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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A short review of pathogenic factors in U.V. light skin carcinogenesis in the mouse is presented. Caffeine and theophylline applied locally during U.V. irradiation caused a 50 percent reduction of skin tumour induction in Swiss mice. These two chemicals are inhibitors of DNA postreplication repair, but they also raise the intracellular level of cyclic AMP by inhibiting cAMP phosphodiesterase with, as a consequence, a possible slowing down of cellular growth. Control experiments using three different chemicals capable of raising the cAMP level in epidermal cells gave negative results. These experimental data are compatible with our original hypothesis according to which production of skin cancers by U.V. radiation is in same way related to DNA repair which helps the cell to survive but allows or favours the occurrence of errors in cellular DNA.
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PMID:Ultraviolet light induction of skin carcinoma in the mouse; influence of cAMP modifying agents. 21 89

A method using mammalian cells in vitro for detection and quantitation of mutagenic actions that appears to be useful for screening for carcinogenesis and genetic damage by environmental agents is presented. The method involves use of stable human--Chinese hamster ovary hybrid cells that have retained a single human chromosome not necessary for cell reproduction. Forward mutations are detected in genes necessary for production of specific human cell surface antigens. Such mutants form colonies in the presence of specific antisera and complement that destroy the unmutagenized cells. Use of the method is illustrated for the action of x-irradiation, N-methyl-N'-nitro-N-nitrosoguanidine, and caffeine. The method appears to be unique in that it permits assessment of lesions that cause loss of all or most of the chromosome as well as various localized gene mutations. The former action is particularly important because of the major involvement of chromosomal lesions in an extremely important class of human genetic disease.
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PMID:Measurement of mutagenesis in mammalian cells. 28 18

A well-documented rationale exists for the study of the induction of cancer at the cellular level. Transformation can be quantitated; its frequency follows a linear relationship with dose and is consistent with a "one-hit" phenomenon. Transformed colonies do produce transformed lines with attributes of neoplastic cells including the production of tumors; in vitro activity correlates with in vivo activity to provide evidence that chemically induced carcinogenesis can be studied in vitro. In vitro techniques utilizing mammalian cells in culture have made possible the rapid evaluation of carcinogenicity of agents in man's environment. Neoplastic transformation is inductive and not the result of the selection of preexisting tumor cells. The addition of a host-mediated step in the bioassay makes it possible to decrease the number of false negatives, which may result from the requirement for metabolic activation of the chemical. Thus the in vitro studies described have a high probability of providing practical methods for determining which chemicals in use have a potential of producing cancer. Furthermore, the nature of the cell-target insult interaction can be determined, as well as the chemical nature of the ultimate carcinogen, the degree to which any agent acts alone, be it a chemical, a virus, or irradiation, and the extent to which one agent interacts with another from the same or a different category of carcinogens. Sequential treatment involving chemicals, viruses, and radiation are important, since combinations of various agents may be responsible for an increased risk of cancer in laboratory animals and human populations. The use of multiple agents may also lead to different but specific new types of assays to use for surveillance of our environment for carcinogenic agents. Pretreatment of Syrian golden hamster embryo cells with either X-irradiation or methyl methanesulfonate, but not UV-irradiation, increases the frequency of chemical transformation as does posttreatment with caffeine. Most, if not all, chemical carcinogens will increase the sensitivity of hamster embryo cells to transformation by a carcinogenic simian adenovirus SA7. The enhancement of virus transformation is related to both the length of chemical treatment and the interval between chemical and viral addition. The mechanism of transformation enhancement by various agents has yet to be explained. They may affect a number of molecular processes or cause a modification of existing DNA and thus provide an explanation for carcinogenesis; in fact, in some systems some of these agents may also show mutagenic activity and produce chromosomal aberrations, However, although DNA is the critical site for a mutagen, the critical target(s) of chemical carcinogens is still unknown.
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PMID:In vitro carcinogenesis with cells in early passage. 37 16

A maximum tolerated dose (15 mug/g) of the carcinogen 4-nitroquinoline 1-oxide (4NQO) induced neither fetal deaths nor malformations when given to pregnant ICR/Jcl mice at the sensitive stages (Days 9 to 11) for the induction of malformations, although these embryotoxicities were detected with urethan and X-ray. This may not be due to the lack of teratogenic actions of 4NQO, but to the difficulty this compound has in reaching the embryo, because direct injection of 4NQO into the amniotic cavity of the Day-11 embryo, so that exposure was more direct, induced a high incidence of malformations. Similarity of the mechanism of chemical carcinogen-initiated teratogenesis and carcinogenesis was also suggested by the following findings. Urethan-initiated teratogenesis was almost completely inhibited by posttreatment with caffeine during the period of 0 to 24 and 24 to 48 hr after urethan treatment, whereas it was not inhibited during the 48- to 72-hr post-urethan and the 6- to 30-hr pre-urethan period. The results are similar to those of 4NQO-initiated transformation in cultured mouse embryo cells and 4NQO- and urethan-initiated lung tumorigenesis in mice. Cells carrying preteratogenic or pretumorigenic damage produced by some chemical carcinogens may be extremely sensitive to caffeine treatment during and/or after the postcarcinogen DNA replication period, thus resulting in decrease of malformations and tumors. The process may be related to error-prone DNA repair, because caffeine is known to inhibit the postreplication repair in cultured mouse cells.
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PMID:Similarity of the mechanism of chemical carcinogen-initiated teratogenesis and carcinogenesis in mice. 40 2

