Distribution, covalent binding, and DNA adduct formation of 7,12-dimethylbenz(a)anthracene in SENCAR and BALB/c mice following topical and oral administration

SENCAR mice are much more susceptible to tumor initiation by 7,12-dimethylbenz(a)anthracene (DMBA) administered topically than p.o. and are also more susceptible to initiation by topically applied DMBA than are BALB/c mice. To determine how the distribution and metabolic activation of DMBA differed in these strains and with route of administration, BALB/c and SENCAR mice were exposed to [3H]DMBA topically and p.o., and the distribution and DNA binding of DMBA were analyzed. Both the amount of DMBA in skin and the covalent binding of DMBA to epidermal DNA were greater following topical administration than after p.o. administration in both strains. Differences in DMBA distribution and macromolecular binding were found between SENCAR and BALB/c mice, with the binding of DMBA to DNA in epidermis tending to be greater in BALB/c mice than in SENCAR mice when differences were observed. The formation of individual DMBA:DNA adducts in epidermis was also examined in SENCAR and BALB/c mice following topical administration of DMBA. No substantial qualitative or quantitative differences in DMBA:DNA adducts were found between SENCAR and BALB/c mice. The anti/syn-DMBA-diol-epoxide-DNA adduct ratios calculated from the three major DMBA:deoxyribonucleoside adducts increased with time in both SENCAR and BALB/c mice. The data suggest that differences in the distribution and macromolecular binding of DMBA are responsible for the much greater skin tumor initiating activity of DMBA applied topically than p.o. but do not account for the greater sensitivity of the SENCAR mouse to DMBA-induced epidermal tumorigenesis.     

Effect of naturally occurring coumarins on the formation of epidermal DNA adducts and skin tumors induced by benzo[a]pyrene and 7,12- dimethylbenz[a]anthracene in SENCAR mice

Several naturally occurring coumarins previously found to be potent inhibitors of mouse hepatic ethoxyresorufin-O-deethylase (EROD) and/or pentoxyresorufin-O-dealkylase (PROD) were examined for their effects on formation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) DNA adducts in mouse epidermis, as well as, their effects on skin tumor initiation by these polycyclic aromatic hydrocarbons (PAH). Bergamottin, a potent inhibitor of hepatic EROD, given topically 5 min prior to an initiating dose of B[a]P, significantly decreased total covalent binding of B[a]P to DNA in a dose-dependent manner 24 h after treatment. A dose of 400 nmol bergamottin reduced covalent binding of B[a]P by 72%. Coriandrin, at a dose of 400 nmol also significantly reduced total covalent binding of B[a]P by 59%. In addition, formation of the major (+)anti-B[a]P-diol epoxide-N2-dGuo adduct was selectively reduced by both of these coumarins. In contrast, bergamottin and coriandrin did not significantly decrease covalent binding of DMBA to epidermal DNA at doses of either 400 nmol or 800 nmol. Imperatorin and isopimpinellin, which are more potent inhibitors of hepatic PROD activity, significantly reduced overall binding of DMBA to epidermal DNA by 67% and 52%, respectively, when applied at doses of 400 nmol. These two coumarins also inhibited B[a]P-DNA adduct formation at similar doses but to a lesser extent. Imperatorin at a dose of 400 nmol dramatically decreased formation of covalent DNA adducts derived from both the anti and syn diol epoxides of DMBA. Bergamottin was a potent inhibitor of tumor initiation by B[a]P while coriandrin was less effective in this regard. Imperatorin was an effective inhibitor of skin tumor initiation by DMBA and also inhibited complete carcinogenesis by this PAH. At dose levels higher than those effective against DMBA, imperatorin also inhibited tumor initiation by B[a]P. The results demonstrate that several naturally occurring coumarins possess the ability to block DNA adduct formation and tumor initiation by PAHs such as B[a]P and DMBA. The mechanism for reduced DNA adduct formation and tumor initiation appears to involve inhibition of the P450s involved in the metabolic activation of these hydrocarbons. Finally, the differential effects of certain coumarins on B[a]P vs DMBA DNA adduct formation and tumor initiation may be useful for dissecting the role of specific cytochromes P450 in their metabolic activation.      

