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

pBR322 plasmid DNA, randomly substituted with arylamine moieties, was introduced into Escherichia coli Uvr endonuclease deficient strains. Plasmid survival was determined by selection in the presence of ampicillin. Modification of plasmid DNA with N-acetoxy-N-trifluoroacetylaminobiphenyl yielded primarily N-(deoxyguanosin-8-yl)-4-aminobiphenyl residues. Reaction of DNA with N-acetoxy-N-acetylaminobiphenyl produced only N-(deoxyguanosin-8-yl)-4-acetylaminobiphenyl adducts. The aminobiphenyl (ABP) and acetylaminobiphenyl adducts reduced the ability of the plasmid DNA to transform E. coli to approximately the same extent in a wild-type strain. In uvrA, uvrB and uvrC, i.e. Uvr endonuclease deficient strains, both adducts produced equivalent decreases in survival, however, the reduction in survival was much more pronounced in the uvr- cells than in the wild-type strain. A similar pattern of toxicity was observed with plasmids carrying N-(deoxyguanosin-8-yl)-2-acetylaminofluorene adducts, although the acetylaminofluorene adduct was approximately 5-fold more effective in reducing the biological activity of the plasmid. In contrast, the deacetylated aminofluorene (AF) lesion, N-(deoxyguanosin-8-yl-2-aminofluorene, exhibited relatively little effect on plasmid survival in uvrA and uvrB cells as compared to the wild-type strain, even though the survival of both ABP and AF adducts was essentially similar in the uvrC and wild-type strains. These data demonstrate that (i) both the deacetylated and acetylated lesions are subject to repair by the Uvr endonuclease complex, and (ii) the presence of the N-acetyl group is not the sole determinant of the differential effects of arylamine adducts in uvr cells. These observations provide indirect evidence that both the N-acetyl and aryl moieties of these adducts alter the conformation of DNA.
Carcinogenesis 1990 Apr
PMID:Comparative survival of aminobiphenyl- and aminofluorene-substituted plasmid DNA in Escherichia coli Uvr endonuclease deficient strains. 218 16

Toxicology and carcinogenesis studies of ampicillin trihydrate and penicillin VK, two widely used beta-lactam antibiotics, were performed in F344/N rats and B6C3F1 mice. In these studies ampicillin trihydrate was administered for 2 years to rats at doses of 0, 750, or 1500 mg/kg and to mice at doses of 0, 1500, or 3000 mg/kg, and penicillin VK was administered to rats and mice at doses of 0, 500, or 1000 mg/kg. Both drugs were administered by oral gavage in corn oil. Toxic lesions of the stomach were seen in rats and mice after ampicillin trihydrate administration and in mice after penicillin VK administration. In male rats that received ampicillin trihydrate there was a marginal increase in incidence of mononuclear cell leukemia and pheochromocytomas of the adrenal gland medulla. There was no evidence for carcinogenic activity in female rats or male and female mice after ampicillin trihydrate administration or in rats and mice after penicillin VK administration.
 ...
PMID:Two-year toxicity and carcinogenicity studies of ampicillin trihydrate and penicillin VK in rodents. 249 39

Plasmid pBR322 was alkylated with either chlorozotocin or with r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo-[a]pyrene (BPDE) before it was transformed into various strains of Escherichia coli. Plasmid survival was determined as ability to convert the bacteria to tetracycline and ampicillin resistance. Increased levels of alkylation caused a decrease in transforming activity in all strains studied. This decrease did not seem to be a result of alkylation induced strand scission, but rather some other biochemical or conformational change induced by the alkylating event. In E. coli AB1157 transformation was decreased by 50% with 6 alkylations/plasmid molecule for BPDE and 8-9 alkylations for chlorozotocin. At these levels of alkylation the loss in supercoiled DNA due to strand scission was less than 5%. Alkylated pBR322 was also transformed into repair-deficient strains of E. coli. In strain JC2924 (recA6) the survival of both BPDE- and chlorozotocin-modified DNA was similar to survival in the repair proficient strain AB1157, which would indicate that postreplicational repair of BPDE- or chlorozotocin-modified plasmid DNA was not significant under these conditions. Chlorozotocin-modified pBR322 did not seem to be repaired by the bacterial uvr-endonucleases as determined by plasmid survival in strains AB1884 (uvrC34), AB1885 (uvrB5) and AB1886 (uvrA6). With BPDE-alkylated plasmid DNA the results were strikingly different. Strains AB1884 and AB1886 were more sensitive to BPDE modified DNA than the wild type strain AB1157. Strain AB1885 was similar to AB1157 in sensitivity to BPDE-alkylated plasmid. These findings suggest that bacterial uvr-endonucleases may be able to recognize and repair BPDE-alkylated pBR322. The role of the uvrB protein in repair of alkylated DNA needs to be further investigated.
Carcinogenesis 1983 Nov
PMID:Differences in transformation of repair-deficient mutants of E. coli with BPDE- or chlorozotocin-modified plasmid DNA. 622 22

