Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Six derivatives of a Chinese hamster ovary cell line have been isolated by selection for hypersensitivity to the cytotoxic effects of the monofunctional alkylating agent methyl methane sulphonate (MMS). These cells are up to 6-fold more sensitive to MMS than the parental line, as estimated from D37 values, and are cross-sensitive to methyl nitrosourea, as well as to the ethyl derivatives of these drugs. Comparisons of their sensitivities to the bifunctional alkylating agents cis-platinum (II) diammine dichloride, mitomycin C and melphalan reveals marked phenotypic diversity, with only one mutant, designated MMS-2, exhibiting appreciable hypersensitivity to all of these agents. No striking hypersensitivity to radiation or to the purine analogue caffeine is apparent in any of the mutant lines. Based on their profiles of sensitivity to DNA damaging agents, it would appear that these mutants are phenotypically unlike any previously described mammalian cell mutants and probably represent a number of different genetic complementation groups. These mutants may facilitate an investigation into the mechanisms of repair of alkylation damage in mammalian cells and could prove to be suitable hosts for the cloning of human DNA repair genes.
Carcinogenesis 1987 Apr
PMID:Isolation of alkylating agent-sensitive Chinese hamster ovary cell lines. 310 49

Earlier results on the photodynamic action of several carcinogenic polycyclic aromatic hydrocarbons, and particularly 7,12-dimethylbenz[a]anthracene (DMBA), have been extended to determine if DMBA + near-u.v. light produces damage to DNA. DMBA by itself (30 min, approximately 24 degrees C) introduces relatively few breaks into genomic DNA. The addition of near-u.v. light, however, inserts large numbers of single-strand breaks in a dose-dependent way. Incubation following exposure initially results in the rapid repair of these breaks. A primary role for DNA damage in photodynamic cell killing is not supported by other observations, however. First, caffeine, an inhibitor of radiation-associated DNA repair processes, has only a minor effect on the oxygen-dependent killing of cells exposed to DMBA + u.v. light. Second, along with the repair of DNA breaks, the insertion of additional breaks becomes evident leading to a massive breakdown of genomic DNA due to an endonucleolytic-like attack. And third, lethally affected cells rapidly lose their surface attachment. Because light induces damage in DNA when DMBA is present, it is likely that DMBA becomes closely associated with DNA. Thus, a starting point for mutagenic and carcinogenic action in the absence of light is suggested although activation of DMBA by a P-450 system does not appear to be a prerequisite of DMBA-DNA association. Still, DNA as such may not be the initial or the primary target for light-induced cell killing. In addition to interacting with DNA, DMBA is sequestered by membranes, suggesting that killing results from an oxygen-dependent release of catabolic enzymes. These enzymes, which may come from lysosomes, degrade DNA but concomitantly release surface-attached cells into the medium.
Carcinogenesis 1987 Oct
PMID:7,12-Dimethylbenz[a]anthracene plus near-u.v. light initiates DNA damage and repair in Chinese hamster cells. 311 14

The Gene-Tox Program has identified 61 chemicals that have been tested in chronic rodent carcinogenesis bioassays and found to be inactive. The genetic toxicology data of these 61 non-carcinogens is reviewed and summarized. A large proportion of these chemicals have been tested to a limited extent in genetic toxicity bioassays: 32 in 2 tests or less. Of the remaining 29 chemicals, 28% have been tested in 9 or more tests which encompass a range of genetic endpoints: gene mutation, chromosomal effects, other genetic endpoints, and cell transformation. The genetic toxicity of 12 chemicals with sufficient data is discussed in detail: benzoin, caffeine caprolactam, ethanol, halothane, hycanthone methanesulfonate, malathion, maleic hydrazide, methotrexate, 1-naphthylamine, 4-nitro-o-phenylenediamine, and p-phenylenediamine. A new technique for the evaluation of multiple test data, the "genetic activity profile", has been applied to 6 of these chemicals, allowing the qualitative and quantitative information to be compared collectively. In the evaluation of the genotoxicity effects of these non-carcinogens, a number of discrepancies between the results from genetic toxicity bioassays and chronic rodent bioassays have been uncovered. These discrepancies are discussed in light of current knowledge on the strengths and weaknesses of both genetic toxicity bioassays and chronic rodent bioassays.
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PMID:The genetic toxicology of Gene-Tox non-carcinogens. 328 85

