Chemical Carcinogenesis In Mouse Skin Research Articles

C-fos proto-oncogene expression on the tumors evoked by chemical carcinogenesis in mouse skin

C-fos proto-oncogene expression on the tumors evoked by chemical carcinogenesis in mouse skin

Ionizing radiation enhances malignant progression of mouse skin tumors.

Chemical carcinogenesis in mouse skin has been divided into the process of initiation, promotion and progression. Recently we have shown that ionizing radiation acts as an initiator in this model system. In this paper we describe a three-stage experiment using ionizing radiation in the third stage of mouse skin carcinogenesis. CD-1 mice were initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) followed by biweekly promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). After 20 weeks of promotion, the animals were treated with either acetone, TPA (twice a week for 2 weeks) or eight fractions of 1 MeV electrons (1 Gy/fraction over a period of 10 days). The conversion of papillomas to squamous cell carcinomas was 80% for animals treated with ionizing radiation compared with 25% for tumor-bearing animals treated with TPA. Ionizing radiation increased the number of cumulative carcinomas per group. The lack of an increase in the number of cumulative papillomas per group due to ionizing radiation suggests that the dose and fractionation protocol used in this study enhanced the progression of pre-existing papillomas.

Expression of long terminal repeat (LTR) sequences in carcinogen-induced murine skin carcinomas

RNA sequences homologous to the Long Terminal Repeat (LTR) sequence of Moloney Murine Leukemia Virus proviral DNA are expressed in murine squamous cell carcinomas of the skin induced by chemical carcinogens. These transcripts range in size from 8.2 to less than 2.4 kb but their size profile varies between individual tumors. These RNAs are not detected in the poly A+ RNA fraction obtained from the epidermis of control mice or carcinogen induced skin papillomas. The poly A+ RNAs from the livers and spleens of some of the mice with skin carcinomas also revealed LTR related sequences, whereas these RNAs were not detected in the livers and spleens of control mice or of carcinogen-treated mice that did not develop carcinomas. Thus, chemical carcinogenesis in mouse skin is associated with constitutive expression of endogenous retrovirus related sequences in the carcinomas as well as in certain apparently normal host tissues.

1α,25-Dihydroxyvitamin D 3 inhibits phorbol ester-dependent chemical carcinogenesis in mouse skin

The effect of topical application of 1α,25-dihydroxyvitamin D 3 (1α,25-(OH) 2D 3) on the promotional phase of skin tumor formation in mice was evaluated using 7,12-dimethylbenz[a]anthracene as the tumor initiator and 12-O-tetradecanlylphorbol-13-acetate (TPA) as the tumor promoter. Fifteen weeks of twice weekly topical application of 1α,25-(OH) 2D 3 1 hour prior to topical treatment with 16 nmol of TPA inhibited tumor formation in a dose-dependent manner. Doses of 0.25–0.50 nmol of the vitamin D 3 metabolite inhibited tumor formation approximately 50% and had no significant effect on the survival or weight gain of the mice. These results indicate that in addition to maintaining calcium homeostasis and affecting the growth and differentiation of certain neoplastic cells, 1α,25-(OH) 2D 3 can also suppress the formation of chemically induced tumors.

Multistage chemical carcinogenesis in mouse skin.

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.

Dose-related inhibition of chemical carcinogenesis in mouse skin by caffeine.

THERE is some evidence that caffeine protects against the effects of chemical carcinogens1,2. Leitner and Shear3 found a reduction in the effectiveness of benzo(a)pyrene as a carcinogen when it was administered by subcutaneous injection together with various purines, including caffeine. An enhancement of the antitumour effect of 1,3-bis(2-chloroethyl)-1-nitrosourea by caffeine has been reported4 but whether the caffeine acts as an anticarcinogen or as a membrane-active agent (a property of caffeine which has been demonstrated5) is not clear. Tumour production in vivo has been shown to be partially suppressed by theophylline6 and it is possible that caffeine which is chemically closely related to theophylline may similarly suppress tumour production.

In vitro binding of labeled 20-methylcholanthrene to a specific cytosol-protein

In vitro binding kinetics and specificity of [20- 3H]methylcholanthrene ([ 3H]MC) interaction with mouse epidermal cytosol in the presence or absence of microsomal metabolizing systems were investigated. After an incubation period of 30 roin at 22°, the samples were dialyzed, subjected to gel filtration, ultrafiltration, and analyzed by 7 % basic polyacrylamide gel electrophoresis. A major portion of the binding appeared in a single peak on the gel which had the same mobility as bovine or mouse serum albumin. In vitro competition by other hydrocarbons or by promoters for binding of MC to this cytosol receptor protein showed an impressive correlation to carcinogenic and promoting activities. Essentially 100% of the MC bound to cytosol without a microsomal metabolizing system was non-covalent. However, binding Of MC to cytosol in the presence of microsomes plus reduced NADPH was party covalent which has previously been reported by Grover and Sims and Meunier and Chaveau. When bovine (BSA) or mouse serum albumin (MSA) was incubated with radioactive MC in the presence of competing non-radioactive carcinogens or promoters, little or no inhibition of binding was found. The finding that both a powerful tumor promoter and a strong carcinogen are competitors for the specific MC binding to the cytosol receptor protein indicates that it may represent a critical interaction for the promoting stage of chemical carcinogenesis in mouse skin.

Inhibition by 5-fluorouracil of the early stages of chemical carcinogenesis in mouse skin.

Summary5-FU was found to inhibit the early stages of DMBA-induced epidermal carcinogenesis in the mouse. The dose which must be employed to obtain this effect is of the same order of magnitude as that required for bringing about regression of established tumors of the mouse skin.