The anti-neoplastic agent procarbazine is genetically active in a variety of short term mutagenicity tests, and it also possesses carcinogenic and teratogenic potential. This compound has consistently yielded false negative results in in vitro microbial mutagenicity tests in the presence and absence of mammalian metabolic activation. In this study, procarbazine was not mutagenic in standard and preincubation Ames tests using large S9 concentrations and bacterial test strains devoid of the rfa mutation. The microtitre fluctuation test is a sensitive technique for the detection of bacterial mutagens. Using this assay, procarbazine proved to be a bacterial mutagen after in vitro metabolic activation at concentrations as low as 200 micrograms/ml. Activity was dependent upon liver S9-concentrations which were higher than those usually attained within agar assays, and was only observed when such fractions were derived from aroclor-treated or phenobarbitone plus beta-naphthoflavone treated rat livers. The excision-repair proficient strain E. coli WP2 was equally, if not more, sensitive than the repair deficient strain E. coli WP2 uvrA. Furthermore, the differential mutagenic effects obtained using S. typhimurium strains TA1535, TA1530 and his G46 indicated that the absence of an rfa mutation was essential for procarbazine mutagenesis. Procarbazine was also mutagenic for E. coli D494 in a forward mutation fluctuation assay measuring resistance to ampicillin. In this assay lower concentrations of S9-fraction were sufficient, reflecting the increased sensitivity of the test strain towards the mutagenic metabolites of the drug. In conclusion, the results suggest that rat liver S9-fraction contains only low levels of enzymes capable of activating procarbazine to a mutagen. This may be a result of rapid breakdown during storage, or due to intrinsically low levels in rat liver extracts. Inducing agents appear to increase these levels. The low concentrations of mutagenic species formed in vitro, may only be detectable using a highly sensitive assay such as the microtitre fluctuation test.
Carcinogenesis 1983
PMID:A demonstration of the in vitro bacterial mutagenicity of procarbazine, using the microtitre fluctuation test and large concentrations of S9 fraction. 633

Human cytochrome P450 1A2 is one of the major cytochrome P450s in human liver. It is known to be capable of activating a number of carcinogens such as arylamines and heterocyclic amines. In order to develop the new bacterial mutagenicity test system with human P450, a full length of human P450 1A2 cDNA inserted into pCW bacterial expression vector was introduced to Escherichia coli WP2 uvrA strain which is a well-known E. coli strain for bacterial reverse mutagenicity assay. Expressed human P450 1A2 showed typical P450 hemoprotein spectra. Maximum expression was achieved at 48 hrs after incubating at 30 degrees C in terrific broth containing ampicillin, IPTG and other supplements. High level expression of P 450 1A2 in E. coli WP2 uvrA membranes was determined in SDS-PAGE. The well-known mutagens 2-aminoanthracene and MelQ increased the revertant colonies of E. coli WP2 uvrA expressing human P450 1A2 without an exogenous rat hepatic post-mitochondrial supernatant (S9 fraction) in a dose-dependent manner. The results show that the functional expression of human P450 in bacterial mutagenicity tester strain will provide a useful tool for studying the mechanism of the mutagenesis and carcinogenesis of new drugs and environmental chemicals.
 ...
PMID:Expression of recombinant human cytochrome P450 1A2 in Escherichia coli bacterial mutagenicity tester strain. 987 48

