Risk of lung cancer from environmental exposures to tobacco smoke.
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Environmental Exposure↗
Biomedical subjects
P Lazarus
Publications and source records attributed to P Lazarus.
CYP1A1 and GSTM1 polymorphisms and oral cancer risk.
The importance of both the CYP1A1 exon 7 (ile:val) and GSTM1 (0/0) polymorphisms in oral cancer susceptibility was assessed by examining polymorphic prevalences in 135 patients with oral cancer and 135 noncancer controls frequency-matched by age at diagnosis (+/- 5 years), race, sex, and institute of patient recruitment. The prevalence of the GSTM1 (0/0) genotype was approximately 51% in both cases and controls. The prevalence of the CYP1A1 (ile:val) polymorphism [including both the (ile/val) and (val/val) genotypes] was significantly higher in cases as compared to controls (17.6% versus 7.6%, respectively; crude odds ratio, 2.6; confidence interval, 1.2-5.7). No association was observed between polymorphic prevalence and levels of smoking or alcohol consumption in cases. These results suggest that the GSTM1 null genotype is not associated with oral cancer risk. These results also suggest that individuals with the CYP1A1 exon 7 ile:val polymorphism are at increased risk for oral cancer, and that this risk may not be influenced by differences in exposure to tobacco smoke.
Adult↗
Typing of common human papilloma virus strains by multiplex PCR.
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Humans↗
Relationship between p53 mutation incidence in oral cavity squamous cell carcinomas and patient tobacco use.
It is well-established that a high incidence of p53 mutations exist in oral cavity squamous cell carcinomas (OCSCCs). To determine whether p53 mutations are etiologically associated with OCSCC development or are associated with exposure to specific carcinogens, we have analyzed the conserved regions of the p53 gene (exons 5-9) in 48 OCSCCs obtained from patients with varied tobacco and alcohol use histories by polymerase chain reaction/single strand conformational polymorphism (PCR/SSCP) and DNA sequencing analysis. Thirty-eight percent (18/48) of the OCSCCs exhibited a mutation in exons 5-9 of the p53 gene. There was a significantly higher incidence of p53 mutations in OCSCCs from tobacco users (predominantly cigarette smokers) compared to those who had never used tobacco. No increase in the incidence of p53 mutation was observed in tobacco users who drank alcohol. G to A transitions and deletions were the predominant mutations observed in OCSCCs from tobacco users. No specific pattern of mutation was observed in OCSCCs from those subjects who had never used tobacco. These data suggest that a history of tobacco use was associated with a high incidence of p53 mutations in patients with OCSCC and that tobacco carcinogens include a specific pattern of mutations in oral cavity tissue in vivo.
Adult↗
p53 mutations in head and neck squamous cell carcinomas from Sudanese snuff (toombak) users.
Toombak is a type of snuff used extensively in the Northern Sudan by a virtually non-smoking/nondrinking population. This Sudanese snuff contains inordinately high levels of the tobacco-specific nitrosamines (TSNAs) Nl-nitrosonornicotine (NNN) and (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These are considered to be major contributors to the induction of cancers of the aerodigestive tract in tobacco chewers, snuff dippers, and smokers. To determine if toombak use may be associated with the induction of mutations in the p53 tumor suppressor gene, we screened four head and neck squamous cell carcinomas (SCCs) obtained from three toombak-using patients and one non-toombak-using patient using polymerase chain reaction/single-stranded conformational polymorphism analysis and DNA sequencing. p53 mutations were found in tumors resected from two of three toombak-using patients, one at codon 282 (CGGarg-->TGGtrp) and the other in intron 6 (AT-->GC). No p53 mutations were observed in the tumor from the non-toombak-using patient. The observed mutations were similar in spectrum to those induced by nitrosamines in mouse lung tumors. No K-ras (codons 12 and 13) or H-ras (codon 12) mutations were found in any of the tumors. These results suggest that toombak components such as TSNAs may induce p53 mutations in head and neck SCCs and are likely contributors to the tobacco-induced carcinogenic load in humans.
Animals↗
A low incidence of p53 mutations in pre-malignant lesions of the oral cavity from non-tobacco users.
