Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human prostate carcinogenesis has been viewed as a multi-step process involving progression from low histologic grade, small, latent carcinoma to large, higher grade, metastasizing carcinoma. However, recent data suggest that a variety of pathogenetic pathways may exist. The precise etiology and pathogenesis of human prostate cancer remain largely undefined. It is difficult to investigate stages in the development of human prostate cancer, but some animal models provide opportunities in this regard. Short-term treatment of rats with chemical carcinogens produces a low incidence (5-15%) of prostate cancer, provided that prostatic cell proliferation is enhanced during carcinogen exposure. Chronic treatment with testosterone also produces a low prostate carcinoma incidence. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens such as N-methyl-N-nitrosourea (MNU) and 3,2'-dimethyl-4-aminobiphenyl (DMAB). Testosterone markedly enhances prostate carcinogenesis even at doses that do not measurably increase circulating testosterone. Thus, testosterone is a strong tumor promoter for the rat prostate. All such MNU- or DMAB-initiated and/or testosterone-promoted tumors are adenocarcinomas; most originate from the dorsolateral and anterior, but not ventral, prostate lobes. These tumors share a number of important characteristics with human prostate cancer. A high frequency (70%) of activation of the K-ras gene by a G35 to A mutation occurs in these carcinomas. Another high incidence prostate carcinogenesis model, representing a different pathogenetic pathway, involves chronic administration of estradiol-17 beta to rats in combination with low-dose testosterone. The resulting carcinomas are low-grade and originate exclusively from periurethral ducts of the dorsolateral and anterior prostate. While it is unknown whether testosterone is a tumor promoter in this system, preliminary studies indicate the formation of a DNA adduct in the target tissue, which suggests that estradiol-17 beta acts as a tumor initiating agent in this system. The high incidence models mentioned earlier are adequate for the study of chemoprevention of prostatic carcinogenesis. Analysis of shifts in the relative incidence of metastasizing carcinoma, grossly apparent but not-metastasizing carcinoma, microscopic-size carcinoma, and carcinoma in situ or atypical hyperplasia may allow study of the modifying effects of potential chemopreventive agents on tumor progression in these animal models of prostatic carcinogenesis.
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PMID:Animal models for the study of prostate carcinogenesis. 128 79

To investigate the role of K-ras mutations in canine non-small cell lung cancer, we first determined the nucleotide sequence of the normal canine K-ras gene and then examined 21 canine lung tumors for activating K-ras mutations. Canine K-ras was analyzed by direct sequencing of polymerase chain reaction products generated with oligonucleotide primers derived from the human K-ras sequence. Four nucleotide differences were found between the canine and human K-ras sequence from position 5 to 211. The deduced amino acid sequence of the canine gene was identical to that of the human. Activated K-ras alleles were detected in 5 of the 21 canine lung tumors examined. The activating lesions were point mutations, predominantly in codon 12. Of the 14 adenocarcinomas examined, 2 (14%) had K-ras mutations. Two of 5 (40%) adenosquamous carcinomas and the only large cell carcinoma also contained activated alleles. The overall frequency of K-ras point mutation in non-small cell lung cancer (25%) is similar to that reported in human non-small cell lung cancer. We conclude that K-ras activation by point mutation is associated with, but not necessary for, non-small cell lung cancer development in the dog.
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PMID:K-ras activation in non-small cell lung cancer in the dog. 132 92

DNA extracted from 29 colorectal carcinomas and 40 sporadic adenomas was amplified by the polymerase chain reaction (PCR) and analysed for the presence of K-ras gene mutations at codon 12 using a panel of synthetic oligonucleotide probes specific for normal and mutated sequences. The presence of mutations was correlated with various histopathological and clinical data. Ten carcinomas (34.5%) and 14 sporadic adenomas (35%) showed K-ras mutations at codon 12. In the carcinoma group, no apparent correlation was found between the presence of mutant oncogenes and the degree of histological differentiation, Dukes' staging or the development of distant metastasis. In the adenoma group, the frequency of mutations increased with the size of the adenoma and the severity of the dysplastic changes. This study confirms that ras gene mutations are common and early events in colon carcinogenesis. They appear to give a selective growth advantage to those polyps with mutations which leads to their increase in size and thus possibly prepare the ground for malignant transformation.
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PMID:K-ras gene mutations in adenomas and carcinomas of the colon. 134 Dec 61