The effects of antibiotics and anti-inflammatory drugs on the promotion stage of lung carcinogenesis initiated with N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats were investigated in two experiments with a similar protocol. In experiment 1, rats received tap water containing 2000 p.p.m. BHP for 12 weeks followed by basal diet or basal diet containing 0.02% erythromycin (EM), 0. 04% ampicillin (ABPC), 1.5% sho-saiko-to, 0.02% EM plus 1.5% sho-saiko-to or 0.04% ABPC plus 1.5% sho-saiko-to for 8 weeks after BHP administration. The development of adenocarcinomas (AC), squamous cell carcinomas (SqC) and adenosquamous carcinomas (ASqC) was completely inhibited in rats given ABPC plus sho-saiko-to and the numbers of lung lesions including alveolar hyperplasias, adenomas and carcinomas were decreased in rats given EM plus sho-saiko-to or ABPC plus sho-saiko-to. Neutrophil and macrophage infiltration into alveolar spaces of the lung were also markedly suppressed. In experiment 2, rats received BHP in the same manner as in experiment 1 and basal diet or basal diet containing 0.04% ABPC, 0.006% piroxicam, 0.04% ABPC plus 0.006% piroxicam and 0.04% ABPC plus 0.75% ougon for 8 weeks. The incidence and number of carcinomas, including ACs, SqCs and ASqCs were decreased in rats given ABPC plus piroxicam or ABPC plus ougon. Bacteria, mainly Escherichia coli, were detected in broncho-alveolar lavage of rats receiving BHP. The results suggest that chronic inflammation might be involved in the progression of lung carcinogenesis by BHP in rats and its suppression may therefore be useful as a chemopreventive strategy in lung cancer clinics.
Carcinogenesis 2000 Feb
PMID:Inhibitory effects of combined administration of antibiotics and anti-inflammatory drugs on lung tumor development initiated by N-nitrosobis(2-hydroxypropyl)amine in rats. 1065 65

The Syrian hamster embryo (SHE) cell-transformation assay represents a short-term in vitro assay capable of predicting rodent carcinogenicity of chemicals with a high degree of concordance (LeBoeuf et al [1996]. Mutat Res 356: 85-127). The SHE assay models the earliest identifiable stage in carcinogenicity, morphological cell transformation. In contrast to other short-term in vitro assays, both genotoxic and epigenetic carcinogens are detected. The SHE assay, originally developed by Berwald and Sachs (J Natl Cancer Inst 35: 641-661) and modified as described by LeBoeuf and Kerckaert (Carcinogenesis 7: 1431-1440), was included in the International Life Sciences Institute, Health and Environmental Sciences Institute (ILSI/HESI). Alternative Carcinogenicity Testing (ACT) collaboration to provide additional information on the use of short-term in vitro tests in predicting carcinogenic potential. A total of 19 ILSI compounds have been tested in the SHE assay: 15 were tested for this project, whereas clofibrate, methapyrilene, reserpine, and Di(2-ethylhexyl)phalate (DEHP) were tested previously. Of the 3 noncarcinogenic compounds tested, 2 were negative in the SHE assay, whereas ampicillin was tested positive. The remaining 16 compounds tested were either known rodent carcinogens and/or human carcinogens. From this group, 15 tested positive in the SHE assay whereas phenacetin, a genotoxic carcinogen, was tested negative. Therefore, overall concordance between the SHE assay and rodent bioassay was 89% (17/19), whereas concordance with known or predicted human carcinogens was 37% (7/19). Based on these data, it is concluded that the SHE cell-transformation assay has utility for predicting the results of the rodent carcinogenesis bioassay but lacks the selectivity to distinguish between rodent and human carcinogens.
 ...
PMID:The syrian hamster embryo (SHE) cell transformation assay: review of the methods and results. 1169 50

As a part of the ILSI-HESI Alternative to Carcinogenicity Testing (ACT) program, we performed a 26-week carcinogenetic study of nonmutagenic drug, ampicillin (ABPC) in Tg-rasH2 mice. ABPC was given to Tg-rasH2 mice (0, 350, 1000, 3000 mg/kg, p.o.) and Non-Tg mice (0, 3000 mg/kg, p.o.) daily for 26 weeks. As a positive control, a single dose of MNU was administered once to Tg-rasH2 mice (75 mg/kg, i.p.). In this study, Tg-rasH2 mice did not demonstrate any increases in tumor development in response to ABPC. Thus, ABPC had no carcinogenicity in the 26-week carcinogenesis study in Tg-rasH2 mice or in a 2-year carcinogenesis study in B6C3F1 mice.
 ...
PMID:Twenty-six week carcinogenicity study of ampicillin in CB6F1-TgrasH2 mice. 1223 39