To determine the incidence of p53 mutations in pre-malignant lesions of the oral cavity from individuals without prior history of tobacco use, we have analyzed the conserved regions of the p53 gene (exons 5-9) in archival oral cavity lesion specimens obtained from patients with varied tobacco use histories, by polymerase chain reaction/single strand conformational polymorphism (PCR/SSCP) and DNA sequencing analysis. Twenty-six lesions were analyzed from 14 patients, with multiple lesions obtained from 8 patients. Six of these patients used tobacco, (3 being cigarette smokers, 1 ex-cigarette smoker, 1 moderate cigar smoker and 1 snuff chewer). The remaining 8 patients had no prior history of tobacco use. Thirteen of the pre-malignant lesions exhibited severe dysplasia, 9 exhibited moderate dysplasia and 4 exhibited mild dysplasia. Four of the 26 lesions exhibited p53 mutations, each being from a tobacco user. None of the 13 lesions from never-tobacco users exhibited p53 mutations. There was a significantly higher p53 mutation incidence in pre-malignant lesions from tobacco users (including ex-smokers) than in non-tobacco users as well as in cigarette smokers plus snuff chewers than in non-tobacco users. Two of the mutations were observed in lesions exhibiting severe dysplasia: 1 in a lesion exhibiting moderate dysplasia and 1 in a lesion exhibiting mild dysplasia. These data suggest that p53 mutation may be a very early event in oral cavity tumor progression and demonstrate that pre-malignant lesions obtained from non-tobacco users do not exhibit p53 mutations.
Adult↗
Identification and partial characterization of the c-jun oncogene in Xenopus laevis.
Sequencing analysis of a 275-nt cDNA fragment encoding the DNA-binding region at the carboxyl terminal of the Xenopus c-jun protein product shows that this region exhibits 77-79% nucleotide homology and 93% amino acid homology with the DNA-binding region of mouse and human c-jun, and contains an intact leucine zipper motif and a basic DNA-binding region. Xenopus c-jun mRNA is induced in quiescent Xenopus A6 kidney cells by 12-O-tetradecanoylphorbol-13-acetate, PDGF and cycloheximide. This 'immediate early' response suggests that Xenopus c-jun may be similar in both structure and function to that observed for its mammalian counterpart.
Amino Acid Sequence↗
Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen.
Tamoxifen (TAM) is a triphenylethylene antiestrogen used for the treatment, and in clinical trials for the prevention, of breast cancer in women. In rats, TAM is a strong liver carcinogen which induces the formation of liver DNA adducts. The DNA of 24 hepatocarcinomas (HCCs) collected at necropsy from individual female Sprague-Dawley rats that were given 22.6 mg/kg TAM daily for 12 months was studied for the presence of mutations in exons 5-9 of the p53 gene by single-strand conformation polymorphism and DNA sequencing analysis. The sequences of introns 5-8 of the rat p53 gene were determined in order to design primers homologous to regions located in these introns. p53 mutations were found in 50% (12 of 24) of the HCCs. These mutations were all specifically clustered in two sites, codons 231 (exon 6-7) and 294 (exon 8). Nine HCCs contained a transition from adenine to guanine in the second base of codon 231 (CAC to CGC), which resulted in a histidine to arginine amino acid substitution; 4 HCCs contained a nonmiscoding transition from cytosine to thymidine in the third base of codon 294 (TGC to TGT; cysteine to cysteine). One HCC contained both mutations. The present report supports previous observations on the genotoxicity of TAM in rodents and raises concerns about its use as a chemopreventive agent against breast cancer in women.
Animals↗
Sequence of the rat hypoxanthine guanine phosphoribosyl transferase (HPRT) transcriptional promoter region in wild-type and mutant rat liver epithelial cell lines.
The hypoxanthine guanine phosphoribosyltransferase (HPRT) gene is mutated by a variety of genotoxic agents in adult rat liver (ARL) epithelial cell lines. By polymerase chain reaction (PCR) amplification and DNA sequencing of rat ARL cell HPRT gene sequences with mouse- and rat-specific oligonucleotides, a large portion of the rat HPRT transcriptional promoter region was sequenced. This region exhibits approximately 60% homology with the corresponding mouse sequence, contains a similar G/C-rich region at its 3' end, and contains a similar series of 6-nucleotide (nt) GGGCGG repeats. To determine if this region is a target for mutation by different genotoxins, HPRT-deficient ARL mutants induced by 2-acetylaminofluorene (AAF), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), or 7,12-dimethyl-benz[a]anthracene (DMBA) were isolated and studied. A 1003-nt fragment of predominantly HPRT regulatory sequences was amplified by PCR using purified genomic DNA from 17 independent mutants and sequenced directly. None of the 17 mutants examined exhibited any alterations in the transcriptional regulatory region or the 5' untranslated region of HPRT exon 1 after direct sequencing analysis of PCR products. In addition, none of the 2-AAF-induced mutants exhibited differences in in vitro transcription rates as determined by nuclear run-on analysis. These data suggest that regulatory sequences of the HPRT gene are not a primary target for mutation by the genotoxins studied.