Tumor-initiating activity of 4-fluoro-7,12-dimethylbenz[a]anthracene and 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene in female SENCAR mice

We have determined the skin tumor-initiating activity in SENCARmice of two A-ring derivatives of 7,12-dimethylbenz[a]anthracene(DMBA). 4-Fluoro-7,12-dimethyibenz[a]-anthracene at a dose of200 nmol per mouse exhibited weak activity, producing 0.6 papillomasper mouse; doses of 10 and 20 nmol per mouse had no activity.A derivative of DMBA with the A-ring reduced, l,2,3,4-tetrahydro-7,12-dimethyl-benz[a]anthracene(1,2,3,4,-H₄-DMBA), had substantial tumor-initiating activitywhen compared with the parent hydrocarbon. In one experiment,doses of 10 and 100 nmol per mouse gave rise to 1.6 and 9.5papillomas per mouse, respectively; similar results were obtainedin 3 additional experiments. Although the tumor-initiating activityof 1,2,3,4,-H₄-DMBA was approximately one-tenth that of DMBA,this derivative was slightly (17%) more active than 3-methylcholanthreneand 3 times more active than benzo[a]pyrene. 1,2,3,4-H₄-DMBAwas tested for the ability to induce mutations to 6-thioguanine-resistancein Chinese hamster V79 cells. In the absence of feeder cellscapable of metabolizing polycyclic hydrocarbons, it was notmutagenic. However, in a cell-mediated mutation assay with secondaryhamster embryo cells as activators, this derivative producedmutations in a dose-dependent manner and was approximately one-tenthas active as DMBA. These results indicate that metabolism ofDMBA at positions 1-, 3-, 2- and 4- is important for biologicalactivity and that for certain derivatives (i.e., 1,2,3,4-H₄-DMBA),alternate pathways of metabolic activation may also be important.     

Oral administration of the citrus coumarin,isopimpinellin, blocks DNA adduct formation and skin tumor initiation by 7,12-dimethylbenz[a]anthracene in SENCAR mice

The current study was designed to evaluate the effects of oral administration of the citrus coumarin, isopimpinellin, on skin tumor initiation by topically applied benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). To evaluate the effects of orally administered isopimpinellin on skin tumor initiation by B[a]P and DMBA, its effects on DNA adduct formation were first evaluated. Female SENCAR mice were pre-treated twice with corn oil, or isopimpinellin (70 mg/kg body wt per os) at 24 h and 2 h prior to topical treatment with B[a]P or DMBA. Another citrus coumarin, imperatorin, was also included in these experiments for comparison. Orally administered isopimpinellin and imperatorin significantly inhibited B[a]P-DNA adduct formation by 37 and 26%, respectively. Imperatorin also blocked DMBA-DNA adduct formation by 43%. In a second dose-response study, orally administered isopimpinellin (35, 70 and 150 mg/kg) blocked DMBA-DNA adduct formation by 23, 56 and 69%, respectively. For the tumor study, mice were pretreated orally with corn oil or isopimpinellin at 24 and 2 h prior to initiation with DMBA, and 2 weeks later promotion began with 12-O-tetradecanoylphorbol-13-acetate (TPA). Isopimpinellin significantly reduced the mean number of papillomas per mouse by 49, 73 and 78% compared to corn oil controls at 30, 70 and 150 mg/kg body wt, respectively. Orally administered isopimpinellin also significantly reduced the percentage of mice with papillomas at the highest dose tested (150 mg/kg). The effectiveness of isopimpinellin given topically over a broad dose range against DMBA tumor initiation was also evaluated for comparison. As part of this study, several parameters of systemic toxicity were evaluated following oral dosing with isopimpinellin and imperatorin. Mice were treated orally with corn oil, isopimpinellin or imperatorin (35, 70 and 150 mg/kg body wt per os) once daily for four consecutive days, killed at 24 h after the last dose, and livers, lungs, and kidneys evaluated histologically. In addition, urinary parameters of nephrotoxicity, blood parameters of liver and kidney function, and thrombin clotting time were assayed. No significant changes in blood clotting, or renal or hepatic function were observed. There was, however, a significant increase in liver wt accompanied by cytoplasmic vacuolation of hepatocytes. There were no histopathological changes in lungs or kidneys. Overall, these data indicate that isopimpinellin (and imperatorin) have chemopreventive effects when administered orally on skin tumor initiation by DMBA.     

