Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of differential efficacies of diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), dipropyl sulfide (DPS) and dipropyl disulfide (DPDS) in preventing benzo(a)pyrene (BP)-induced cancer in mice has been investigated by determining their effects on the enzymes of BP activation/inactivation pathways. With the exception of DATS, treatment of mice with other organosulfides (OSCs) caused a small but significant increase (37-44%) in hepatic ethoxyresorufin O-deethylase (EROD) activity. However, the forestomach EROD activity did not differ significantly between control and treated groups. Only DAS treatment caused a modest but statistically significant reduction (about 25%) in pulmonary EROD activity. These results suggest that while reduction of EROD activity may, at least in part, contribute to the DAS-mediated inhibition of BP-induced lung cancer, anticarcinogenic effects of OSCs against BP-induced forestomach carcinogenesis seems to be independent of this mechanism. Treatment of mice with DAS, DADS and DATS resulted in a significant increase, as compared with control, in both hepatic (3.0-, 3.2- and 4.4-fold, respectively) and forestomach (1.5-, 2.7- and 2.7-fold, respectively) glutathione transferase (GST) activity toward anti-7beta,8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE), which is the ultimate carcinogen of BP. The pulmonary GST activity was not increased by any of the OSCs. Even though epoxide hydrolase (EH) activity was differentially altered by these OSCs, a correlation between chemopreventive efficacy of OSCs and their effects on EH activity was not apparent. The results of the present study suggest that differences in the ability of OSCs to modulate GST activity toward anti-BPDE may, at least in part, account for their differential chemopreventive efficacy against BP-induced cancer in mice.
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PMID:Mechanism of differential efficacy of garlic organosulfides in preventing benzo(a)pyrene-induced cancer in mice. 931 Feb 61

Significant interindividual variations in health outcome may be caused by the inheritance of variant polymorphic genes, such as CYP2D6 and CYP2E1 for activation, and GSTM1 and GSTT1 for detoxification of chemicals. However, mechanistic studies linking the inheritance of predisposing genes with genotoxic effects towards cancer have yet to be systematically conducted. We have studied 54 lung cancer patients and 50 matched normal controls, who have been cigarette smokers, to elucidate the role of polymorphic genes in cancer. Our data indicates that the inheritance of unfavorable CYP2D6, CYP2E1, and GSTT1 genes in strongly correlated with the smoking-related lung cancer. For heavy cigarette smokers (> 30 pack-years), the smoking habit is the strongest predictor of lung cancer risk irrespective of the inheritance of unfavorable metabolizing genes. For moderate to light smokers (< 30 pack-years), the genetic predisposition plays an important role for the risk (odds ratio = 3.46; 95% Cl = 0.46-40.2). Using a subgroup of the study population, we observed that cigarette smokers having the defective GST genes have significantly more chromosome aberrations as determined by the fluorescence-in-situ-hybridization (FISH) technique than smokers with the normal GST genes (P < 0.001). In conclusion, our study provides data to indicate that individuals who have inherited unfavorable metabolizing genes have increased body burden of toxicants to cause increased genetic damage and to have increased risk for cancer. Studies like ours can be used to understand the basis for interindividual variations in cancer outcome, to identify high risk individuals and to assess health risk.
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PMID:Interactions between genetic predisposition and environmental toxicants for development of lung cancer. 932 44

Genotoxic effects linking cigarette smoking with lung cancer have not been consistently demonstrated, therefore claims for the cause-effect relationships are vigorously contested. Using matched populations of 22 lung cancer patients who have been cigarette smokers (LCP), 22 non-cancerous cigarette smokers (SC) and 13 non-smokers (NSC), we have applied the fluorescence in situ hybridization (FISH) tanden probe assay to elucidate the frequency of chromosome breakage among the participants. Two probes were used, a classical satellite probe which hybridizes to the large heterochromatin region of chromosome 1, and an alpha-satellite probe which targets a small region adjacent to the heterochromatin probe. The highest frequency of structural aberrations was observed in LCP (1.4 +/- 0.1) followed by SC (1.25 +/- 0.1) and NSC (0.4 +/- 0.1). Aberration frequencies were not significantly different between LCP and SC (p > 0.05), however, a statistically significant difference was detected between the smoker populations combined (LCP and SC) and the NSC (p < 0.001). The breakage frequencies showed a positive correlation with duration of smoking for LCP (r = 0.5; p < 0.01), but not for SC (P > 0.05). In addition, the aberration frequencies were influences by the inheritance of polymorphic glutathione S-transferase (GST) genes. LCPs missing one or the other GST (GSTM1 or GSTT1) genes were found to have significantly higher chromosome breaks compared to LCPs with both genes present (p < 0.05). Our data indicate that genetic predisposition and chromosome aberrations may be mechanistically related to the initiation of lung carcinogenesis; therefore, they may be useful biomarkers for lung cancer among cigarette smokers.
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PMID:Predisposing genes and increased chromosome aberrations in lung cancer cigarette smokers. 933 Jun 22