2-Acetylaminofluorene↗
Aldolase-DNA interactions in a SEWA cell system.
In this report we demonstrate the novel finding that aldolase A interacts with DNA sequences in mouse SEWA sarcoma cells. This interaction was initially observed through the identification of a 40 kDa protein which was eluted from a DNA affinity chromatography column consisting of the long terminal repeat (LTR) of the endogenous intracisternal A-type particle (IAP). Microsequencing analysis identified this 40 kDa protein as the glycolytic enzyme, aldolase A. The use of specific anti-aldolase antibodies enabled the identification and subsequent purification of aldolase from the nuclear protein fraction of two SEWA sublines, one that is adherent and one that grows in suspension. In order to confirm our initial finding that aldolase is capable of interacting with DNA, proteins from each subline were immunopurified with anti-aldolase antibodies, eluted and then tested for their ability to interact with IAP-LTR DNA sequences. Interestingly, only aldolase derived from the anchorage dependent SEWA cells was capable of interacting with the IAP-LTR, however, several cell lines derived from human tumors also exhibited this activity. Subsequent studies revealed the ability of aldolase to interact with some but not every DNA sequence tested, implying that there may be a minimal DNA conformation and/or sequence requirement for this activity. The presence of aldolase A in the nuclei and its ability to interact with certain DNA sequences suggest a novel role for this metabolic enzyme.
Animals↗
The regulation of translation by the 5' untranslated region of Xenopus c-myc I mRNA during early development.
The translational efficiency of chloramphenicol acetyltransferase (CAT) mRNA containing 5' untranslated region (UTR) sequences of Xenopus c-myc I mRNA was examined in the Xenopus oocyte and early embryo. In contrast to their reduced translation in the oocyte, CAT mRNAs containing 5' UTR sequences located between the c-myc I P0 and P2 promoters translate as efficiently as CAT mRNA controls when injected into early embryos. This pattern of differential regulation of c-myc I translation is similar to that observed for mouse c-myc 5' UTR-containing CAT transcripts during Xenopus oogenesis and early embryogenesis [Lazarus, P., Parkin, N. & Sonenberg, N. (1988). Oncogene, 3, 517-521]. Oocyte-specific translational inhibition was not observed for CAT mRNAs containing c-myc I 5' UTR sequences located 3' of the P2 promoter. No significant alteration in c-myc I 5' UTR/CAT mRNA stability was observed in the oocyte as compared with CAT mRNA controls. The significance of this promoter-dependent translational regulation with respect to c-myc expression and early Xenopus development is discussed.
Animals↗
[Treatment of poisoning with anti-arrhythmia agents and glycosides].
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Aged↗
Developmental regulation of translation by the 5' noncoding region of murine c-myc mRNA in Xenopus laevis.
The translational efficiency of chloramphenicol acetyltransferase (CAT) mRNA containing a 5' noncoding sequence derived from exon 1 of the murine c-myc gene (360CAT) has been examined at different stages of Xenopus egg development. In contrast to its reduced translation in the Xenopus oocyte, 360CAT mRNA is translated as efficiently as CAT mRNA when injected into either mature Xenopus eggs or Xenopus embryos. No significant alteration of 360CAT mRNA stability was observed up to 10 h post-fertilization in Xenopus embryos as compared to that of CAT mRNA. The increase in 360CAT mRNA translational efficiency in Xenopus embryos was not observed with CAT mRNAs possessing other inhibitory 5' noncoding sequences. The increase in 360CAT mRNA translational efficiency is attributed to a trans-acting factor synthesized or activated following Xenopus oocyte maturation. The possible significance of the 5' noncoding region of c-myc mRNA in developmental expression of c-myc is discussed.
Animals↗
Mechanism of decrease of protein synthesis by sodium cyanate in murine P388 leukemia cells.
