mezerein and Cocarcinogenesis

Topics: Animals; Carcinogens; Cocarcinogenesis; Diterpenes; Epidermal Cells; Fluocinolone Acetonide; Mice; Neoplasms, Experimental; Ornithine Decarboxylase; Phorbol Esters; Polyamines; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

We have measured the levels of thioredoxin, thioredoxin reductase and glutaredoxin enzyme activity in mouse skin following topical application of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC) activator and tumor promoter. The specific activity of thioredoxin and thioredoxin reductase in extracts from normal epidermis increased by 40 and 50%, respectively, after single or multiple application of TPA. Multiple applications (twice per week for 2 weeks) of TPA increased glutaredoxin activity by >300%. Induction of the proteins lasted several days. Other PKC activators, like 12-O-retinoylphorbol 13-acetate, mezerein, 1-oleoyl-2-acetylglycerol and the calcium ionophore A23187, also induced all the enzyme activities. Phorbol and 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate, weak activators of PKC, selectively induced the thioredoxin system only and did not influence glutaredoxin activity. Multiple applications of TPA to tumor initiated (7,12-dimethyl[a]benzanthracene-treated) skin resulted in elevated levels of both the thioredoxin and glutaredoxin systems when examined 6 days after the last phorbol ester treatment. Induction of thioredoxin, thioredoxin reductase and glutaredoxin activities by TPA and calcium ionophores may play a general role in the epigenetic mechanism of tumor promotion via thiol redox control mechanisms.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Calcimycin; Calcium; Carcinogens; Cocarcinogenesis; Diglycerides; Diterpenes; Enzyme Activation; Enzyme Induction; Epidermis; Female; Fluocinolone Acetonide; Gene Expression Regulation; Glutaredoxins; Glutathione; Ionophores; Mice; Oxidation-Reduction; Oxidoreductases; Phorbol Esters; Protein Kinase C; Proteins; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Thioredoxin-Disulfide Reductase; Thioredoxins; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

We earlier showed that a polyphenolic fraction isolated from green tea (GTP) affords protection against tumor promotion and tumor progression in SENCAR mouse skin. The present study was designed to further evaluate the protective effect of GTP against the induction and subsequent progression of papillomas to squamous cell carcinomas (SCCs) in experimental protocols where papillomas were developed with a low or high probability of their malignant conversion. Topical application of GTP (6 mg/animal) 30 min prior to that of 12-O-tetradecanoylphorbol-13-acetate (TPA) either once a week for 5 weeks (high risk TPA protocol) or once a week for 20 weeks (low risk TPA protocol) or mezerein (MEZ) twice a week for 20 weeks (high risk MEZ protocol) in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin resulted in significant protection against skin tumor promotion in terms of tumor incidence (32-60%), multiplicity (49-63%) and tumor volume/mouse (73-90%) at the termination of the experiment at 20 weeks. In three separate malignant progression experiments when papilloma yield in DMBA-initiated and TPA or MEZ promoted low and high risk protocols was stabilized at 20 weeks, animals were divided into two subgroups. These animals were either topically treated twice weekly with acetone (0.2 ml/animal, spontaneous malignant conversion group) or with GTP (6 mg/animal in 0.2 ml acetone) for an additional period of 31 weeks. During these treatment regimens, all suspected carcinomas were recorded and each one was verified histopathologically either at the time when tumor-bearing mouse died/moribund or at the termination of the experiment at 51 weeks. GTP resulted in significant protection against the malignant conversion of papillomas to SCC in all the protocols employed. At the termination of the experiment at 51 weeks, these protective effects were evident in terms of mice with carcinomas (35-41%), carcinomas per mouse (47-55%) and percent malignant conversion of papillomas to carcinomas (47-58%). The kinetics of malignant conversion suggest that a subset of papillomas formed in the early phase of tumor promotion in all the protocols had a higher probability of malignant conversion into SCCs because all the positive control groups (acetone treated) produced nearly the same number of carcinomas (33-38 in a group of 20 animals) at the end of the progression period. In the GTP-treated group of animals the number of carcinomas formed was less (14-20 in a group of 20 anima