The glutathione S-transferases (GSTs), a family of multifunctional proteins, catalyze the glutathione conjugation reaction with electrophilic compounds biotransformed from xenobiotics, including carcinogens, and are grouped into four classes, Alpha, Mu, Pi and Theta. Some of these forms are suggested to act to prevent carcinogenesis by detoxifying proximate or ultimate carcinogens. In neoplastic cells, specific forms are known to be expressed and have been known to participate in their resistance to anticancer drugs. In this article, we review recent findings regarding the respective molecular forms involved in carcinogenesis and their usefulness as tumor markers. GST M1 and GST T1 genes are polymorphic in the population and losses of these genes have been suggested as possible markers for greater susceptibility to lung cancer among smokers and several other cancers. Since many GST inducers prevent rodent chemical carcinogenesis, potential chemopreventive agents have been screened by their induction capabilities. However, reliable markers useful to predict results of prospective chemopreventive trials in populations are not established. Immunohistochemical studies have revealed that many cancers, histologically classified as adenocarcinomas or squamous cell carcinomas, express GST P1-1. Its expression is regulated at transcriptional level and regulatory elements of the gene have been clarified. However, transacting factors responsible for expression in cancer tissues remain to be clarified. In addition, stability of GST P1 mRNA is suggested to be partly responsible in some cell lines. Plasma or serum GST P1-1 levels are increased in 30-50% of patients with cancers of the gastrointestinal tract. This form is also suggested to participate in resistance to anticancer drugs such as cisplatin and daunorubicin, and its expression in cancer tissues may be of prognostic value in cancer patients. Further studies on this enzyme family are clearly needed to obtain a better understanding of cancer prevention and therapy.
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PMID:[Usefulness of glutathione S-transferase as a tumor marker]. 943 92

The paper presents the results of study on polymorfisms of xenobiotic biotransformation enzymes (CYP1A1, glutathione S-transferase MI and N-acetyltransferase 2) and p53 tumor suppressor protein in patients with lung, stomach and intestine cancer. The frequency of CYP1A1-Val allele in all studied cancer groups was 3 to 5 times higher than in healthy control group. The carriers of homozygous glutathione S-transferase M1 gene deletion and slow acetylator phenotype were also of higher lung cancer risk. The substantial increase in slow acetylator phenotype frequency was shown also in the group of intestine cancer patients. The p53 Arg/Pro polymorphism study revealed the elevated frequency of Arg allele in lung and stomach cancer groups. The risk of lung cancer for the carriers of susceptible alleles depended on the age and smoking status of the patients. The results testify to a high possibility of studied polymorphic genes to be the markers of susceptibility to oncopathologies.
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PMID:[Genes and enzymes of the xenobiotic-metabolizing system in cancer pathology]. 944 23

Deficiencies of the glutathione transferase isoenzymes GSTM1-1 and GSTT1-1 have been shown to be risk modifiers in a number of different cancers but there have been no similar studies with GSTP1-1, the only member of the Pi class of glutathione S-transferases expressed in humans. Over-expression of GSTP1-1 in tumours suggests that it may be a significant factor in acquired resistance to certain anticancer drugs. We previously identified a cDNA clone with two amino acid substitutions (I105V, A114V). This clone suggests that the GSTP1 gene is polymorphic and it is possible that the different genotypes may be associated with altered cancer risk or drug resistance. In the present study, we report methods for genotyping individuals at codons 105 and 114 of GSTP1 and demonstrate that these two loci are polymorphic in several different racial groups. We also detected significant linkage disequilibrium between these two loci. To determine if either of the alleles at these two loci were associated with altered cancer susceptibility, we genotyped individuals with colorectal cancer or lung cancer. A total of 131 colorectal and 184 lung cancer patients were compared with 199 control individuals. Overall, there were no significant associations between the GSTP1 polymorphisms and either form of cancer.
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PMID:Polymorphism of the Pi class glutathione S-transferase in normal populations and cancer patients. 951 Nov 78

The literature suggests that the concomitant exposure to polycyclic aromatic hydrocarbons (PAH) and ferric oxide particles could enhance lung cancer incidence in environmental and occupational settings. High levels of tracheobronchial tumours were obtained in hamsters exposed to benzo[a]pyrene (B[a]P) adsorbed onto ferric oxide carrier particles. Therefore, we have assessed the toxic effects of exposure to haematite (Fe2O3) and B[a]P in male Sprague-Dawley rats. Animals were instilled with the chemicals alone (3 mg of Fe2O3 or B[a]P) or in combination (3 mg Fe2O3 + 3 mg B[a]P). Bronchoalveolar lavages (BAL) and biological samples (serum and urine) were collected 48 h after the intoxication. Clara cell protein (CC16) and alpha-glutathione S-transferase (alpha-GST), as peripheral markers of both tracheobronchial epithelial cell integrity and renal dysfunction, were determined in BAL fluid, serum and urine. Malondialdehyde (MDA), a marker of lipid peroxidation, was measured in BAL fluid and serum. We observed a significant increase of CC16 concentrations in BAL fluid after Fe2O3 + B[a]P instillation (p < 0.05) in serum after Fe2O3 and Fe2O3 + B[a]P exposure (p < 0.01) and in urine after B[a]P administration (p < 0.01). Instillation of Fe2O3 + B[a]P produced an increased amount of alpha-GST in BAL fluid (p < 0.01), whereas B[a]P alone caused a significant elevation of alpha-GST in serum and urine (p < 0.01). Moreover, Fe2O3 or Fe2O3 + B[a]P instillation induced a significant increase in MDA levels in BAL fluid (p < 0.01 and p < 0.05). In conclusion, Fe2O3 may have a low pulmonary toxicity. However, B[a]P manifested a rapid and high toxicity in the respiratory tract and kidneys. When B[a]P was adsorbed on haematite particles, both its retention in the respiratory tract and pulmonary toxicity increased.
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PMID:Peripheral markers (Clara cell protein and alpha-glutathione S-transferase) and lipidoperoxidation (malondialdehyde) assessment in Sprague-Dawley rats instilled with haematite and benzo[a]pyrene. 952 33

