UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
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Upregulation of p53 protein induces either growth arrest or apoptosis in response to cellular injury This is signaled from a highly conserved p53 domain between codons 64 and 92, where a functional polymorphism results in either a proline (p53-72P) or an arginine (p53-72R) at codon 72. Preliminary studies suggest that p53-72R may be a risk factor for cervical cancer and, consistent with this, preferential mutation and retention of the p53-72R allele has also been demonstrated in other cancers of squamous cell origin. Here we examine the relationship between allelic forms of p53 and nonmelanoma skin cancer, by determining the correlation with susceptibility to sunburn, which is a known risk factor, and then by p53 sequence analysis of a large series of tumors. We found a significant positive association between p53-72R and susceptibility to sunburn, as assessed by skin phototype and minimal erythemal dose following solar-simulated radiation (p = 0.0001 for trend). We also found a significant association between p53-72R homozygosity and nonmelanoma skin cancer in renal transplant recipients (basal cell carcinoma, p < 0.01; squamous cell carcinoma, p < 0.05) but not in immunocompetent patients compared with skin type matched controls. p53 sequence data revealed mutations in 30 of 70 (42.9%) nonmelanoma skin cancers, 28 (93%) of which were in the p53-72R allele. Loss of heterozygosity occurred more frequently in p53-72RP than in p53-72RR tumors (p = 0.0001) with preferential loss of p53-72P in heterozygotes (p = 0.016), irrespective of the mutant status of the concomitant allele. Together these data infer functional differences between polymorphic forms of p53 that are likely to be relevant to skin carcinogenesis.
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PMID:Relationship between p53 codon 72 polymorphism and susceptibility to sunburn and skin cancer. 1514 Feb 41

Photodermatology has become an important part of the dermatologist's area of focus. This subspeciality is not only involved with studying basic biological processes such as the effects of ultraviolet (UV) irradiation on the skin's immune system (photo-immunology), melanocytes or DNA (carcinogenesis), but also with clinical issues such as photoprotection, photosensitive skin diseases (photodermatoses) and phototherapy. Increasing knowledge about the effects of UV irradiation on the skin, with or without photosensitising agents, has led to the development of new forms of photo(chemo)therapy. These allow good therapeutic results to be achieved in the treatment of not only psoriasis, but also other chronic inflammatory skin diseases, with minimal side effects. DNA can absorb UV irradiation. This can lead to irreversible DNA damage and mutations in genes responsible for cell cycle control. These events can lead to skin cancer. The presence of pheomelanin, which is an inferior type of UV light-absorbing melanin, can add to this process of DNA damage. The three most important types of skin cancer are basal cell carcinoma (more than 30,000 new patients per year in the Netherlands), squamous cell carcinoma and melanoma.
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PMID:[Photo dermatology]. 1240 6

Basal cell carcinoma (BCC) patients demonstrate marked variation in tumour numbers and site. Previous studies also show an association between age at first BCC presentation and development of BCC on the trunk. In this study we have investigated the association between age at first presentation and the rate of development of truncal and non-truncal tumours in 747 patients with BCC. We used negative binomial regression analysis to show that increasing age at first presentation was associated with an increased rate of BCC development (rate ratio 1.01/year, 95% CI 1.01-1.02, P < 0.001). In particular, development of tumours was greater in cases aged 60.0-69.9, 70.0-79.9 and 80.0-89.9 years than in those 40.0-49.9 years (P = 0.05, 0.01 and 0.039, respectively). While few cases aged over 70 years of age first present with a truncal BCC, the numbers of BCC/year were greater than in those with a head/neck BCC. The data suggest different genetic factors mediate the appearance of BCC in patients of different ages particularly those aged above and below 60 years.
Carcinogenesis 2002 Dec
PMID:The rate of increase in the numbers of primary sporadic basal cell carcinomas during follow up is associated with age at first presentation. 1250 28

1,25-Dihydroxyvitamin D(3) (1,25D(3)) is the biologically active form of vitamin D(3) that interacts with the nuclear vitamin D(3) receptor (VDR) to modulate gene expression in a tissue-specific fashion. 1,25D(3) is a potent regulator of cell proliferation, differentiation and apoptosis in a variety of cell types, including keratinocytes. In these studies, we assessed the sensitivity of mice homozygous for a null allele of the VDR (VDR(-/-) mice) and their wild-type counterparts (VDR(+/+) mice) to oral administration of the carcinogen 7,12-dimethylbenzanthracene (DMBA). Although the protocol was optimized for the induction of mammary tumors, 85% of VDR(-/-) mice developed persistent skin tumors within 60 days of carcinogen exposure. In VDR(-/-) mice exposed to DMBA, papillomas arose on all areas of the body, with an average tumor burden of 5.3 papillomas/mouse. No papillomas or any other skin lesions were observed in age- and sex-matched VDR(+/+) mice dosed with DMBA and followed for 6 months. The majority (80%) of skin tumors that developed in VDR(-/-) mice were classified histologically as sebaceous, squamous or follicular papillomas. Other types of lesions, including basal cell carcinoma, hemangioma and melanotic foci, were occasionally observed in VDR(-/-) mice (but not in VDR(+/+) mice) exposed to DMBA. Quantification of epidermal thickness and BrdU incorporation indicated that skin from VDR(-/-) mice exhibited hyperproliferation beginning at 7 weeks of age, which was exacerbated by DMBA treatment. Untreated aging VDR(-/-) mice did not exhibit tumor formation, but did develop a progressive skin phenotype characterized by thickened wrinkled skin, dermoid cysts and long curly nails. Together with previous reports that 1,25D(3) inhibits papilloma formation induced by topical DMBA-TPA regimens, our observation of enhanced sensitivity of VDR(-/-) mice to chemically induced skin carcinogenesis offers compelling evidence that disruption of VDR signaling predisposes to neoplasia.
Carcinogenesis 2002 Dec
PMID:Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis. 1250 34

Basal cell carcinoma (BCC) is the most common tumor in the Caucasian population. Although BCC rarely metastasize and cause death, they are problematic due to their destructive growth and the frequent localization on the face. Until now the knowledge of genes differentially expressed in BCC has been incomplete. To elucidate the complex alterations in BCC-associated gene expression, we took advantage of 2 techniques: the differential display RT-PCR (DD-PCR) and the differential hybridization of cDNA arrays. Using DD-PCR, we showed differential expression of genes known from other biological contexts (e.g., rac, ubiquitin hydrolase), which could now be associated with BCC. In addition, we detected unknown genes possibly contributing to the carcinogenesis of BCC. Of the 588 genes screened by differential hybridization of the Atlas human cDNA array, differences in the expression levels of BCC were observed for 10 genes. These data were obtained with RNA probes pooled from several BCC of different donors and were subsequently confirmed by semiquantitative RT-PCR for Janus protein tyrosine kinase 3 (Jak3), microsomal glutathione S-transferase 1 (GST 12), teratocarcinoma-derived growth factor cripto, glutaredoxin and the monocyte chemoattractant protein 1 (MCP-1) in 10 individual BCC specimens, 2 squamous cell carcinoma (SCC), the cell line HaCaT and cultured normal human keratinocytes (NHK) in comparison to normal skin. These genes are candidates from gene families with known association to tumors, but they have not been reported in the carcinogenesis of BCC yet. In summary, both approaches allow the detection of differentially expressed genes possibly involved in the carcinogenesis of BCC.
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PMID:Molecular basis of basal cell carcinoma: analysis of differential gene expression by differential display PCR and expression array. 1253 21

Microsatellites of DNA--short, tandem repeat segments dispersed throughout the human genome--probably play a role in carcinogenesis. In this study the presence of microsatellite instability (MSI) was evaluated in skin cancers. Only one specimen (basal cell carcinoma) out of twelve skin cancers exhibited MSI at chromosome 2. MSI was not found in benign skin lesions (seborrhoeic verruca, keratoacanthoma, senile keratosis).
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PMID:[Preliminary evaluation of microsatellite instability in skin cancers]. 1255 30

Diethylphthalate and dimethylphthalate are used as phthalate plasticizers, in an extensive array of products. The chronic dermal toxicity of diethylphthalate was evaluated in male and female F344/N rats and B6C3F1 mice in 2-year studies. In a series of special studies, the tumor initiation or promotion potential of diethylphthalate or dimethylphthalate was evaluated in male Swiss (CD-1(R)) mice by an initiation/promotion model of skin carcinogenesis. The genetic toxicity of diethylphthalate and dimethylphthalate in Salmonella typhimurium and cultured Chinese hamster ovary cells was also evaluated. 4-WEEK STUDY IN F344/N RATS: Groups of 10 male and 10 female rats were dermally administered diethylphthalate at volumes of 0, 37.5, 75, 150, or 300 &mgr;L (0, 46, 92, 184, or 369 &mgr;g) applied neat, 5 days per week for 4 weeks. All male and female rats survived to the end of the study. No evidence of dermatotoxicity was observed, with no adverse clinical signs observed and no effects on weight gain or feed consumption. Relative liver weights of 300 &mgr;L males and females and 150 &mgr;L females were greater than those of controls. Relative kidney weights of 150 and 300 &mgr;L males and 150 &mgr;L females were greater than those of controls. No other adverse effects were observed in this study. 4-WEEK STUDY IN B6C3F1 MICE: Groups of 10 male and 10 female mice were dermally administered diethylphthalate at volumes of 0, 12.5, 25, 50, or 100 &mgr;L (0, 15, 31, 62, or 123 &mgr;) applied neat, five days per week for 4 weeks. One control female died before the end of the study; all other mice survived. No evidence of dermatotoxicity or other adverse clinical signs were observed, and no clear adverse effects on weight gain or feed consumption were seen. Absolute and relative liver weights of 25 and 100 &mgr;L females were greater than those of the controls. Based on these 4-week study results, doses of 0, 35, and 100 &mgr;L diethylphthalate were recommended for the 2-year mouse studies. A chronic study in male and female B6C3F1 mice at 0, 35, and 100 &mgr;L (applied neat, once per day, 5 days per week) was started and subsequently stopped after 32 weeks when significant body weight reductions were noted in treated animals (males and females, 100 &mgr;L groups: 19% lower; males, 35 &mgr;L group: 12% lower; females, 35 &mgr;L group: 10% lower than controls). Based on these body weight reductions, doses of 0, 7.5, 15, and 30 &mgr;L in 100 &mgr;L acetone were recommended for the restart of the 2-year mouse study. 2-YEAR STUDY IN F344/N RATS: Based upon the results of the 4-week study, doses of 0, 100, or 300 &mgr;L diethylphthalate (0, 123, or 369 &mgr;) were chosen for the 2-year rat study. Groups of 60 male and 60 female rats received the doses applied neat 5 days per week for 103 weeks and up to 10 animals per group were evaluated after 15 months. Survival, Body Weights, and Clinical Findings: Survival of dosed rats during the first 15 months was similar to that of controls. However, 2-year survival was significantly reduced in all groups of male rats (survival probabilities, males: 0 &mgr;L, 8%; 100 &mgr;L, 12%; and 300 &mgr;L, 12%). The mean body weights of 300 &mgr;L males were slightly less than those of the controls throughout the study. No adverse clinical signs were observed, including no evidence of dermatotoxicity. Pathology Findings: No morphological evidence of dermal or systemic toxicity was observed in male or female rats. Skin neoplasms were not observed in female rats and were only rarely observed in male rats. A high incidence of anterior pituitary adenoma occurred in all groups of male and female rats. The incidence of anterior pituitary adenomas in the 0, 100, and 300 &mgr;L groups were: males, 39/44, 41/49, 41/49; females, 38/50, 33/49, 33/48. The incidence of this benign tumor in control males (84%) exceeded the historical control mean incidence [feed controls, (28.7%)] and range (12% to 60%). Anterior pituitary adenomas were considered a primary contributing factor in the increased mortality observed in all grtor in the increased mortality observed in all groups, regardless of treatment. A dose-related decreasing trend in the incidence of mammary gland fibroadenomas was observed in female rats (21/50, 12/48, 7/50). The incidence of mononuclear cell leukemia in male rats in this study was lower than the historical incidence and may be attributable to the shortened life span of male rats. Similarly, the incidence of interstitial cell tumors of the testes was markedly decreased in all groups of males (4/50, 3/50, 8/50), relative to historical control rates (90.1&percnt;; range 74&percnt;-98&percnt;). The incidence of fatty liver degeneration was notably lower in dosed rats than in controls (males: 26/50, 8/50, 4/51; females: 23/50, 11/50, 3/50). 2-YEAR STUDY IN B6C3F1 MICE: Groups of 60 male and 60 female mice received doses of 0, 7.5, 15, or 30 μL diethylphthalate (0, 9, 18, or 37 μ) in 100 μL acetone 5 days per week for 103 weeks with a 1 week recovery period, and up to 10 animals per group were evaluated after 15 months. Survival, Body Weights, and Clinical Findings: Two-year survival of dosed mice was similar to that of controls: 43/50, 41/48, 46/50, and 43/50 (males), and 41/50, 38/51, 37/49, and 36/49 (females). Mean body weights of dosed male and female mice were similar to those of the controls throughout the study. No adverse clinical signs were observed in mice, including no gross evidence of dermatotoxicity. Feed consumption by male and female mice was similar to or up to 13% greater than that by controls. Pathology Findings: No morphological evidence of dermal toxicity was observed in male or female mice. No skin neoplasms were observed in dosed male mice. In female mice receiving 30 μL, one squamous cell carcinoma and one basal cell carcinoma were seen at the site of application. An increased incidence of liver neoplasms was observed in dosed male and female mice. The incidence of hepatocellular adenoma or carcinoma (combined) in B6C3F1 mice in the 0, 7.5, 15, and 30 μL groups were: (males) 9/50, 14/50, 14/50, and 18/50; (females) 7/50, 16/51, 19/50, and 12/50. The incidence of adenoma or carcinoma (combined) was increased in 30 μL male mice and the incidences of adenoma and of adenoma or carcinoma (combined) were increased in 7.5 and 15 μL females. A positive dose-related trend in the incidence of adenoma or carcinoma (combined) was also observed in male mice. The incidence of basophilic hepatic foci was increased in 15 μL male mice (0/50, 1/50, 9/50, 3/50). The increased incidence of liver neoplasms in this study was considered equivocal because the incidence of hepatocellular neoplasms in control and dosed males was within the historical range and because there was no clear dose-response relationship in females. No other treatment-related findings were observed in this study. 1-YEAR INITIATION/PROMOTION STUDY IN MALE SWISS (CD-1®) MICE: Groups of 50 male mice were dosed dermally with diethylphthalate or dimethylphthalate to study their effect as initiators and promoters. Diethylphthalate and dimethylphthalate were tested as initiators with and without the known skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Diethyl phthalate and dimethylphthalate were tested as promoters with and without the known skin tumor initiator 7,12-dimethylbenzanthrancene (DMBA). Comparative control groups used during the study of diethylphthalate and dimethylphthalate included: vehicle control (acetone/acetone); initiation/promotion control (DMBA/TPA); initiator control (DMBA/acetone); and promoter control (acetone/TPA). Based on the incidence of skin neoplasms diagnosed histologically and the multiplicity of skin neoplasms, there was no suggestion that either diethylphthalate or dimethylphthalate was able to initiate skin carcinogenesis when chronically promoted by TPA. Further, there was no evidence that either diethylphthalate or dimethylphthalate was able to promote skin carcinogenesis in skin previously initiated with DMBA. High incidences of both squamous cell papillomas and squamous cell carcinomas occurred among the initiation/promotion control animals initiated with DMBA and promoted with TPA. All TPA-dosed groups had significantly greater incidences of dermal acanthosis, ulceration, exudation, and hyperkeratosis than controls. GENETIC TOXICOLOGY: Neither diethylphthalate (10-10,000 μ/plate) nor dimethylphthalate (33-6,666 μ/plate) induced gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without rat and hamster liver S9. In cultured Chinese hamster ovary cells, both diethylphthalate and dimethylphthalate induced sister chromatid exchanges in the presence of S9. Neither induced sister chromatid exchanges in the absence of S9. Neither chemical induced chromosomal aberrations, with or without S9, in cultured Chinese hamster ovary cells. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of diethylphthalate in male or female F344/N rats receiving 100 or 300 μL. The sensitivity of the male rat study was reduced due to low survival in all groups. There was equivocal evidence of carcinogenic activity of diethylphthalate in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenomas. In an initiation/promotion model of skin carcinogenesis, there was no evidence of initiating activity of diethylphthalate or dimethylphthalate in male Swiss (CD-1®) mice. Further, there was no evidence of promotion activity of diethylphthalate or dimethylphthalate in male Swiss (CD-1®) mice. The promoting activity of TPA following DMBA initiation was confirmed in these studies. Minor dermal acanthosis was observed following dermal application of diethylphthalate in male and female F344/N rats dosed for 2 years and in male Swiss (CD-1®) mice dosed for 1 year. Synonyms: Diethylphthalate (CAS No. 84-66-2): 1,2-benzenedicarboxylic acid, diethyl ester; DEP; diethyl 1,2-benzenedicarboxylate; diethyl o-phthalate; diethyl phthalate; ethyl phthalate; o-benzenedicarboxylic acid diethyl ester; phthalic acid, diethyl ester; RCRA U088 Dimethylphthalate (CAS No. 131-11-3): 1,2-benzenedicarboxylic acid, dimethyl ester; dimethyl 1,2-benzenedicarboxylate; dimethyl benzene-o-dicarboxylate; dimethyl benzeneorthodicarboxylate; dimethyl o-phthalate; dimethyl phthalate; DMP; FIFRA 028002; methyl phthalate; go-dimethyl phthalate; phthalic acid, dimethyl ester; phthalic acid methyl ester; RCRA U102
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PMID:NTP Toxicology and Carcinogenesis Studies of Diethylphthalate (CAS No. 84-66-2) in F344/N Rats and B6C3F1 Mice (Dermal Studies) with Dermal Initiation/ Promotion Study of Diethylphthalate and Dimethylphthalate (CAS No. 131-11-3) in Male Swiss (CD-1(R)) Mice. 1261 2

3,3'-Dimethylbenzidine dihydrochloride is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. 3,3'-Dimethylbenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering 3,3'-dimethylbenzidine dihydrochloride (approximately 99% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 9 or 14 months. The 14-month exposures were planned as 24-month exposures but were terminated early because of rapidly declining animal survival, due primarily to neoplasia. These studies were performed only in rats because similar studies were being performed in mice at the National Center for Toxicological Research (NCTR). Hematologic and serum chemical analyses and thyroid hormone determinations were conducted in conjunction with the 13-week and 9-month studies. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. 14-Day Studies: Rats were exposed to 3,3'-dimethylbenzidine dihydrochloride in drinking water at doses ranging from 600 to 7,500 ppm. All five males and one female in the 7,500 ppm group and 1/5 males in the 5,000 ppm group died. Final mean body weights were decreased in males receiving 1,250 ppm or more and in all exposed females, and final mean body weights of animals receiving 2,500 ppm or more were lower than initial weights. Water consumption decreased with increasing chemical concentration. Compound-related effects observed in rats receiving 5,000 ppm or more included minimal to slight hepatocellular necrosis, accumulation of brown pigment (presumably bile) in individual hepatocytes, increased severity of nephropathy relative to controls, and severe lymphocytic atrophy of the thymus. Treated animals also showed an increased severity of atrophy of the bone marrow relative to controls, varying degrees of lymphocytic atrophy of the mandibular and mesenteric lymph nodes and spleen, increased vacuolization and necrosis of cells of the adrenal cortex, focal acinar cell degeneration in the pancreas, and, in males, increased immature sperm forms in the testis and epididymis. 13-Week Studies: 3,3'-Dimethylbenzidine dihydrochloride was administered in drinking water at doses of 300, 500, 1,000, 2,000, and 4,000 ppm. All rats receiving 4,000 ppm and 4/10 males and 1/10 females receiving 2,000 ppm died before the end of the studies. Depressions in final mean body weight relative to controls ranged from 12% to 48% for males and from 9% to 42% for females. Water consumption decreased with increasing dose. At compound concentrations of 300 to 2,000 ppm, mean water consumption was 29% to 83% of control values. Compound-related effects included an increase in the severity of nephropathy relative to controls; hepatocellular necrosis and accumulation of brown pigment (presumably bile) in sinusoidal lining cells; lymphocytic atrophy of the thymus, spleen, and mandibular and mesenteric lymph nodes; atrophy of the bone marrow in the higher-dose groups; degeneration of pancreatic acinar cells; and, in males, immature sperm forms in the testis and epididymis. Decreases in serum triiodothyronine (T3) values were observed in exposed females, and decreases in mean thyroxin (T4) concentrations in exposed males and females; no significant changes were observed in thyroid stimulating hormone (TSH) levels in exposed rats. Based on the decreased survival, reductions in water consumption and body weight gain, and chemical-induced hepatocellular and renal lesions observed in the 13-week studies, the doses selected for the 9- and 14-month drinking water studies of 3,3'-dimethylbenzidine dihydrochloride were 0, 3 3,3'-dimethylbenzidine dihydrochloride were 0, 30, 70, and 150 ppm. Seventy rats of each sex were used in the control group, 45 in the low-dose group, 75 in the mid-dose group, and 70 in the high-dose group. 9-Month Studies: Ten rats of each sex in the control and 150 ppm dose groups were evaluated after 9 months. Chemical-related effects observed in exposed animals included alveolar/bronchiolar carcinoma in one male, basal cell carcinoma of the skin in one male, a squamous cell carcinoma of the oral cavity in one female, preputial gland carcinoma in two males, clitoral gland carcinoma in three females, adenocarcinoma of the small intestine in two males, Zymbal's gland carcinoma in two males and three females, hepatocellular carcinoma in two males, and adenomatous polyps of the large intestine in three males. Other effects seen in dosed rats included focal cellular alteration in the liver, lymphoid atrophy in the spleen, and increased severity of nephropathy relative to controls. An increase in serum T3 values was observed in exposed males, and a decrease in mean T4 concentrations in exposed males and females. TSH concentrations were increased in exposed male and female rats. Body Weights and Survival in the 14-Month Studies: The average amount of 3,3'-dimethylbenzidine dihydrochloride consumed per day was approximately 1.8, 4.0, or 11.2, mg/kg for low-, mid-, or high-dose male rats and 3.0, 6.9, or 12.9 mg/kg for low-, mid-, or high-dose female rats. The mean body weight of high-dose males was about 85&percnt; of the control value by week 28. By the end of the study, mean body weights of low-, mid-, and high-dose males were 97&percnt;, 92&percnt;, and 70&percnt; of the control values, respectively. Mean body weights of high- and mid-dose females were about 85&percnt; of the control values at week 32 and week 44, respectively. At the end of the study, mean body weights of exposed females were about 94&percnt;, 81&percnt;, and 74&percnt; of the control values for low-, mid-, and high-dose groups, respectively. Because of extensive neoplasia, many exposed males and females were dying or were sacrificed moribund in the first year, and all high-dose males died by week 55. The studies were terminated at weeks 60 to 61, at which time the group survivals were male: control, 60/60, low dose, 41/45; mid dose, 50/75; high dose, 0/60; female: 59/60; 39/45; 32/75; 10/60. Nonneoplastic Effects in the 14-Month Studies: Increases in nonneoplastic lesions in dosed rats included cystic degeneration and foci of cellular alteration in the liver; exacerbation of nephropathy; and focal or multifocal hyperplasia of the Zymbal's gland, preputial and clitoral glands, and alveolar epithelium. Neoplastic Effects in the 14-Month Studies: Neoplasms were observed in exposed rats at many sites: skin, Zymbal's gland, preputial and clitoral glands, liver, oral cavity, small and large intestine, mammary gland, lung, brain, and mesothelium. The incidence of these neoplastic effects in male and female rats is summarized in the table at the end of this section (see page 8 of the Technical Report). Genetic Toxicology: 3,3'-Dimethylbenzidine dihydrochloride was mutagenic in Salmonella typhimurium strain TA98 with exogenous metabolic activation; it was not mutagenic in strains TA100, TA1535, or TA97 with or without activation. 3,3'-Dimethylbenzidine dihydrochloride induced sister-chromatid exchanges (CHO) and chromosomal aberrations in CHO cells in the absence of exogenous metabolic activation; these effects were not evident in test with S9 activation. Sex-linked recessive lethal mutations were induced in germ cells of adult male Drosophila melanogaster administered 3,3'-dimethylbenzidine dihydrochloride in feed or by injection. No reciprocal translocations occurred in D. melanogaster germ cells following exposure to 3,3'-dimethylbenzidine dihydrochloride. Conclusions: Under the conditions of these 14-month drinking water studies, there was clear evidence of carcinogenic activity of 3,3'-dimethylbenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, small and large intestine, lung, and mesothelium. Increased incidences of neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, mammary gland, and lung. Increased incidences of neoplasms of the brain and mononuclear cell leukemia may have been related to chemical administration. Synonyms: o-tolidine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-diamine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-biphenyldiamine dihydrochloride; 4,4'-diamino-3,3'-dimethylbiphenyl dihydrochloride
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PMID:NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethylbenzidine Dihydrochloride (CAS No. 612-82-8) in F344/N Rats (Drinking Water Studies). 1263 69

The genetic susceptibility to basal cell carcinoma (BCC) among Danish psoriatic patients was investigated in association studies with 12 single nucleotide polymorphisms on chromosome 19q13.2-3. The results show a significant association between BCC and the A-allele of a polymorphism in ERCCI exon4 (Odds ratio 12;95% Confidence Interval 1.17-124; p(chi2, two-side) = 0.019) and to a lesser extent with XPD exon6 (p = 0.06). This is in accordance with recent studies of a different group of BCC cases (Rockenbauer et al. (in press) Carcinogenesis; Yin et al. (manuscript submitted for publication). Cancer Epidemiol. Biomarkers Prev), which places two highly influential markers between these two genes. The analysis also confirmed that considerable linkage disequilibrium exists between SNPs both within genes and between genes in this region. The combined studies suggest that genetic variation in nucleotide excision repair is of importance for the development of BCC.
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PMID:Twelve single nucleotide polymorphisms on chromosome 19q13.2-13.3: linkage disequilibria and associations with basal cell carcinoma in Danish psoriatic patients. 1264 71

The new genetic information, in particular the greatly increased density of markers in the chromosomal maps, may permit analysis of the importance of genes in the development of disease exclusively from molecular epidemiological studies. Motivated by our previous results on the same region in relation to basal cell carcinoma we have investigated the occurrence of post-menopausal breast cancer in relation to a number of single nucleotide polymorphisms in the chromosomal region 19q13.2-3. A case-control study including 425 human cases and a similar number of controls was nested in a population-based prospective investigation encompassing 24 697 Danish post-menopausal women (aged 50-64 at inclusion) living in Copenhagen or Aarhus. We combined three markers located together in or near the gene RAI into a high-risk haplotype. Compared with all other haplotypes, those who were homozygous had a rate ratio of 1.64 (95% CI 1.17-2.29, P < or = 0.004) for development of breast cancer. When we further focused on those persons with post-menopausal breast cancer before age 55 the rate ratio increased to 9.5 (95% CI 2.21-40.79, P < or = 0.003). The likely explanation for our results is a common recessive genetic variant located in or near the gene RAI, which, when homozygous, conveys an increased risk of breast cancer. Presumably it is identical to the genetic variant previously observed in the same region that increases the risk of basal cell carcinoma before age 50.
Carcinogenesis 2003 May
PMID:A specific haplotype of single nucleotide polymorphisms on chromosome 19q13.2-3 encompassing the gene RAI is indicative of post-menopausal breast cancer before age 55. 1277 Oct 34

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