Phenoxodiol,a novel isoflavone derivative,inhibits dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats

The present study was undertaken to evaluate the potential cancer chemopreventive effects of novel synthetic derivatives of isoflavones. Initially these agents were tested in a mouse mammary organ culture (MMOC) model. Phenoxodiol (2H-1-benzopyran-7-O1,3-(4-hydroxyphenyl)), the most effective in this assay, was selected for further testing in female Sprague-Dawley rats. The agent was tested at 0 (basal diet), 50 and 75 mg/kg diet. Mammary carcinomas in these three groups were induced by dimethylbenz[a]anthracene (DMBA) injected 1 week after the animals started eating the experimental diets. Phenoxodiol significantly reduced tumour incidence rate at both doses (P相似文献   

Inhibition of the binding of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene to DNA in mouse skin epidermis by 1-ethynylpyrene

The effects of 1-ethynylpyrene (EP), 1-vinylpyrene (VP) and 2-ethynlnaphthalene (EN) on the covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) and of benzo[a]-pyrene (B[a]P) to the epidermal DNA in mouse skin were investigated. When applied topically, 5 min before an initiating dose of 10 nmol DMBA or of 200 nmol B[a]P, EP was an effective inhibitor of the formation of the covalent complexes of these procarcinogenic polycyclic aromatic hydrocarbons (PAHs) with the epidermal DNA. VP, applied under the same conditions, was a significantly less effective inhibitor of the binding of DMBA to DNA and showed even weaker inhibition of the binding of B[a]P. EN was ineffective as an inhibitor of the binding of either DMBA or B[a]P. These results establish that both the pyrene nucleus and the ethynyl substituent of EP contribute to the effective inhibition of the binding of DMBA and B[a]P to the epidermal DNA of mouse skin. No significant changes in the ratios of the anti- to the syndiol epoxide-DNA adducts of DMBA or of B[a]P were produced by doses of EP that produced inhibitions of the binding to DNA. At doses of VP that inhibited covalent binding of both DMBA and B[a]P, no changes in DMBA-DNA adduct distributions were observed but changes in the relative proportions of several B[a]P-DNA adducts were noted. These data are discussed in terms of the potential of aryl acetylenes to act as suicide inhibitors (mechanism-based inactivators) of cytochrome P450-dependent monooxygenase isozymes.     

The plasticizer benzyl butyl phthalate (BBP) inhibits 7,12- dimethylbenz[a]anthracene (DMBA)-induced rat mammary DNA adduct formation and tumorigenesis