Evidence for a mutation theory of cancer is presented by reviewing the experimental work on 4-nitroquinoline 1-oxide (4NQO) carcinogenesis. 4NQO almost completely mimics u.v. light and produces 4NQO-purine adducts on DNA. When 4NQO-treated cells are held in liquid medium under appropriate conditions, the 4NQO adducts disappear from DNA, in parallel to decrease of premutational damage in Escherichia coli, or pretransformational damage in cultured mouse cells. Post-treatment with caffeine greatly diminishes the yields by 4NQO of mutants in E. coli, malignant transformants in cultured mouse cells and tumour nodules in the lung of mice. Potentially tumourigenized stem cells in the lung remain sensitive to selective killing by caffeine for at least 5 days after 4NQO treatment, in spite of their DNA being apparently replicated, an indication that carcinogen-damaged DNA in the stem cell can be transmitted to its successive daughter stem cells for many generations. This peculiar characteristic is discussed as a possible lead to the crux of the mutation theory of cancer in vivo, and a model for carcinogenesis is proposed.
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PMID:A test for mutation theory of cancer: carcinogenesis by misrepair of DNA damaged by 4-nitroquinoline 1-oxide. 40 31

The effect of phenacetin and caffeine on urinary bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Animals were given a high or low dose of BBN for 4 weeks and then phenacetin or caffeine was administered for 30 or 32 weeks, respectively. All the animals were examined histologically after 36 experimental weeks. The incidence of papillary or nodular hyperplasia, papilloma, and cancer of the urinary bladder was significantly higher in the groups treated with BBN and then with phenacetin than in those treated with BBN alone, especially with a high dose of BBN. Simple hyperplasia and papillary or nodular hyperplasia developed in the urinary bladder of rats treated with phenacetin alone. Papillary proliferative growth of the renal pelvis was seen in one rat treated with a low dose of BBN and phenacetin. Treatment with caffeine after BBN had no enhancing effect and caffeine alone caused no remarkable changes.
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PMID:Effect of phenacetin and caffeine on the urinary bladder of rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. 66 40

The modulating effects of caffeine, nicotine, ethanol and sodium selenite on development of N-nitrosobis(2-oxopropyl)-amine (BOP)-initiated pancreatic tumors were investigated. Female Syrian golden hamsters were given s.c. injections of BOP (10 mg/kg body weight) or saline alone once a week for 3 weeks and then administered 2000 p.p.m. caffeine, 25 p.p.m. nicotine, 20% ethanol or 4 p.p.m. sodium selenite in their drinking water for the next 37 weeks. Control animals were given tap water alone after BOP initiation. Only the BOP-treated groups developed pancreatic adenocarcinomas and dysplasias. The multiplicity of pancreatic carcinomas was significantly higher (P less than 0.05) in animals receiving caffeine than in the controls. In addition, caffeine treatment slightly increased the incidence of carcinomas. Nicotine and ethanol also showed tendencies to enhance pancreatic carcinogenesis, although there were statistically no significant differences regarding lesion development. In contrast, sodium selenite administration was associated with a tendency for a decrease in the number of carcinomas and dysplasias. Thus, among these chemicals of obvious significance to human life-style, caffeine enhanced the development of pancreatic tumors when administered during the post-initiation phase in this hamster model.
Carcinogenesis 1992 Aug
PMID:Effects of caffeine, nicotine, ethanol and sodium selenite on pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine. 132 27

Salted tea prepared in Kashmir by adding sodium bicarbonate shows high methylating activity (equivalent to 3 p.p.m. N-methylnitrosourea) upon in vitro nitrosation. Pure caffeine treated under conditions of the tea preparation formed caffeidine and caffeidine acid. We report here the formation of two new compounds, mononitrosocaffeidine, an asymmetric nitrosamine, and dinitrosocaffeidine, a N-nitrosamide, on in vitro nitrosation of caffeidine. Mononitrosocaffeidine is also found after nitrosation of the typical Kashmir tea. The nitrosation of caffeidine acid produced N,N'-dimethyl-parabanic acid, mononitrosocaffeidine and N,N'-dimethyl-N-nitrosourea. In view of the well-known structure-activity relationships of these N-nitroso compounds, their possible endogenous formation due to high consumption of salted tea may be a critical risk factor for the high occurrence of oesophageal and gastric cancers in Kashmir.
Carcinogenesis 1992 Nov
PMID:Caffeine-derived N-nitroso compounds--I: Nitrosatable precursors from caffeine and their potential relevance in the etiology of oesophageal and gastric cancers in Kashmir, India. 133 Mar 53