The frequency of H-ras, K-ras, and N-ras mutations and the presence of high-risk human papillomavirus (HPV 16, 18, and 33) DNA were studied in 75 paraffin-embedded specimens obtained from 68 Japanese patients with a variety of prostate carcinomas by using polymerase chain reaction and DNA hybridization with sequence-specific oligonucleotides. Ten specimens each of normal and benign hyperplastic prostatic tissues from the same number of patients were also examined for this analysis. Of 68 carcinoma cases, ras gene mutations were present in 16 cases (24%) and HPV DNAs in 28 cases (41%). Eleven mutations were detected in codon 61 of H-ras, 4 in codon 12 of N-ras, and 2 in codon 61 of K-ras. HPV 16, 18, and 33 DNAs were found in 11, 17, and 5 cases, respectively. Eight of the 16 cases with ras mutation also harbored HPV DNAs. The frequency of ras mutations and the HPV infection increased in patients with advanced stages of the tumor and with the higher Gleason score. There was the predominant presence of H-ras codon 61.2 (CAG-->CTG) mutation and HPV 18 DNA in prostatic carcinomas metastasizing to the bone. None of the normal or benign hyperplastic prostatic specimens contained either ras mutation or HPV DNA. Our results suggest that ras gene mutations and HPV infections are relatively frequent, at least in prostate carcinoma of Japanese patients. These two factors appear to be related to the progression of the tumor. Moreover, H-ras codon 61.2 mutation and HPV 18 infection may have some predictive roles for bone metastasis in prostate carcinoma.
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PMID:Presence of ras oncogene mutations and human papillomavirus DNA in human prostate carcinomas. 138 50

RAS protein (p21 ras) requires farnesyl (an intermediate of cholesterol synthesis) for activation. Activating mutations of K-ras gene have been detected in most human pancreatic adenocarcinomas. In the present study, the effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, the rate-limiting enzyme of cholesterol synthesis, on the growth of five pancreatic cancer cell lines (human-CAV, MIA Paca2, CAPAN2 and PANC1, and hamster-H2T) in vitro and of two cell lines (CAV and H2T) in vivo was examined. Inhibition of cell growth was observed with lovastatin doses at or above 2.5 micrograms/mL for H2T, CAV, MIA Paca2, and CAPAN2 or 10 micrograms/mL in PANC1. The H2T cell line was studied further to determine the reversibility of growth inhibition. Mevalonic acid (1 mmol/L) reversed lovastatin-induced inhibition of cell growth if it was added with lovastatin (2.5 micrograms/mL). Similarly, removal of lovastatin from the medium within 24 hours after treatment allowed recovery of cell growth. The effect of lovastatin on cell growth was irreversible after 48 hours of exposure. The survival fraction of H2T cells was markedly decreased by 1- or 24-hour exposure to 75 micrograms/mL but not to doses ranging from 0.5 to 60 micrograms/mL of lovastatin. Growth of pancreatic carcinoma xenografts (CAV and H2T) in nude mice was inhibited by a subcutaneous infusion of lovastatin (50 micrograms/h). These results indicate that mevalonic acid or a metabolite in the cholesterol synthesis pathway is necessary for growth of pancreatic cancer cells and suggest that lovastatin should be further examined as a potential therapeutic agent for pancreatic cancer.
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PMID:Inhibition of pancreatic adenocarcinoma cell growth by lovastatin. 149 46

Twenty-three clinically silent prostatic carcinomas discovered in Japanese men at autopsy were surveyed for ras proto-oncogene mutations by mutation-specific oligonucleotide probe hybridization after polymerase chain reaction (PCR) amplification from a section of formalin-fixed, paraffin-embedded tissue. Six of the 22 that were satisfactory amplified contained activating point mutations in codon 12 of K-ras, a significantly higher frequency than has been reported in patients with clinically advanced disease in the United States. Of the six cases with activating point mutations in codon 12 of K-ras, one had a GGT----GAT transition, four had GGT----GTT transversions, and one had both GGT----GAT and GGT----GTT mutations. Sections from the same tissues were immunohistochemically stained with an anti-ras p21 antibody. Carcinoma cells stained for ras p21 to some degree in 13 cases. Immunohistochemically detectable expression of p21 was always focal and was not necessarily associated with K-ras mutation. K-ras oncogene activation in prostatic carcinoma appears to merit additional study as a significant event in the pathogenesis of this neoplasm.
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PMID:K-ras activation and ras p21 expression in latent prostatic carcinoma in Japanese men. 156 75

Activation of ras oncogenes is commonly found in human neoplasms. We have investigated 280 human lung cancer specimens for ras activation, including 38 that have not been reported previously, using an oligonucleotide detection assay. From a total of 141 adenocarcinoma samples from smokers, 41 tested positive for a point mutation in codon 12 of K-ras (30%), while three tumors had another type of ras activation. Only two of 40 cases from nonsmokers had a K-ras mutation (5%), suggesting that K-ras mutations may be directly caused by exposure to carcinogens in tobacco smoke. The majority of the point mutations in adenocarcinomas were guanine to thymine transversions in codon 12 of the K-ras oncogene. Occasional point mutations in ras oncogenes were detected in adenosquamous carcinomas (one of five cases) and large cell carcinoma (one of 24 cases), but no ras activations were found in small cell carcinomas (six cases), squamous carcinomas (48 cases), carcinoid carcinomas (15 cases), or thymoma (one case). Analysis of the clinical and pathological features of the adenocarcinoma cases showed no apparent associations between the K-ras activation and age at diagnosis, sex, disease stage, and the occurrence of other neoplasms. K-ras-positive adenocarcinomas tended to be less differentiated than the K-ras-negative ones (P = 0.044, chi 2 test for trend). K-ras mutations identify a subgroup of patients with adenocarcinoma of the lung who have a very poor prognosis despite radical resection of their tumor. Although K-ras has been proposed as a target for antitumor therapy, its major clinical significance could be to aid in the selection of patients for specific therapeutic interventions, such as adjuvant chemotherapy.
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PMID:Clinical significance of ras oncogene activation in human lung cancer. 156 97