Although the risk for cancer is multifactorial, a substantial portion of cancer incidence rates is related to environmental factors, including diet and environmental chemicals. The magnitude of the contribution to cancer of the breast from exposure to environmental chemicals remains unclear. The phthalate ester plasticizers are abundantly-produced industrial chemicals that have become widely- dispersed environmental pollutants. The present studies were conducted to determine the effect of the phthalate ester, benzyl butyl phthalate (BBP) on mammary gland carcinogenesis induced in the female rat by the polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA). Exposure to BBP (i.p. injection) at 100 and 500 mg/kg doses for 5 days resulted in a significant 72 and 92% inhibition, respectively, in the in vivo formation of mammary DMBA-DNA adducts, compared to controls. Treatment with BBP (i.g. intubation) for 7 days resulted in a significant (48%) inhibition in mammary DMBA-DNA adduct formation only for those animals receiving the 500 mg/kg dose, compared to controls. Administration of BBP (i.g.) at 500 mg/kg for 7 days also was associated with a significant 8.5-fold increase in the liver activity of 7-ethoxyresorufin-O-deethylase. No change in liver glutathione-S- transferase activity was observed for animals treated with both BBP (i.g.) doses. Treatment with BBP (i.g.) at 250 and 500 mg/kg doses for 7 days prior to DMBA administration resulted in a significant 37% decrease in mammary tumor incidence for both doses, compared to controls. The number of mammary adenocarcinomas per rat was significantly inhibited by 60 and 70% for rats exposed to BBP at the 250 and 500 mg/kg doses, respectively, compared to controls. Therefore, the present studies indicate that BBP acts as a blocking agent toward DMBA-induced rat mammary DNA adduct formation and mammary carcinogenesis. This effect partly may be due to increased metabolism of BBP in the liver. These results underscore the need to further examine the effect of BBP and other phthalates on the various stages of mammary carcinogenesis, as well as on the metabolism of mammary carcinogens.      

Comparison of the tumor-initiating activity of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene in female SENCAR and CD-1 mice

The derivation of mice resistant and susceptible to skin tumorigenesisusing the initiation-promotion regimen is described. Dose-responserelationships for tumor-initiating activities of 7,12-dimethylbenz[a]-anthracene(DMBA) and benzo[a]pyrene (BP) in the susceptible line (SENCAR)are presented. A single topical dose of either 0.1, 1.0, 10or 100 nmol DMBA, followed one week later by twice weekly applicationsof 8.5 nmol 12–0-tetradecanoylphorbol-13-acetate (TPA)for 19 weeks, produced 0, 3.3, 4.9 and 23.1 papillomas per mouse,respectively. Single topical initiating doses of either 50,100 or 200 nmol BP produced 1.7, 3.8 or 7.8 papillomas per mouse,respectively, after 28 weeks of promotion with 8.5 nmol TPA.SENCAR mice were compared with CD-1 mice for the initiatingactivity of DMBA and BP. Initiating doses of 0.1, 1.0, 10 and100 nmol DMBA produced 0.6, 3.8, 7.0 and 24 papillomas per mouse,respectively, in SENCAR mice and in CD-1 mice produced 0, 0.2,3.0 and 5.6 papillomas per mouse, respectively, after 25 weeksof promotion with TPA. With BP as the initiator, 10, 50, 100and 200 nmol doses produced 0.9, 1.6, 3.8 and 8.3 papillomasper mouse, respectively, in SENCAR mice and in CD-1 mice produced0.1, 0.7,1.8 and 3.8 papillomas per mouse, respectively, after25 weeks of promotion with TPA. SENCAR mice were compared with CD-1 mice for possible differencesin the oxidative metabolism of DMBA using epidermal homogenatesas the enzyme source. Basal levels of monooxygenase activitytoward DMBA were similar in both mouse stocks. Epidermal monooxygenaseactivities following pre-treatment with inducers including DMBA,3-methylcholanthrene, dibenz[a,c]anthracene, Aroclor 1254 and2,3,7,8-tetrachlorodibenzo-p-dioxin, also were quite similarin both mouse stocks. High-pressure liquid chromatographic profilesof ethyl acetate/ acetone (2:1) extractable metabolites revealeda close similarity in the patterns as well as the rates of formationof specific metabolites. Metabolites of DMBA tentatively identifiedbased on cochromato-graphy with purified reference standardsincluded phenols, 12-hydroxymethyl-7-methylbenz[a]anthracene,7-hydroxymethyl-12-methylbenz[a]antnracene, 7,12-dihydroxymethylbenz[a]anthracene,(±)-trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthraceneand (±)-trans-5,6-dihydro-5,6-dihydroxy-7,12-dimethylbenz[a]anthracene.The results suggested that differences in oxidative metabolismof DMBA were not responsible for the differences in sensitivityto tumor-initiation between SENCAR and CD-1 mice.     

Alterations in epidermal polyamine levels and DNA synthesis following topical treatment with chrysarobin in SENCAR mice

A single topical application of chrysarobin (220 nmol) to SENCAR mouse skin produced alterations in epidermal polyamine levels distinctly different from that following a single topical treatment with 3.4 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA). Putrescine and spermidine levels were elevated prior to the induction of epidermal ornithine decarboxylase. In this regard, putrescine levels were elevated at 6 and 24 h after a single application of chrysarobin. In addition, putrescine levels were elevated with a second major peak at 64 h after chrysarobin which coincided with elevated epidermal ornithine decarboxylase activity. Spermidine levels were substantially elevated from 24 to 96 h (peak at 60 h) after a single treatment. TPA treatment produced peak elevations in epidermal putrescine levels at 6 h and epidermal spermidine levels at 24 h after a single treatment. Epidermal spermine levels were dramatically depressed following treatment with chrysarobin (peak depression of approximately 60% below control at 24 h), but only slightly altered following treatment with TPA. The time courses for changes in epidermal DNA synthesis in mouse skin following single treatments with 3.4 nmol of TPA or 220 nmol of chrysarobin also showed considerable differences. TPA treatment produced several waves of DNA synthesis at approximately 18 and 48 h after treatment, while chrysarobin produced a single broad peak at 72 h after treatment. Treatment with chrysarobin was also associated with an initial, dramatic inhibition in epidermal DNA synthesis (to 23% of the control value) which was much more extensive than that elicited by TPA. Inhibition of epidermal DNA synthesis following treatment with chrysarobin was observed within a few hours after treatment and remained depressed until approximately 36 h after treatment. Following treatment with both chrysarobin and TPA, higher levels of epidermal DNA synthesis correlated closely with higher molar ratios of spermidine/spermine, indicating a strong relationship between epidermal spermidine levels and epidermal cell proliferation induced by both promoters. The data suggest that TPA and chrysarobin bring about initial changes in epidermal polyamines by distinct mechanisms; however, both compounds ultimately lead to a dramatic stimulation of epidermal DNA synthesis. These data further support our working hypothesis that anthrones promote skin tumors by an initial mechanism different from that of the phorbol esters.     

Melanoma induction in a hairless mouse with short-term application of dimethylbenz[a]anthracene

Melanomas have been induced in hamsters and guinea pigs with short-term, low dose applications of dimethylbenz [a]anthracene (DMBA) alone. In mice, however, melanoma induction has required either croton oil or ultraviolet radiation promotion in addition to DMBA. In this study, we report the development of a malignant melanoma, with metastases, in a hairless mouse after six applications of 0.25% DMBA alone. At sacrifice, a large primary tumour with characteristics of intralesional transformation was present, along with numerous pigmented macules and papules. Metastases were present in lymph nodes and lungs. There was a marked similarity between this melanoma and its precursor lesions and those seen in an earlier, Weiser-Maple guinea pig model, which, in turn, resembled human melanoma.     

Benzo(a)pyrene diol epoxide-I-DNA adduct formation in the epidermis and lung of SENCAR mice following topical application of crude coal tar

The levels of benzo[a]pyrene diol epoxide-I-deoxyguanosine (BPDE-I-dG) adduct formation in epidermis and lung of SENCAR mice following the topical application of benzo[a]pyrene (BP) alone, crude coal tar (CCT) alone, and the two combined were determined in an enzyme linked immunosorbent (ELISA) assay using monoclonal antibodies. Topical application of two doses of BP (20 micrograms) at 72-h intervals, with sacrifice 24 h later resulted in the formation of 197 fmol and 205 fmol BPDE-I-dG adducts per mg DNA in epidermis and lung, respectively. Topical application of 0.5 ml CCT alone resulted in the formation of 278 fmol and 410 fmol BPDE-I-dG adducts per mg DNA in epidermis and lung, respectively. Simultaneous topical application of 20 micrograms BP and CCT (0.1-0.5 ml) resulted in substantially lower BPDE-I-dG adducts in the epidermis as well as in the lung. Our results suggest that CCT may contain inhibitors of carcinogen-DNA adduct formation and that topical application of CCT produces greater effects on DNA-adduct formation in lung than in epidermis. Thus the cancer-causing potency of the polycyclic aromatic hydrocarbons (PAHs) in CCT may be reduced by other anticarcinogenic constituents present in CCT and systemic absorption of carcinogenic PAHs in CCT applied to skin might have tumorigenic effects in other tissues.     

Comparison of blood protein and target organ DNA and protein binding following topical application of benzo[a]pyrene and 7H-dibenzo[c,g]carbazole to mice

7H-Dibenzo[c,g]carbazole (DBC) induces skin and liver tumorsin mice following topical application, whereas benzo[a]pyrene(BP) induces only skin tumors. DBC also binds to liver DNA toa much greater extent than does BP. The present study examinedfactors that might account for the difference in DNA bindingactivity. [³H]DBC was applied topically to CD-1 mice at dosesof 15, 100 and 1000 nmol/mouse and tissues and blood sampleswere taken 24 h later. Absorption of DBC from skin into bloodand binding to blood proteins occurred linearly with dose. DBCbound to albumin at a 50-fold higher level than to globin andlevels of albumin adducts showed good correlation with levelsof DNA adducts in liver. Hepatic preference over skin in DNAbinding was found to be dose-dependent For comparison of [3H]BPand [3H]DBC binding, doses of 1000 nmol/mouse were used andthe mice were sacrificed at 12, 24 and 48 h. The rate of DBCuptake from skin was 70% higher than for BP over the first 24h, which was reflected in 40-50% higher plasma levels of DBCradiolabel. Skin protein and DNA binding were 2- to 5-fold higherfor BP than DBC. Conversely, total 3H radioactivity levels inliver were 2- to 3-fold higher and liver DNA and protein bindingwere 15- to 20-fold and 3- to 5-fold higher respectively forDBC. Blood protein adduct levels were similar for both chemicals,suggesting that DBC metabolites formed in the liver were tooreactive to re-enter the systemic circulation. Only minor amountsof the radiolabel in the liver were present as the parent compoundsby 12 h after dosing. These results indicate that more rapidabsorption from skin and selective accumulation in the livercontribute to the greater liver DNA binding seen with DBC, butthe types of liver metabolites appear to be the major factoraccounting for the binding difference.     

Ras gene mutations in 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat sarcomas

Tumor induction in rats by 7,12-dimethylbenz[a]anthracene (DMBA) will generate malignancies that display reproducible chromosomal abnormalities involving rat chromosome (RNO) 2. Thus, it has been reported that rat DMBA erythroleukemias display RNO2 abnormalities, which in this case were closely correlated to mutations in the Nras oncogene located in RNO2q34. Our cytogenetic analysis in a series of 17 DMBA-induced rat sarcomas showed that 11 (65%) tumors had a significant increase in RNO2 copy number. Furthermore, the incidence of point mutations in codons 12, 13 and 61 of Hras, Kras, and Nras was examined in the same set of sarcomas, and mutations were detected in three (18%) tumors, in codon 61 of Kras (CAA-->CAT) (1 of 17) and Nras (CAA-->CTA) (2 of 17). We conclude that the high frequency of RNO2 gain was in accordance with previous studies of DMBA-induced rat neoplasms, supporting the idea of a significant role of RNO2 in DMBA carcinogenesis. However, there was no clear-cut relationship between activated Nras and gain of RNO2 material, implying that mutational activation of Nras is not the causative factor underlying the gain of RNO2 copy number in rat DMBA sarcomas, in contrast to what has been suggested for DMBA-induced erythroleukemias.     