Human over-use of analgesics containing phenacetin, antipyrene (phenazone) and caffeine has been associated with the development of both renal pelvic and bladder tumors. In Sprague-Dawley rats antipyrene has been shown to be a weak complete urinary tract carcinogen. The present study was designed to evaluate the promoting capacity of antipyrene in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced urinary tract carcinogenesis. One hundred and eighty male Sprague-Dawley rats were divided into groups of 30 and were treated with the following chemicals in the diet: group 1 received a control diet without chemicals; group 2 was treated with 0.2% FANFT in the diet for five weeks followed by control diet; group 3 received 0.2% FANFT for five weeks followed by 0.535% antipyrene in the diet; group 4 was treated with 0.535% antipyrene; group 5 was treated with 0.102% caffeine; and group 6 was treated with 0.535% antipyrene and 0.102% caffeine in the diet. Ten of 27 rats in group 3 (37%) developed urinary tract tumors (P greater than 0.001, five of which were renal pelvic tumors and five were bladder tumors. The majority of the tumors were well differentiated non-invasive urothelial carcinomas. None of the rats in other groups developed urinary tract tumors. In addition, renal papillary necrosis (RPN) was found in 33% of the rats in group 3, 50% in group 4, and 10% in group 6. The present study clearly shows that antipyrene acts as a promoter of FANFT-induced urinary tract carcinogenesis and that it is nephrotoxic to the renal papilla resulting in renal papillary necrosis.
Carcinogenesis 1988 May
PMID:The influence of antipyrene on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced urinary tract carcinogenesis. 336 39

The effects of coffee on exocrine pancreatic secretion are unknown but may be important, because a link between chronic stimulation of pancreatic secretion and experimental chemical carcinogenesis and an association between coffee drinking and human pancreatic adenocarcinoma have been reported. We measured exocrine pancreatic trypsin and gastric acid secretions collected through orogastroduodenal tubes and serum gastrin in eight non-coffee drinkers and eight coffee drinkers. During fasting, after one interdigestive cycle control period, one of four 250-ml samples [plain water, water plus caffeine (4.6 mg/kg), decaffeinated coffee (127.9 mg/kg), caffeinated coffee (127.9 mg/kg)] was administered through the orogastric tube. Caffeinated and decaffeinated coffee (p = 0.008), caffeine (p = 0.03), and an unidentified substance(s) in coffee other than caffeine (p = 0.008) were associated with increased interdigestive exocrine pancreatic trypsin secretion. In addition, we also confirmed that coffee and caffeine stimulated gastric acid secretion (p = 0.02) and decaffeinated coffee raised serum gastrin concentrations (p = 0.005). If an association between coffee and pancreatic carcinogenesis exists, chronic stimulation of the exocrine pancreas by secretagogues could result in a gland susceptible to carcinogenesis.
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PMID:The acute effects of coffee and caffeine on human interdigestive exocrine pancreatic secretion. 357

The present experimental study was undertaken to clarify whether phenacetin and caffeine exert a cocarcinogenic and/or promoting effect on N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-initiated urothelial carcinogenesis. BBN was initially administered to female Wistar rats by gavage in 3 consecutive fractionated doses of 100 mg/kg body weight each at 24-hour intervals. Phenacetin was continuously fed at a daily dose of 500 mg/kg body weight, and caffeine was given in the drinking water at a dose of 110 mg/kg body weight/day throughout the experiment. After an experimental period of 21 months the incidence of BBN-induced tumors in the urinary bladder (number of rats with a bladder tumor) had not increased following additional administration of phenacetin alone (47%) or in combination with caffeine (48%) compared with the control group, the animals of which received exclusively BBN (44%). However, there was a significant enhancement of a multifocal tumor development (number of rats with more than 1 tumor in the bladder), when additionally phenacetin was fed alone (44% of the tumor-bearing animals) or in combination with caffeine (47%) compared with the control rats treated with BBN alone which showed only solitary tumors. Similarly, the incidence of a multicentric tumor development had increased, although not significantly, following administration of phenacetin alone or simultaneously with caffeine for 15 months. Caffeine revealed no complete initiating carcinogenic potential for the resting as well as the regenerating bladder urothelium stimulated to proliferate by either a partial cystectomy or cyclophosphamide. Furthermore, no cocarcinogenic and/or promoting activity of caffeine on BBN-initiated bladder tumor development was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of phenacetin and caffeine on N-butyl-N-(4-hydroxybutyl)-nitrosamine-initiated urothelial carcinogenesis in rats. 361 38

