimental protocols.
A carcinogen has recently been defined as an agent that causes a neoplasm by a two-step process involving initiation and promotion. The difference between the two steps is said to be qualitative rather than quantitative. According to this theory, the hydrocarbon carcinogen, 7,12-dimethylbenz-alpha-anthracene (DMBA) has both initiating and promoting properties, and it has been claimed that when the dose level is lowered, the promoting activity is first reduced while its initiating activity is retained, until at a small dose even the promoting property has completely disappeared, and only the initiating property remains. The theory also says, however, that for carcinogens individual doses are additive, and for pure initiators individual doses are additive even at subthreshold doses. Promoters are said to act in a synergistic way on initiated skin, and a threshold exists below which there is no effect. Experiments were carried out to test the validity of these claims. DMBA was applied twice a week in very small (10 or 4 nmol) doses to the skin of hairless mice, with or without previous initiation. When, after DMBA initiation, DMBA or 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were applied twice a week at small equimolar doses, a real synergistic effect, said to characterize promotion, was obtained with DMBA also, and with an even higher tumor crop and many more carcinomas than those elicited by TPA. Promotion with repeated doses of 10 nmol DMBA resulted in very significantly more carcinomas than with 4 nmol DMBA, which again gave more carcinomas than promotion with 10 nmol TPA. Repeated doses of TPA alone gave a 9% tumor rate, and TPA is thus a complete carcinogen. Reverse experiments were not innocuous. These results contradict the hypothesis that very small doses of DMBA have only initiating properties with only additive and not synergistic effects, and that TPA is only a promoter. It is most probable that the difference between the tumorigenic and carcinogenic effects of DMBA and TPA is not qualitative, but quantitative. TPA is highly toxic; it induces cell death followed by pronounced regeneration, and even DNA alterations. It is a complete, but weak carcinogen. DMBA is a strong complete carcinogen, binding covalently to DNA and altering it in various ways, but in equimolar doses it is less acutely toxic than TPA.(ABSTRACT TRUNCATED AT 400 WORDS)
Iversen
O H
OH
Institute of Pathology, University of Oslo, Norway.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced*; D004357:Drug Synergism; D051379:Mice; D008812:Mice, Hairless; D010212:Papilloma / Q000139:chemically induced*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013223:Statistics as Topic; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000633:toxicity*
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate