G→A mutations in p53 and Ha‐ras genes in esophageal papillomas induced by N‐nitrosomethylbenzylamine in two strains of rats

Lozano, Jean-Claude; Nakazawa, Hisayoshi; Cros, Marie-Pierre; Carbral, Ricardo; Yamasaki, Hiroshi

doi:10.1002/mc.2940090107

Cited by 57 publications

(32 citation statements)

References 29 publications

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“…In contrast, the IARC mutation spectrum data on all gastric cancers document a higher frequency of 35.1% at CpG sites Vs 23.2% at nonCpG sites [IARC R12 release, 2007] [57]. Presence of alkyl nitrosamine in food stuffs, leading to O 6 -alkyl guanine adducts and base mispairing during replication, resulting in G>A (or C>T on the other strand of the DNA) transition [79] has been implicated in the etiopathogenesis of oesophageal and gastric carcinomas [80,81,82]. However, to establish a correlation between the enhanced tranvertions in our patients and the presence of carcinogens already reported or unreported to be present in the local food stuffs needs further investigations.…”

Section: Mutation Pattern Data (21) (%) Mutation Effect Data (21) (%)mentioning

confidence: 99%

P53- The Molecular Guardian Crashes in Gastric Adenocarcinomas - A Study in an Ethnic Kashmiri Population

Abdullah¹,

A²,

Dil-Afroze³

et al. 2010

J Carcinogene Mutagene

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Section: Mutation Pattern Data (21) (%) Mutation Effect Data (21) (%)mentioning

confidence: 99%

P53- The Molecular Guardian Crashes in Gastric Adenocarcinomas - A Study in an Ethnic Kashmiri Population

Abdullah¹,

A²,

Dil-Afroze³

et al. 2010

J Carcinogene Mutagene

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“…Additional evidence in support of this concept is the observation that transgenic rats carrying the human c-Ha-ras proto-oncogene are highly susceptible to the induction of esophageal tumors with NMBA (Asamoto et al, 2002). As has been found in human esophageal tumors, G:C→ A:T transition mutations have been observed in the p53 tumor suppressor gene in ∼30 % of rat esophageal papillomas (Lozano et al, 1994;. These mutations have been found to be evenly distributed across the gene; no "hot-spots" were found for these mutations in the gene.…”

Section: Rat Esophageal Tumor Modelmentioning

confidence: 74%

“…Mutations in oncogenes and tumor suppressor genes in rat esophageal tumors are most likely due to formation of methylated guanine adducts in esophageal DNA. In contrast to human esophageal tumors, a large majority, between 60 and 100%, of NMBA-induced rat esophageal papillomas have a G:C→ A:T transition mutation in codon 12 of the H-ras gene (Lozano et al, 1994;). One study indicated that G →A mutations in codon 12 of the gene occur at very low frequency in early premalignant lesions of the esophagus and increase proportionately in lesions that progress to papilloma (Liston et al, 2000).…”

Section: Rat Esophageal Tumor Modelmentioning

confidence: 99%

Chemoprevention of esophageal squamous cell carcinoma

Stoner

Wang

Chen

2007

Toxicology and Applied Pharmacology

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Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancerrelated mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, and to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.

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“…Rat mammary and esophageal tumors caused by MNU and NMBA, respectively, are known to have high incidences of c-Ha-ras gene codon 12 mutations (GGA to GAA). [26][27][28] In contrast, mutations in the c-Ha-ras gene are rare in bladder or liver tumors induced by carcinogens in rats. [34][35][36] We have found that our Hras128 strain is highly susceptible to MNU-induced mammary, 9) N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder 37) and, in the present work, NMBA-induced esophageal carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…23,24) In line with this hypothesis, G to A mutations in codon 12 of c-Ha-ras are frequent in tumors induced by NMBA in rats. [25][26][27][28] Mammary carcinomas induced by N-methyl-N-nitrosourea (MNU) in rats also often demonstrate c-Ha-ras mutations. 29) We have reported the Hras128 rats carrying the same human c-Ha-ras proto-oncogene to be highly susceptible to mammary carcinogenesis induced by MNU, and we showed that the induced carcinomas contain minor popula- 3 To whom requests for reprints should be addressed.…”

mentioning

confidence: 99%

Transgenic Rats Carrying Human c‐Ha‐ras Proto‐oncogene Are Highly Susceptible to N‐Nitrosomethylbenzylamine Induction of Esophageal Tumorigenesis