One objective of this study was to determine the effects of N-hydroxy-2-acetylaminofluorene (N-OH-AAF) treatment on DNA synthesis in regenerating rat liver. Rats were subjected to a two-thirds hepatectomy followed 20 h later by i.p. injection of N-OH-AAF. 4 h after carcinogen injection, it was found that N-OH-AAF caused a dose-dependent inhibition of [3H]thymidine incorporation into liver DNA. This inhibition was followed by a gradual, but incomplete recovery beginning 28 h after carcinogen treatment. Radioimmunoassay of deoxyguanine-C8 adducts remaining in liver DNA indicated that the recovery began prior to detection of adduct removal. The second objective of the study was to determine the effects of DNA damage on the size distribution and elongation of nascent hepatocyte DNA. Hepatocytes, which have been shown to demonstrate a pattern of inhibition and subsequent recovery of DNA synthesis following UV irradiation similar to that seen in vivo upon treatment with N-OH-AAF (Zurlo and Yager, 1984), were cultured under conditions that promote replicative DNA synthesis. The size distribution of nascent DNA after UV irradiation was determined by pH step gradient alkaline elution analysis. [3H]Thymidine pulse times and subsequent chase times were adjusted to equalize amounts of DNA synthesis in control and UV-irradiated cells. The results show that UV irradiation caused a dose-dependent decrease in the size distribution of nascent DNA suggesting an inhibition of elongation. Pulse-chase studies revealed that subsequent joining of nascent chains in UV-irradiated hepatocytes occurred at a rate comparable to or faster than controls and that this could be inhibited by caffeine. The results obtained from both the in vivo and in vitro studies show that resumption of DNA synthesis and nascent strand elongation occur on damaged templates. These observations along with our previous studies demonstrating the ability of UV-irradiated hepatocytes to carry out enhanced reactivation of UV-irradiated herpes virus lend support to the idea that DNA damage leading to inhibition of DNA synthesis may induce SOS-type processes which if mutagenic may play a role in the initiation of carcinogenesis.
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PMID:Effects of carcinogen treatment on rat liver DNA synthesis in vivo and on nascent DNA synthesis and elongation in cultured hepatocytes. 372 70

The effects of modification of poly(ADP-ribosyl)ation reactions have been examined in normal (F107) and ataxia telangiectasia (AT23) fibroblasts following damage by methyl methanesulphonate (MMS) and u.v. light. The technique of benzoylated DEAE (BD)-cellulose chromatography was utilized to estimate both the extent and nature of the damage to DNA induced by these agents and to examine the effects of an inhibitor of poly(ADP-ribose) synthetase, 3-aminobenzamide (3AB), on these parameters. Single strand breakage, determined by nucleoid sedimentation, and levels of poly ADP(ribose) synthesis were monitored. Increase in the proportion of DNA containing single-stranded regions, as measured by stepwise elution from BD-cellulose, was observed following MMS damage in both cell types. In the presence of 3AB, a further accumulation of DNA containing single-stranded regions occurred, with the effect being more prominent in AT23 fibroblasts. U.v. light damage did not induce increased binding to BD-cellulose in normal cells, and the increase observed in AT23 cells was much less than that seen following alkylation damage. Examination of the nature of single-stranded damage by caffeine gradient elution from BD-cellulose following MMS treatment revealed discrete structural lesions, which were enhanced in the presence of 3AB. A similar effect was exerted by arabinofuranosyl cytosine. The behaviour of these intermediates, which could be associated with repair, was not in accord with the suggestion that 3AB inhibits only the ligation stage of the repair process. Our results suggest that specific intermediate stages in DNA repair are sensitive to 3AB, and it seems likely that these stages occur prior to ligation.
Carcinogenesis 1987 Jan
PMID:Inhibition of poly(ADP-ribose) synthesis may affect DNA repair prior to ligation. 380 93