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antioxidants; Carcinoma, Squamous Cell; Catechin; Cocarcinogenesis; Disease Progression; Diterpenes; Flavonoids; Mice; Mice, Inbred SENCAR; Papilloma; Phenols; Plant Extracts; Polymers; Skin Neoplasms; Tea; Terpenes

To develop mouse strains useful for studies of susceptibility and resistance to the induction of skin tumors, three new inbred SENCAR strains were independently derived by random inbreeding of outbred SENCAR mice. Characterization of these mice for sensitivity to skin tumor development indicated that mice of all three strains displayed increased sensitivity to initiation by 7,12-dimethylbenz[a]anthracene (DMBA), urethane, or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). Promotion by mezerein as well as carcinogenesis by repeated treatment with DMBA or MNNG produced papillomas with a high frequency of conversion to squamous cell carcinomas (SCCs). Compared with outbred SENCAR mice, development of both squamous papillomas and carcinomas was increased at least two-fold by all protocols tested. The F1 hybrid between SENCARA/Pt males and resistant BALB/cAnPt females was resistant to the induction of both papillomas and SCCs after initiation by 2 microg of DMBA and promotion by 20 weekly applications of 2 microg of TPA. Papillomas developed in all of the SENCARA/Pt mice, none of the BALB/cAnPt mice, and 12% of the F1 progeny. Thus, at these doses of initiator and promoter, resistance was incompletely dominant in the F1 hybrid. However, the responsiveness of the F1 mice could be increased substantially by increasing the dose of the promoter.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Carcinoma, Squamous Cell; Cocarcinogenesis; Disease Susceptibility; Diterpenes; Female; Male; Methylnitronitrosoguanidine; Mice; Mice, Inbred BALB C; Mice, Inbred SENCAR; Papilloma; Phenotype; Sensitivity and Specificity; Skin Neoplasms; Terpenes; Urethane

Previous studies in our laboratory have shown that promotion of two-stage skin carcinogenesis in the SENCAR mouse model was inhibited in mice fed energy-restricted/low-fat diets, and elevated in mice fed high-fat diets. Studies reported here describe the influence of dietary energy restriction from fat and carbohydrate (ER) or high-fat (HF) diet on early promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) and on late promotion by mezerein (MEZ). Female SENCAR mice were initiated topically with 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA) in 0.2 ml acetone at 9 weeks of age. For the following 2 weeks they received 3.2 nmol TPA in 0.2 ml acetone twice weekly, and for the next 16 weeks they received 10 nmol MEZ in 0.2 ml acetone twice weekly. All mice were fed control diet before TPA began and following the final MEZ treatment. Control mice received the control diet (c) throughout TPA and MEZ (C/C). The six experimental groups received: (1) ER diet throughout TPA and MEZ treatment (ER/ER); (2) HF diet throughout TPA and MEZ treatment (HF/HF); (3) ER during TPA (ER/C); (4) ER during MEZ (C/ER); (5) HF diet during TPA (HF/C); or (6) HF diet during MEZ (C/HF). Papilloma incidence and multiplicity, and carcinoma incidence were similarly reduced in the mice fed ER diet during MEZ (ER/ER and C/ER groups). In comparing the HF groups, papilloma multiplicity was highest in the HF/C group, intermediate in the C/C and lowest in the C/HF groups, but papilloma and carcinoma incidences were not modified by the HF diet protocols. Papilloma regression was greater in the C/HF group (27%, 4 regressions/15 tumor-bearing mice) than in the controls (0/18) during weeks 21-23, immediately following the end of MEZ treatment (P < 0.05).