Diethylnitrosamine (DEN) and methylazoxymethanol acetate (MAM) are not transplacental carcinogenic but embryotoxic to Wistar rats when administered by i.p. injection on day 12 of gestation. MAM, a weak teratogen to rats during this period, induced a dose dependent increase in the number of resorptions to 15% and 40% of the litters following doses of 15 and 25 mg/kg bw, respectively. Rats similarly treated with 70, 150, and 180 mg DEN/kg bw resulted in increases in total DNA mass of day 13 embryos by 31%, 45% and 52%, respectively, compared to the saline treated controls. Twenty percent reduction in total DNA amount was detected following 25 mg MAM/kg bw. Benzoylated DEAE-cellulose (BD-cellulose) chromatography fractionates DNA on the basis of secondary structure by stepwise elution of double-stranded DNA with 1.0M NaCl solution (SE-DNA) followed by elution of DNA containing single-stranded regions with caffeine solution (CE-DNA). Day 13 embryonic DNA was monitored by in vivo labelling with [methyl-3H]-thymidine (3H-TdR) on days 6 and 7 of gestation. Significant increases in percentages of caffeine-eluted DNA (%CE-DNA) compared to control values were detected 24 h after treatment of day 12 embryos with 70, 150, and 180 mg DEN/kg bw. Such increases were not observed after MAM. Incorporation of [methyl-14C]-thymidine (14C-TdR) into embryonic DNA demonstrated the effects of treatment with these compounds on DNA synthesis in vivo. When compared to saline controls, DEN induced significant increases in 14C-TdR incorporation into embryo DNA, 1 h prior to analysis, but the increases were not proportional to the doses administered. Similar analysis of MAM treated samples showed no significant changes to %CE-DNA values. The relative %CE-DNA is expressed as the ratio of the percentage of caffeine-eluted 14C-labelled DNA to %CE-DNA (i.e., %CE-14C-DNA:%CE-3H-DNA). In the majority of control embryos the 14C-specific activity of CE-DNA was higher than the 14C-specific activity of SE-DNA. No significant change to relative %CE-DNA values of embryos to those of the controls was observed 24 h after treatment of day 12 gestation rats with single doses of DEN and MAM. The results of this study support the hypothesis that initiation mechanisms of teratogenesis and transplacental carcinogenesis are different. The pertinence of %CE-DNA and relative %CE-DNA values to teratogenesis and transplacental carcinogenesis is also discussed.
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PMID:Changes in secondary structure of DNA of rat embryos following treatment with diethylnitrosamine and methylazoxymethanol acetate in vivo. 136 96

Caffeine is sequentially metabolized by cytochrome P4501A2 (CYP1A2), N-acetyltransferase (NAT) and/or xanthine oxidase (XO). In the present study the activity of these three enzymes was estimated from ratios of the metabolites formed from dietary caffeine and excreted into the urine collected as spot samples. In the urine samples from 10 out of 377 subjects concentrations of caffeine metabolites were too low to allow reliable measurements of the ratios. In 335 healthy subjects the NAT activity showed a typically bimodal distribution with 47% fast acetylators and 53% slow acetylators, consistent with a Danish population. The ratios reflecting CYP1A2 and XO activities were log normal and normal distributed, respectively. In 103 non-smoking men and 90 non-smoking women the ratio of caffeine metabolites expressing CYP1A2 activity was 4.7 +/- 1.6 and 4.3 +/- 1.9 as compared to 7.8 +/- 2.5 and 7.3 +/- 3.0 in 31 male and 25 female subjects smoking 10 cigarettes/day or more respectively, verifying induction of CYP1A2 by tobacco (P less than 0.05), but minimal sex-related differences. In 12 non-smoking pregnant women and in 28 women using oral contraceptives the CYP1A2 ratio was 29 and 20% reduced respectively (P less than 0.05). In a multivariate analysis the only significant predictor of the XO ratio was the consumption of caffeine with an increase of 2% per cup of coffee or equivalent (P less than 0.05). In 23 healthy male subjects 30 days of vigorous exercise increased the CYP1A2 ratio by 70% and the XO ratio by 42% (P less than 0.05), but left the NAT ratio unchanged. In nine healthy volunteers daily ingestion of 500 g of broccoli for 10 days increased the CYP1A2 ratio by an average of 12% (P less than 0.05), compared to a control period with ingestion of an equivalent weight of non-cruciferous green vegetables. The ratios of metabolites from dietary caffeine in spot urine samples offer ethical, non-invasive and reliable estimates of CYP1A2, NAT and XO. These enzymes are highly relevant for the bioactivation of potentially toxic compounds and the formation of oxygen radicals. The method is applicable in large-scale epidemiological studies, allowing, for example, prospective testing of the relationship between these enzyme activities and the development of disease. Exercise may increase CYP1A2 activity to a magnitude corresponding to heavy smoking, as well as XO by mechanisms that remain to be clarified.
Carcinogenesis 1992 Sep
PMID:Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. 139 40


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