A dietary case-control study based on 818 newly diagnosed breast cancer (BC) patients was conducted in Israel between 1975 and 1978. The role of coffee and total methylxanthine intake from coffee, tea, cola, chocolate, and cocoa drinks was evaluated in the BC patients as compared to that in two matched control populations [surgical controls (SC) and neighborhood controls (NC)]. Because it has been suggested that caffeine enhances mammary carcinogenesis in rats fed high polyunsaturated fat diets, analysis was done also in relation to fat consumption. When comparison was done to both matched control groups, a nonsignificant negative association was found between consumption of cups of coffee and BC (odds ratios of greater than or equal to 4 cups of coffee/day vs. less than or equal to 1 per week = 0.6 for BC/NC and 0.7 for BC/SC). This association was observed in all 3 ethnic subgroups studied. The pattern was stronger among the high-fat consumers after controlling for several hormonal confounding factors (two-tailed P-value for linear trend = 0.06 for SC and P = 0.05 for NC). In addition, when the consumption of methylxanthine of BC patients was compared to that of benign breast patients, adjusted by age and ethnic group, a diminished risk was found (odds ratio for BC of the highest level of methylxanthine vs. lowest level = 0.59).
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PMID:Coffee and methylxanthines and breast cancer: a case-control study. 385 60

The use of mutagenicity data has been proposed and widely accepted as a relatively fast and inexpensive means of predicting long-term risk to man (i.e., cancer in somatic cells, heritable mutations in germ cells). This view is based on the universal nature of the genetic material, the somatic mutation model of carcinogenesis, and a number of studies showing correlations between mutagenicity and carcinogenicity. An uncritical acceptance of this approach by some regulatory and industrial concerns is over-conservative, naive, and scientifically unjustifiable on a number of grounds: Human cancers are largely life-style related (e.g., cigarettes, diet, tanning). Mutagens (both natural and man-made) are far more prevalent in the environment than was originally assumed (e.g., the natural bases and nucleosides, protein pyrolysates, fluorescent lights, typewriter ribbon, red wine, diesel fuel exhausts, viruses, our own leukocytes). "False-positive" (relative to carcinogenicity) and "false-negative" mutagenicity results occur, often with rational explanations (e.g., high threshold, inappropriate metabolism, inadequate genetic endpoint), and thereby confound any straightforward interpretation of mutagenicity test results. Test battery composition affects both the proper identification of mutagens and, in many instances, the ability to make preliminary risk assessments. In vitro mutagenicity assays ignore whole animal protective mechanisms, may provide unphysiological metabolism, and may be either too sensitive (e.g., testing at orders-of-magnitude higher doses than can be ingested) or not sensitive enough (e.g., short-term treatments inadequately model chronic exposure in bioassay). Bacterial systems, particularly the Ames assay, cannot in principle detect chromosomal events which are involved in both carcinogenesis and germ line mutations in man. Some compounds induce only chromosomal events and little or no detectable single-gene events (e.g., acyclovir, caffeine, methapyrilene). In vivo mutagenicity assays are more physiological but appear to be relatively insensitive due to the inability to achieve sufficiently high acute plasma levels to mimic cumulative long-term effects. Examination of the mutagenicity of naturally occurring analogs may indicate the irrelevance of a test compound's mutagenicity (e.g., deoxyguanosine and the structurally related antiviral drug, acyclovir, have identical mutagenicity patterns). Life-threatening or severe debilitating diseases (e.g., cancer, severe psychoses, severe crippling arthritis, sight-threatening diseases) may justify treatment with mutagenic or even carcinogenic therapeutic agents (benefit/risk considerations).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mutagenicity in drug development: interpretation and significance of test results. 399 35


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