Sodium cyanate is a selective in vivo inhibitor of protein synthesis in a variety of mammalian tumor cells without a corresponding effect on the normal tissues of tumor-bearing animals. The in vivo decrease of protein synthesis observed 4 h post-NaOCN i.p. administration in the murine P388 leukemia cell cannot be explained by decreased amino acid pools in the mouse peritoneal cavity. In addition, the decrease in protein synthesis observed with NaOCN in isolated P388 cells was shown not to be secondary to (a) alterations in the kinetics of amino acid transport or (b) effects on total nucleotide pools. The incorporation of [14C]phenylalanine in P388 cell-free lysates from NaOCN-pretreated mice was significantly decreased to approximately 55% of control lysates in the presence of exogenous amino acids. The addition of exogenous calf liver tRNA to the lysates did not alter this result. However, no difference was observed in polyuridylic acid-directed [14C]phenylalanine incorporation into polypeptides in micrococcal nuclease-treated P388 lysates from NaOCN-pretreated or control mice. Quaternary initiation complex (48S) formation and mRNA synthesis were found to be significantly decreased by 35 and 38%, respectively, in P388 cells from NaOCN-pretreated mice. DNA synthesis was decreased by 66% of control at 1 h and 62% at 4 h post-NaOCN i.p. administration. No apparent effect with NaOCN was observed on total RNA synthesis in P388 cells. These results suggest that the decrease in P388 cell protein synthesis observed with NaOCN in vivo appears to be due to alterations manifested in the synthesis of cellular mRNA and protein synthesis initiation processes. NaOCN does not appear to affect the P388 cell ribosomal machinery, tRNA, or protein synthesis elongation processes.
Adenosine Triphosphate↗
Further studies on amino acid transport in murine P388 leukemia cells in vitro. Presence of system y+.
The transport of glycine and L-lysine into murine P388 leukemia cells has been examined. Glycine transport appears to be shared by both systems A and ASC in P388 cells. Glycine transport is Na+-dependent and is effectively blocked by alpha-(methylamino)isobutyric acid, threonine and alanine but only a marginal reduction in transport is seen with 100-fold excess cold 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid. System gly is not expressed in P388 cells. Lysine is largely transported by a Na+-independent, pH-insensitive system with a Km of 0.079 mM. Lysine transport is relatively unaffected by the addition of 100-fold excess cold alpha-(methylamino)isobutyric acid, 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid and the anionic amino acids, L-glutamate and L-aspartate. A partial inhibition of lysine transport was observed with L-threonine and L-leucine while L-arginine and L-histidine radically decreased lysine transport. Lysine appears to be transported by a system similar to the system y+ seen in cultured human fibroblasts, Ehrlich ascites cells, and hepatoma cell lines.
Amino Acids↗
[Therapy of the anticholinergic syndrome in poisonings].
Underlying literature and taking into consideration own experiences in the anticholinergic syndrome the following view is taken: Physostigmine salicylate is the remedy of choice for the treatment of the anticholinergic syndrome and altogether causes only slight side effects. While for differential-diagnostic reasons the application is recommended under hospital conditions, the pre-hospital application is to be estimated as problematical. The improvement of the clinical symptoms under the influence of physostigmine salicylate must not lead to the neglect of the control of the patient. A differentiated use of physostigmine salicylate is necessary, and it cannot be regarded as "universal antidote" in intoxications caused by central-nervous effective substances.
Adolescent↗
Characterization of L-threonine and L-glutamine transport in murine P388 leukemia cells in vitro. Presence of an N-like amino acid transport system.
The transport of L-threonine and L-glutamine into murine P388 leukemia cells has been characterized. Threonine appears to be a specific substrate for a Na+-dependent amino acid transport system similar to system ASC of the HTC hepatoma cell. Threonine transport is uninhibited by 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid and alpha-(methylamino)isobutyric acid, shows a pattern of transport similar to that seen in HTC hepatoma cells over the pH range of 5.5-7.5, and is inhibited by L-serine and L-cysteine. Approximately two-thirds of glutamine transport into P388 cells also appears to enter P388 cells via this ASC-analogous system. However, based upon (a) inhibition studies with threonine (where the K1 of threonine inhibition of glutamine transport was 7-fold the Km of threonine transport), (b) inhibition analysis of glutamine transport with various amino acids and amino acid analogues, and (c) different patterns of transport between threonine and glutamine over the pH range of 5.5-7.5, approximately one-third of glutamine transport can be attributed to a second Na+-dependent amino acid transport system. This system appears to be similar to the system N of rat hepatocytes. Glutamine and threonine do not appear to enter P388 cells via systems A or L to any significant degree. P388 cells do not appear to exhibit 'adaptive regulation' of amino acid transport. Differences in 'adaptive regulation' could therefore not be utilized for comparing threonine and glutamine transport.
Aminoisobutyric Acids↗