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Carcinogens; Cocarcinogenesis; Diet, Fat-Restricted; Dietary Carbohydrates; Dietary Fats; Diterpenes; Energy Intake; Female; Mice; Mice, Inbred SENCAR; Papilloma; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate

The dorsal skins of 6-8 week old female SENCAR mice were initiated with a single application of 10 nmol of 7,12-dimethylbenz[a]anthracene (DMBA) and subsequently promoted twice/week with topical applications of vitamin E (dl-alpha-tocopherol, 80 mumol/treatment). Vitamin E from two separate commercial suppliers was tested. For comparison, a group of similar mice, also initiated with DMBA, was promoted twice/week with the known tumor promoter 12-O-tetradecanoylphorbol-13- acetate (TPA, 2 micrograms/treatment). Papillomas appeared 39 and 50 days respectively after promotion began with vitamin E from the two different sources, as compared with 32 days in the group receiving TPA promoted. Hundred per cent of TPA-promoted animals and 92-96% of the vitamin E-promoted mice developed tumors. A maximum of 15 papillomas/animal appeared in the TPA-promoted mice. The two vitamin E preparations were somewhat less effective than TPA and showed different relative potencies, producing about seven and 12 papillomas per animal respectively. Unlike TPA, vitamin E showed very little ability to produce an inflammatory response in skin. To test whether initiated cells that did not appear as papillomas after vitamin E promotion were still viable, and had proceeded past stage I of promotion (conversion), the group that developed 12 papillomas/animal from vitamin E promotion was further promoted with mezerein, a stage II promoter. In this group, the papilloma frequency then increased to approximately 17/animal. The animals were followed over the course of their lifespan and monitored for skin carcinomas. In the TPA-promoted group 64% of the mice developed carcinomas, while the two vitamin E-promoted groups showed 48 and 60% incidence respectively. These results indicate that topically applied vitamin E acts as a complete tumor promoter in DMBA-initiated mouse skin, with an efficiency approaching that of TPA. Since vitamin E is a powerful antioxidant, they also suggest that reduction of cellular oxidant levels may trigger the tumor promotional process, and it may therefore be prudent to avoid repetitive or prolonged topical exposure of human skin to antioxidants like vitamin E.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenicity Tests; Carcinogens; Carcinoma; Cocarcinogenesis; Diterpenes; Female; Mice; Papilloma; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Vitamin E

XB2 cells, a teratocarcinoma derived cell line of keratinocyte lineage, have been shown to proliferate and differentiate in low calcium medium (0.03 mM Ca2+) at a density of 500 cells/9.6 cm2 without the need for fibroblast feeder layers or conditioned medium. The degree of differentiation can be assessed by measurements of keratin production and stratification of colonies of cells. Both of these parameters, as well as the proliferative capacity of the cells, can be altered by treatment of the cultures with various promoting agents and non-genotoxic carcinogens. Treatment with teleocidin and 12-O-tetradecanoyl phorbol-13-acetate induced large increases in proliferation, stratification and keratinization; mezerein-treated cells showed increased stratification at higher doses; butylated hydroxyanisole treatment resulted in hyperkeratinization and hyperstratification to lower levels than that seen with the phorbol-ester-like promoters; butylated hydroxytoluene had purely hyperproliferative effects. We suggest that this culture system may provide a useful model for studies of the mechanism of promotion and non-genotoxic carcinogenesis in epithelial tissues.

Topics: Animals; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Calcium; Carcinogens; Cell Differentiation; Cell Division; Cocarcinogenesis; Diterpenes; Keratins; Lyngbya Toxins; Mice; Teratoma; Terpenes; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Susceptibility of hairless inbred S/RV Cri-ba or Bare mice to skin tumor development with suboptimal doses of 7,12-dimethylbenz[a]anthracene (DMBA), DMBA-TPA two stage protocol and two stage promotion using 12-O-tetradecanoylphorbol-13-acetate (TPA) as sub-stage 1 promoter and mezerein (MEZ) or phorbol retinoate acetate (PRA) as substage 2 promoter was determined. A single application of 40 or 20 nmol DMBA induced 4-5 papillomas per mouse 40 weeks after initiation while no tumors appeared after similar treatment with 10 or 4 nmol DMBA. Dose response studies for DMBA initiation revealed that 10 nmol DMBA dose saturated the sites for initiation in the resting epidermis. In two stage promotion experiments, MEZ was found to be a potent stage 2 promoter, while PRA acted as a weak complete promoter.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenicity Tests; Cocarcinogenesis; Diterpenes; Dose-Response Relationship, Drug; Female; Mice; Mice, Hairless; Papilloma; Phorbol Esters; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate

Several structurally different tumor promoters altered to various degrees both glutathione (GSH) peroxidase (EC 1.11.1.9) and ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17) activities in mouse epidermis in vivo. At 5 h after their application to the skin, the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the stage 2 promoter mezerein were the most potent in inhibiting GSH peroxidase activity and inducing ODC activity. In comparison, the effects of anthralin, phorbol-12,13-didecanoate, benzoyl peroxide, H2O2, and phorbol-12,13-dibenzoate were much smaller, whereas the nontumor promoter phorbol, the hyperplastic agent ethyl phenylpropiolate, and the stage 1 promoter 4-O-methyl TPA did not alter GSH peroxidase and ODC activities. Various treatments including i.p. injections of 40 micrograms of Na2SeO3 and 100 mumol of GSH and/or topical applications of 40 mumol of D-alpha-tocopherol (vitamin E) 20 or 15 min, respectively, before tumor promoter treatment inhibited in an additive manner the effects of either TPA or mezerein on both GSH peroxidase activity and ODC induction. Moreover, these Na2SeO3, GSH, and/or vitamin E treatments inhibited in the same additive manner the tumor-promoting activity of TPA in the initiation-promotion protocol. However, when tested in the 2-stage promotion protocol with 4 doses of TPA followed by twice weekly applications of mezerein, Na2SeO3 plus vitamin E and GSH plus vitamin E treatments inhibited remarkably the tumor-promoting activity of mezerein but were ineffective in the first stage of promotion. The sequence and magnitude for the effects of 7,12-dimethylbenz[alpha]anthracene (DMBA) on GSH peroxidase and ODC activities were very different from those of the tumor promoters. In contrast with their antitumor-promoting activity, the treatments with Na2SeO3 plus vitamin E and GSH plus vitamin E failed to inhibit the carcinogenicity of a single large dose of DMBA and even enhanced the induction of skin tumors by repeated applications of subcarcinogenic doses of DMBA. These results suggest that the promoting component of DMBA carcinogenesis may be different from that of TPA. Moreover, the anticarcinogenicity of Na2SeO3, GSH, and vitamin E may be linked to their ability to facilitate or enhance the activity of the natural GSH-dependent antioxidant protective system of the epidermal cells during the later stages of skin tumor promotion.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cocarcinogenesis; Diterpenes; Enzyme Induction; Female; Glutathione; Glutathione Peroxidase; Mice; Ornithine Decarboxylase; Papilloma; Selenium; Skin Neoplasms; Terpenes; Time Factors; Vitamin E

Application of the alkane n-dodecane to the dorsal skin of 6-8 week old female SENCAR mice initiated with 10 nmol dimethylbenz[a]anthracene led to papilloma formation in the majority of treated animals. Compared to the potent phorbol diester 12-O-tetradecanoylphorbol-13-acetate (TPA), n-dodecane was several orders of magnitude less potent on a dose basis, and maximal papilloma response required more extended application (22 weeks for 50 mg dodecane compared to 12 weeks for 2 micrograms TPA). In two-stage promotion experiments n-dodecane appeared to act as a stage II promoting agent at appropriate doses, being comparable in activity to mezerein--an agent with well-characterized activity of this type. Dodecane, unlike mezerein, did not induce the formation of a significant number of pyknotic cells, however, suggesting that the weak promoting activity of dodecane in stage 1 was not a result of toxicity. In comparison with TPA, both mezerein and n-dodecane at promoting doses induced less sustained hyperplasia in SENCAR mouse skin, a finding also consistent with the proposal that n-dodecane is principally active in stage II of two-stage promotion models. Both agents induced ornithine decarboxylase activity in SENCAR mouse skin, the maximal induction being observed at apparently the same time after a single application.