Analysis of 7-methylbenz[a]anthracene-DNA adducts formed in SENCAR mouse epidermis by 32P-postlabeling

The present study has analysed the DNA adducts formed in SENCAR mouse epidermis following topical application of 7-methylbenz[a]anthracene (7- MBA). Mice were treated with 400 nmol of 7-MBA, which represents an initiating dose of this hydrocarbon for SENCAR mice. DNA adducts were analysed 24 h after topical application of the hydrocarbon by 32P- postlabeling coupled with either HPLC analysis or an improved TLC procedure giving better resolution of DNA adducts through the use of a D6 solvent [isopropanol:4N NH4OH (1:1)] following D5. Twenty-four hours after topical application of 400 nmol 7-MBA, the level of total covalent binding was 0.37 +/- 0.07 pmol/mg DNA as determined by 32P- postlabeling. This level of binding correlated well with the relative tumor initiating activity of this hydrocarbon compared to 7,12- dimethylbenz[a]anthracene (6.4 +/- 0.01 pmol/mg DNA) and dibenz[a,j]anthracene (0.03 +/- 0.01 pmol/mg DNA). Analysis of the 32P- labeled 3',5'-diphosphodeoxyribonucleosides by HPLC and TLC revealed the presence of deoxyguanosine (dGuo) and deoxyadenosine (dAdo) adducts formed from both the anti- and syn-bay-region diol-epoxides of 7-MBA (anti- and syn-7-MBADEs). The major DNA adduct derived from 7-MBA in mouse epidermis was tentatively identified as (+) anti-7-MBADE-trans-N2- dGuo. In addition, a minor dGuo adduct derived from the bay-region syn- diol-epoxide of 7-MBA was detected as well as a minor dAdo adduct from this diol-epoxide. Another minor dAdo adduct was also detectably present which arose from either the anti- or syn-diol epoxide. Furthermore, several unidentified DNA adducts were present in both HPLC and TLC chromatograms of DNA samples from 7-MBA-treated mice. These results are discussed in terms of the role of specific 7-MBA-DNA adducts in tumor initiation by this hydrocarbon.      

Preventive and curative effect of melatonin on mammary carcinogenesis induced by dimethylbenz[a]anthracene in the female Sprague-Dawley rat

Introduction  

It has been well documented that the pineal hormone, melatonin, which plays a major role in the control of reproduction in mammals, also plays a role in the incidence and growth of breast and mammary cancer. The curative effect of melatonin on the growth of dimethylbenz [a]anthracene-induced (DMBA-induced) mammary adenocarcinoma (ADK) has been previously well documented in the female Sprague-Dawley rat. However, the preventive effect of melatonin in limiting the frequency of cancer initiation has not been well documented.     

Tumor initiating activity of 9- and 10-fluoro-7,12-dimethylbenz[a]-anthracene (DMBA) and the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on tumor initiation by monofluoro derivatives of DMBA in SENCAR mice

We have determined the skin tumor initiating activity in SENCARmice of 6 monofluoro derivatives of 7,12-dimethylbenz[a]anthracene(DMBA). 9-Fluoro-DMBA (9-F-DMBA) was approximately as active,and 10-F-DMBA was more active than the parent hydrocarbon, DMBA.The difference between DMBA and 10-F-DMBA was most dramaticat the highest initiating doses of 10-F-DMBA tested. 4-F-DMBA,which was only weakly active as an initiator, was also testedas a complete carcinogen on mouse skin; after 30 weeks of treatment,50- and 100-nmol weekly doses failed to elicit papillomas orcarcinomas. Animals treated with 50 nmol of DMBA weekly exhibiteda 100% papiloma incidence and a 42% carcinoma incidence. Pretreatmentwith 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) effectivelyinhibited tumor initiation with all of the monofluoro derivativesof DMBA tested. The ED₅₀ (dose of TCDD producing half-maximalinhibition) for the inhibition of DMBA initiation in SENCARmice was determined to be 1.8 x 10^–3 µg/mouse (5.6pmol). The results indicate that the introduction of a fluorineatom in ring D of DMBA has no effect (positions 9 and 11) orenhances (position 10) tumor initiating activity. We believe10-F-DMBA to be the first example of a hydrocarbon with a fluorosubstituent giving rise to increased tumor initiating activity.The results also indicate that structural modifications thatalter tumor initiating activity do not alter the ability ofTCDD to inhibit tumorigenesis by DMBA.