Ampicillin trihydrate is a broad-spectrum semi-synthetic penicillin that is effective in the treatment of gram-positive and gram-negative bacterial infections produced by Streptococcus, Bacillus anthracis, Haemophilus influenzae, Neisseria gonorrhoeae, and Escherichia coli. This antibiotic is used in the treatment of upper respiratory tract infections, genital and urinary tract infections, and otitis media in children. Toxicology and carcinogenesis studies of ampicillin trihydrate (97%-99% pure) were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Male and female rats received doses of 0, 750, or 1,500 mg/kg, and male and female mice received doses of 0, 1,500, or 3,000 mg/kg. Doses selected for the 2-year studies were based on the lack of body weight effects and histopathologic effects at 2,400 mg/kg in the 14-day studies and 3,000 mg/kg in the 13-week studies. Clinical signs in the 13-week studies included diarrhea at 3,000 mg/kg in male and female rats and male mice. Corn oil suspensions containing more than 300 mg ampicillin trihydrate/ml were too viscous to be administered by gavage; therefore, a high dose of 1,500 mg/kg was selected for rats and a high dose of 3,000 mg/kg was selected for mice. During the 2-year studies, mean body weights of male and female rats were similar to or slightly increased over those of the corresponding vehicle control groups. Mean body weights of low dose and high dose male mice were similar to those of the corresponding vehicle group during year 1 of the study but were slightly below those of the vehicle control group during the last half of the study. Mean body weights of low dose and high dose female mice were greater than those of the vehicle controls throughout most of the study. No significant differences in survival were observed in groups of rats or mice of either sex. Clinical signs observed in dosed rats included diarrhea, excessive urination, and chromodacryorrhea and in dosed mice included increased salivation and decreased activity. In male rats, administration of ampicillin trihydrate was associated with an increased incidence of mononuclear cell leukemia (vehicle control, 5/50; low dose, 14/50; high dose, 13/50). Malignant lymphomas were observed in one additional vehicle control male rat and two low dose male rats. Lymphocytic leukemia was seen in one high dose rat. High dose male rats showed increased incidences of pheochromocytomas of the adrenal gland medulla (13/50; 12/50; 23/49). Malignant pheochromocytomas were observed in 1/50 vehicle control, 5/50 low dose, and 1/49 high dose male rats. The incidence of adrenal gland medullary hyperplasia was not increased in male rats (14/50; 10/50; 8/49). There were increased incidences of C-cellhyperplasia of the thyroid gland in low dose male and high dose female rats. High dose male rats showed increased incidences of hyperkeratosis and acanthosis of the forestomach. In male and female mice, ampicillin trihydrate administration was associated with increased incidences of forestomach lesions, including ulcers, inflammation, hyperkeratosis, acanthosis, and evidence of fungal infection. Ampicillin trihydrate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Syrian hamster or male Sprague-Dawley rat liver S9 when tested according to preincubation protocol. Ampicillin trihydrate was not mutagenic in L5178Y mouse lymphoma cells with or without metabolic activation. Ampicillin trihydrate did not cause chromosomal aberrations or sister-chromatid exchanges in Chinese hamster ovary cells with or without metabolic activation. An audit was conducted for these 2-year studies. Animal/carcass identification discrepancies were observed in rats and mice. The most common findings were the failure to clip some toes in rats and opened ear holes in mice. A review of the inlife data (including body weights, clinical observations, and dosing records) indicrecords) indicated that animals had not been interchanged among groups. The data are considered adequate to support the conclusions. Under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenicity of ampicillin trihydrate for male F344/N rats as shown by increased incidences of pheochromocytomas of the adrenal medulla and by marginally increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenicity for female F344/N rats receiving 750 or 1,500 mg/kg or for male and female B6C3F1 mice receiving 1,500 or 3,000 mg/kg per day. Nonneoplastic lesions of the forestomach were seen in male rats and male and female mice. Synonyms and trade names: Acillin; Amcap; Amcill; Aminobenzylpencillin trihydrate; a-Aminobenzylpencillin trihydrate; Amperil; Ampichel; Ampikel; Ampinova; Amplin; Cymbi; Divercillin; Liffampil; Morepen; Pen A; Pensyn; Polycillin; Princillin; Principen; Ro-ampen; Trafarbiot
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Ampicillin Trihydrate (CAS No. 7177-48-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 35