Topics: Acetone; Alkanes; Animals; Cocarcinogenesis; Diterpenes; Female; Mice; Papilloma; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate

Intracutaneous injection of cholera toxin into mice induced epidermal hyperplasia to a greater extent than 12-O-tetradecanoylphorbol-13-acetate. It also induced adenylate cyclase and though weakly, ornithine decarboxylase of the epidermis. Cholera toxin, however, showed no tumor promoting activity in mouse skin carcinogenesis. In the single stage promotion, cholera toxin (50 ng) was injected once a week for 10 weeks into the skin of SENCAR mice initiated with 25 micrograms 7,12-dimethylbenz[a]anthracene, but no tumors developed. In the two-stage promotion test, cholera toxin (10-100 ng) was injected for one or two weeks into the initiated skin and then mezerein (4 micrograms) was applied twice a week for 18 weeks, but the toxin did not increase incidence or numbers of papillomas.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Cholera Toxin; Cocarcinogenesis; Cyclic AMP; Diterpenes; Enzyme Induction; Epidermis; Hyperplasia; Mice; Ornithine Decarboxylase; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate

Papillomas induced by standard initiation-promotion protocols progress to carcinomas at a low frequency. Experimental protocols were developed to elicit papillomas with a higher probability of malignant conversion. SENCAR mice initiated by 7,12-dimethylbenz[a]anthracene were promoted by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 5, 10, 20 or 40 weeks. With promotion for 10 weeks or more, a peak of papilloma incidence at 16-20 weeks was followed by a 35-40% decrease within 3 months. A much lower papilloma response was seen in mice promoted for 5 weeks, but these papillomas persisted. The yield of malignant tumors was similar in all four groups, with 20-25 carcinomas per group of 30 mice. Thus, the papillomas induced by the first few TPA treatments are much more likely to progress to carcinomas than those which appear later. In a separate study, initiated Charles River CD-1 mice were promoted with TPA for either 12 or 52 weeks. Acetone solvent treatment was begun at Week 13 in the group treated 12 weeks with TPA. At Week 16, the papilloma incidence was identical in the two groups of mice. However, by Week 28, the papilloma yield in the continuous TPA group had increased and was twice that of the acetone group, in which papillomas had regressed. The first carcinoma arose 14 weeks earlier with continuous TPA, but the final number of carcinomas per group of 40 mice was 17 with TPA and 20 with acetone. Neither the increase in papillomas in TPA-treated mice nor the regression of papillomas after cessation of promotion with TPA affected the final carcinoma yield. This result suggests that TPA-dependent papillomas are very unlikely to progress to carcinomas. In a third experiment, promotion of initiated SENCAR mice with mezerein resulted in a small number of papillomas which had a much higher probability of progression to carcinomas than the large number of papillomas promoted by TPA. The ability to induce papillomas promoted by TPA. The ability to induce papillomas with a known probability of conversion to carcinomas will facilitate the identification of markers associated with malignant progression.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma; Cocarcinogenesis; Diterpenes; DNA; Female; Keratins; Mice; Mice, Inbred Strains; Papilloma; Probability; Terpenes; Tetradecanoylphorbol Acetate; Time Factors

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the non-promoter mezerein both induce ornithine decarboxylase activity in mouse epidermis by a route which can be blocked by indomethacin. In two-stage tumor promotion experiments in mice with mezerein as the stage II promoter, TPA was effective as the stage I promoter whether it was applied before or after an initiating dose of 7,12-dimethylbenz[a]anthracene (DMBA). There appear to be at least 4 events in promotion, only 3 of which are caused by second stage promoters.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Cocarcinogenesis; Diterpenes; Enzyme Induction; Female; Mice; Models, Biological; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Papilloma; Phorbols; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Time Factors