The activity of chemical carcinogens is a complex balance between metabolic activation by cytochrome P450 monooxygenases and detoxification by enzymes such as glutathione S-transferase (GST). Regulation of these proteins may have profound effects on carcinogenic activity, although it has proved impossible to ascribe the observed effects to the activity of a single protein. GstP appears to play a very important role in carcinogenesis, although the precise nature of its involvement is unclear. We have deleted the murine GstP gene cluster and established the effects on skin tumorigenesis induced by the polycyclic aromatic hydrocarbon 7, 12-dimethylbenz anthracene and the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate. After 20 weeks, a highly significant increase in the number of papillomas was found in the GstP1/P2 null mice [GstP1/P2(-/-) mice, 179 papillomas, mean 9.94 per animal vs. GstP1/P2(+/+) mice, 55 papillomas, mean 2.89 per animal, (P < 0.001)]. This difference in tumor incidence provides direct evidence that a single gene involved in drug metabolism can have a profound effect on tumorigenicity, and demonstrates that GstP may be an important determinant in cancer susceptibility, particularly in diseases where exposure to polycyclic aromatic hydrocarbons is involved, for instance in cigarette smoke-induced lung cancer.
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PMID:Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. 956 Feb 66

A cisplatin-resistant cell line, SBC-3/CDDP, was established from a human small-cell lung cancer cell line, SBC-3. The SBC-3/CDDP cells were 13.1-fold more resistant to cisplatin than the parent SBC-3 cells. We investigated the cellular changes of this cell line with regard to the development of resistance to cisplatin. The SBC-3/CDDP cells showed various characteristics as follows: a) increased intracellular glutathione and glutathione S-transferase content b) decreased intracellular accumulation of cisplatin, c) increased topoisomerase I activity and the same topoisomerase II activity as the parent SBC-3 cells, and 4) strong cross-resistance to the platinum analogues and mitomycin C, moderate cross-resistance to 7-ethyl-10-hydroxy-camptothecin (SN-38), 4-hydroperoxy cyclophosphamide, etoposide, Adriamycin and methotrexate, and collateral sensitivity to vinca alkaloids and 5-fluorouracil. From these observations, the SBC-3/CDDP cells could be useful as a well characterized cisplatin-resistant cell line, and the resistance pattem in this cell line will give us much information for eradication of cisplatin-resistant tumor cells.
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PMID:Cisplatin-resistant human small cell lung cancer cell line shows collateral sensitivity to vinca alkaloids. 961 43

Industrialized regions in Poland are characterized by high ambient pollution, including polycyclic aromatic hydrocarbons (PAHs) from coal burning for industry and home heating. In experimental bioassays, certain PAHs are transplacental carcinogens and developmental toxicants. Biologic markers can facilitate evaluation of effects of environmental PAHs on the developing infant. We measured the amount of PAHs bound to DNA (PAH-DNA adducts) in maternal and umbilical white blood cells. The cohort consisted of 70 mothers and newborns from Krakow, Poland, an industrialized city with elevated air pollution. Modulation of adduct levels by genotypes previously linked to risk of lung cancer, specifically glutathione S-transferase MI (GSTM1) and cytochrome P4501A1 (CYP1A1) Msp restriction fragment length polymorphism (RFLP), was also investigated. There was a dose-related increase in maternal and newborn adduct levels with ambient pollution at the women's place of residence among subjects who were not employed away from home (p < or = 0.05). Maternal smoking (active and passive) significantly increased maternal (p < or = 0.01) but not newborn adduct levels. Neither CYP1A1 Msp nor GSTM1 polymorphisms was associated with maternal adducts. However, adducts were significantly higher in newborns heterozygous or homozygous for the CYP1A1 Msp RFLP compared to newborns without the RFLP (p = 0.04). Results indicate that PAH-induced DNA damage in mothers and newborns is increased by ambient air pollution. In the fetus, this damage appears to be enhanced by the CYP1A1 Mspl polymorphism.
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PMID:Relationship between ambient air pollution and DNA damage in Polish mothers and newborns. 964 44


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