Ras oncogene mutations are found in a significant number of human colonic carcinomas. Correlation between patient survival and ras mutations was explored and compared with other clinical parameters. Colonic carcinoma embedded in paraffin was subjected to the polymerase chain reaction using primers to amplify codon 12 of the K-ras oncogene. Oligonucleotide probes to six mutations were used to identify mutated genes. A total of 71 cases were successfully amplified. Some 54% of the cases had mutations. There was no correlation between presence of a mutation and age. Patients in Stage D, patients with a family history of carcinoma, and males have a greater incidence of ras mutations. Patients in Stage C had a lower incidence of mutations. Presence of the mutation did not correlate with decreased survival except in Stage D. Some 61% of long-term survivors with colon carcinoma living for more than 6 yr had ras mutations. The absence of K-ras mutations did not identify long-term survivors.
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PMID:Lack of ras mutations and prediction of long-term survival in carcinoma of the colon. 157 89

The role of the type II cell in the development of pulmonary tumors induced in the adult A/J mouse (6 weeks of age) by treatment with a single dose (100 mg/kg, i.p.) of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was investigated. Twenty-four h following treatment with NNK, the concentration of O6-methylguanine was similar in Clara and type II cells. However, hyperplasias were detected only along the alveolar septa in lungs 14 weeks after carcinogen treatment. Examination of the ultrastructure of several hyperplasias revealed that the proliferating cells resembled type II pneumocytes. The proliferating cells were cuboidal in shape, with centrally localized ovoid nuclei characterized by minor indentations. Lamellar bodies, one of the major hallmarks of the type II cell, were present in the cytoplasm. The progression of pulmonary lesions was followed by sacrificing mice at 4-week intervals from 14 to 54 weeks after treatment with NNK. From 34 to 42 weeks after treatment, progression to neoplasia was demonstrated by a decline in the frequency of hyperplasias and an increase in the frequency of adenomas. Approximately 50% of the adenomas were observed arising within hyperplasias. Carcinomas appeared to increase in frequency 34 weeks after carcinogen treatment and comprised greater than 50% of the pulmonary lesions by 54 weeks. Approximately 30% of the carcinomas were observed arising within adenomas. The growth pattern of carcinomas began to change from solid to mixed (solid and papillary) 42 weeks after NNK. Moreover, electron micrographic analysis demonstrated that, within a hyperplasia, proliferating type II cells could change from cuboidal to columnar in shape and could also exhibit nuclear indentations, both characteristics displayed by the Clara cell. Thus, this divergence of the type II cell from its well characterized morphological features indicates that the selective growth advantage which these initiated cells possess can result in changes to the normal ultrastructure of this cell as it progresses toward malignancy. DNA was isolated from 20 hyperplasias and screened for the presence of an activated K-ras gene. This gene was activated in 17 of 20 lesions, with 85% of the mutations involving a GC to AT transition within codon 12 (GGT to GAT), a mutation consistent with base mispairing produced by the formation of the O6-methylguanine adduct. This specificity for activation of the K-ras gene was identical to that observed previously in adenocarcinomas induced by NNK.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of the alveolar type II cell in the development and progression of pulmonary tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in the A/J mouse. 159 28

Recent advances in understanding the molecular etiology of colorectal carcinoma have made possible a discussion of molecular targets for therapy of the disease. The genes for two inherited predispositions, familial adenomatous polyposis and the Lynch syndrome, have been mapped to specific chromosomal locations. At least five of the genes that are altered in structure or expression to give rise to the tumorigenic phenotype have been isolated by molecular cloning: The K-ras and N-ras protooncogenes have been shown to be altered by point mutation, and expression of the c-myc protooncogene is deregulated. The p53 and DCC genes, both tumor suppressor genes or antioncogenes, are deleted or altered so as to be rendered nonfunctional. Although a single tumor may not suffer all these changes, available evidence indicates that most colorectal tumors contain at least one of these alterations. In addition, work in cell culture and animal systems indicates that tumor cells may be converted to nonmalignant cells by reversing the effects of just one of these changes.
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PMID:Are there molecular targets for therapy of colon cancer? 166 28


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