Topics: Carcinogens; Cell Membrane; Cocarcinogenesis; Diterpenes; Free Radicals; Hydrogen Peroxide; Neutrophils; Oxygen; Phorbol Esters; Phorbols; Protease Inhibitors; Superoxides; Terpenes; Tetradecanoylphorbol Acetate; Vitamin A

Topics: Alkaloids; Antipain; Cocarcinogenesis; Diterpenes; Humans; Indoles; Inflammation; Lyngbya Toxins; Neutrophils; Oxygen; Phorbol Esters; Phorbols; Superoxides; Terpenes; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin A

The effects of nonpromoting and weakly promoting diterpenes on skin tumor promotion by 12-O-tetradecanoylphorbol 13-acetate (TPA) were investigated. When phorbol and phorbol 12,13-diacetate (both nonpromoting) were given simultaneously with TPA after 7,12-dimethylbenz[a]-anthracene (DMBA) initiation in female mice, they had no effect on TPA promotion. However, the nonpromoter 4-O-methyl-TPA and the weak promoter mezerein were found to inhibit TPA promotion in a dose-dependent manner when given simultaneously with TPA. Because mezerein was found to be an effective inhibitor of TPA promotion when given simultaneously and because it induces many biological responses similar to those to TPA, the capacity of mezerein to act as an incomplete promoter in a two-stage promotion protocol was also investigated. Twice-weekly applications of 1,2, or 5 mug of TPA for 2 weeks after DMBA initiation produced 0, 0, and 0.5 papilloma per mouse, respectively, at 20 weeks. When the twice-weekly applications of TPA for 2 weeks were followed by twice-weekly treatments with 2 mug of mezerein for 18 weeks, the number of papillomas per mouse was 2.2, 3.5, and 9.0, respectively. Twice-weekly applications of 2 mug of TPA for 2 weeks followed by twice-weekly treatments with 1, 2, or 4 mug of mezerein for 18 weeks produced 2.1, 3.5, and 6.8 papillomas per mouse, respectively, in DMBA-treated mice. Twice-weekly doses as high as 40 mug of 4-O-methyl-TPA were not effective in producing tumors when given after a limited treatment with TPA; however, 4-O-methyl-TPA had weak activity as a first-stage promoter. The results suggest that although mezerein by itself is a weak promoter and mimics TPA in many biochemical and morphological effects it is a potent second-stage promoter in a two-stage promotion regimen.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Chemical Phenomena; Chemistry; Cocarcinogenesis; Diterpenes; Dose-Response Relationship, Drug; Drug Synergism; Female; Mice; Neoplasms, Experimental; Phorbol Esters; Phorbols; Skin; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate

Skin tumors in mice can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a noncarcinogenic tumor promoter. The initiation phase requires only a single application of either a direct-acting carcinogen or a procarcinogen which has to be metabolized before being active; it is essentially an irreversible step which probably involves a somatic cell mutation as evidenced by a good correlation between the carcinogenicity of many chemical carcinogens and their mutagenic activities. There is a good correlation between the skin-tumor-initiating activities of several polycyclic aromatic hydrocarbons (PAH) and their ability to bind covalently to epidermal DNA. Results from our laboratory as well as others suggest that "bay region" diol-epoxides are the ultimate carcinogenic form of PAH carcinogens. Potent inhibitors and stimulators of PAH tumor initiation appear to affect the level of the PAH diol-epoxide reacting with specific DNA bases. REcent data suggest that the tumor-promotion stage involves at least 3 important steps: (1) the induction of embryonic-looking cells (dark cells) in adult epidermis; (2) an increased production of epidermal prostaglandins and polyamines; (3) sustained proliferation of dark cells. Retinoic acid specifically inhibits step 2, whereas the anti-inflammatory steroid fluocinolone acetonide is a potent inhibitor of steps 1 and 3. The mechanism and the importance of a specific sequence for each step in chemical carcinogenesis in mouse skin will be discussed in detail.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benzopyrenes; Cocarcinogenesis; Diterpenes; DNA; Epidermis; Mice; Neoplasms, Experimental; Phorbol Esters; Polyamines; Skin Neoplasms; Terpenes