Asamoto

Toriyama‐Baba

Ohnishi

et al. 2002

Japanese Journal of Cancer Research

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A transgenic rat line carrying three copies of the human c-Ha-ras proto-oncogene, including its own promoter region, has been established in our laboratory (Hras128 rats), and shown to be highly susceptible to induction of mammary and urinary bladder tumors. Mutation analysis of induced lesions indicated the majority to contain some but not all cells with transgene mutation. In the present study, the susceptibility of Hras128 rats to N-nitrosomethylbenzylamine (NMBA) induction of esophageal tumors was examined with a similar mutation analysis of the transgenes. Male 6-week-old Hras128 and wild littermate rats were treated with NMBA, 0.5 mg/kg subcutaneously, 3 times a week for 5 weeks and then maintained for 5 weeks without any further treatment. Multiple esophageal tumors, squamous cell papillomas and carcinomas, rapidly developed within this 10-week experimental period in Hras128 rats (11.05 ± ± ± ±7.83/rat). In contrast, wild-type littermates had only small numbers of mostly benign tumors (1.67 ± ± ± ±2.06/rat). The Hras128 rats had no other tumors or abnormalities. In their esophageal lesions, codon 12 GGC to GAC mutations of the transgene were frequently detected by restriction fragment length polymorphisms (RFLP) and subsequent direct sequencing analysis (19/25, 76%). In the endogenous rat c-Ha-ras gene they were less frequent (2/25, 8%), than in wild-type rats (8/14, 57.1%). The densities of mutated bands in the RFLP analysis indicated that mutated cells were major populations in tumors, in contrast to the case with mammary and urinary bladder lesions. Furthermore, activated ras protein, detected by binding to raf protein, was clearly increased in tumors as compared to surrounding epithelium or the normal esophagus of untreated rats. The results show that Hras128 rats are highly susceptible to NMBA esophageal carcinogenesis, as well as induction of mammary and urinary bladder tumors, but that tissue-specific characteristics exist for the roles of transgene ras mutations.Key words: Transgenic rats -c-Ha-ras -Esophageal tumors -N-Nitrosomethylbenzylamine Transgenic mice are widely used for analysis of gene function and as animal models for various diseases. In the field of chemical carcinogenesis, transgenic mice harboring a human c-Ha-ras proto-oncogene, 1, 2) v-Ha-ras transgenic mice (Tg.AC mice),3) pim-1 transgenic mice 4) and p53 knockout mice 5) have been shown to be highly susceptible to tumor induction by certain carcinogens, with indication that the transgene is actively involved. However, for studies of chemical carcinogenesis, 6) rats have been more frequently used, so that abundant information has accumulated regarding various biological characteristics of preneoplasias. 7,8) Therefore the Hras128 rats generated in our laboratory have great potential for studies of neoplasia. 9,10) For esophageal tumors, rats are preferable to mice 11,12) due to the availability of the organotropic carcinogens and the larger size of the organ.Human esophageal squamous cell carcinomas are presumed to be caused by ...

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G→A mutations in p53 and Ha‐ras genes in esophageal papillomas induced by N‐nitrosomethylbenzylamine in two strains of rats

Cited by 57 publications

References 29 publications

P53- The Molecular Guardian Crashes in Gastric Adenocarcinomas - A Study in an Ethnic Kashmiri Population

P53- The Molecular Guardian Crashes in Gastric Adenocarcinomas - A Study in an Ethnic Kashmiri Population

Chemoprevention of esophageal squamous cell carcinoma

Transgenic Rats Carrying Human c‐Ha‐ras Proto‐oncogene Are Highly Susceptible to N‐Nitrosomethylbenzylamine Induction of Esophageal Tumorigenesis

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