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)

It has become clear that several polymorphisms of human drug-metabolizing enzymes influence an individual's susceptibility for chemical carcinogenesis. This review gives an overview on relevant polymorphisms of four families of drug-metabolizing enzymes. Rapid acetylators (with respect to N-acetyltransferase NAT2) were shown to have an increased risk of colon cancer, but a decreased risk of bladder cancer. In addition an association between a NAT1 variant allele (NAT*10, due to mutations in the polyadenylation site causing approximately two fold higher activity) and colorectal cancer among NAT2 rapid acetylators was observed, suggesting a possible interaction between NAT1 and NAT2. Glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) are polymorphic due to large deletions in the structural gene. Meta-analysis of 12 case-control studies demonstrated a significant association between the homozygous deletion of GSTM1 (GSTM1-0) and lung cancer (odds ratio: 1.41; 95% CI: 1.23-1.61). Combination of GSTM1-0 with two allelic variants of cytochrome P4501A1 (CYP1A1), CYP1A1 m2/m2 and CYP1A1 Val/Val further increases the risk for lung cancer. Indirect mechanisms by which deletion of GSTM1 increases risk for lung cancer may include GSTM1-0 associated decreased expression of GST M3 and increased activity of CYP1A1 and 1A2. Combination of GST M1-0 and NAT2 slow acetylation was associated with markedly increased risk for lung cancer (odds ratio: 7.8; 95% CI: 1.4-78.7). In addition GSTM1-0 is clearly associated with bladder cancer and possibly also with colorectal, hepatocellular, gastric, esophageal (interaction with CYP1A1), head and neck as well as cutaneous cancer. In individuals with the GSTT1-0 genotype more chromosomal aberrations and sister chromatid exchanges (SCEs) were observed after exposure to 1,3-butadiene or various haloalkanes or haloalkenes. Evidence for an association between GSTT1-0 and myelodysplastic syndrome and acute lymphoblastic leukemia has been presented. A polymorphic site of GSTP1 (valine to isoleucine at codon 104) decreases activity to several carcinogenic diol epoxides and was associated with testicular, bladder and lung cancer. Microsomal expoxide hydrolase (mEH) is polymorphic due to amino acid variation at residues 113 and 139. Polymorphic variants of mEH were associated with hepatocellular cancer (His-113 allele), ovarian cancer (Tyr-113 allele) and chronic obstructive pulmonary disease (His-113 allele). Three human sulfotransferases (STs) are regulated by genetic polymorphisms (hDHEAST, hM-PST, TS PST). Since a large number of environmental mutagens are activated by STs an association with human cancer risk might be expected.
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PMID:Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. 1002 93

Lactic acidosis is a rare complication in lung cancer. We report a case of lung cancer accompanied by both syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lactic acidosis. A 70-year-old man was referred to our hospital for examination of a left hilar mass shadow on a chest X-ray film. Small cell lung cancer (SCLC) was demonstrated by brushing the bronchial mucosa of the left lower lobe bronchus. His laboratory data showed SIADH and lactic acidosis that were probably due to SCLC. Fluid restriction improved SIADH, and combination chemotherapy for SCLC improved the lactic acidosis although the tumor size did not change.
Lung Cancer 1998 Dec
PMID:Small cell lung cancer accompanied by lactic acidosis and syndrome of inappropriate secretion of antidiuretic hormone. 1004 78

The cyclin-dependent kinase inhibitor 2a (Cdkn2a) locus encodes two distinct tumor suppressors, p16INK4a and p19ARF, whose functions interrelate in the regulation of cell proliferation as key components of the retinoblastoma and p53 pathways, respectively. In many types of cancer, alterations of Cdkn2a abrogate the functions of both suppressors, implying that both are integral to the genesis of certain cancer types. While this has been observed in mouse lung adenocarcinogenesis, recent observations also suggested that naturally occurring variation at the Cdkn2a locus is probably operative in the development of these tumors. Firstly, two common haplotypes of mouse Cdkn2a have been identified, each of which encodes cosegregating variants of p16INK4a and p19ARF. The p16INK4a variants differ at amino acids 18 (histidine or proline) and 51 (valine or isoleucine), whereas the p19ARF variants differ only at amino acid 72 (histidine or arginine). Secondly, genetic resistance to lung tumor formation appears to segregate with one particular haplotype, which also is deleted preferentially in lung adenocarcinomas of Cdkn2a heterozygous mice. Here we attempt to explain these observations and to characterize further the roles of p16INK4 and p19ARF in mouse lung tumorigenesis by examining the function and expression of each of the variants of Cdkn2a. Functional analysis showed that the proline 18/isoleucine 51 p16INK4a variant was diminished in cdk6 binding, cdk6 inhibition and NIH/3T3 fibroblast growth suppression compared with the histidine 18/valine 51 variant, whereas both of the p19ARF variants suppressed growth with similar potencies. Also, the different alleles for p16INK4a and p19ARF were transcribed equally in the normal lungs of Cdkn2a heterozygotes, as determined by comparative reverse transcription-polymerase chain reaction-single-stranded conformation polymorphism analysis. These results indicate that strain-specific variation in p16INK4a function is exploited in mouse lung tumorigenesis and strongly implicate a role for p16INK4a in lung cancer predisposition and development.
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PMID:Cdkn2a encodes functional variation of p16INK4a but not p19ARF, which confers selection in mouse lung tumorigenesis. 1036 10

On returning from a medical meeting, we learned that sadly a patient, "Mr. B.," had passed away. His death was a completely unexpected surprise. He had been doing well nine months after a course of intensive radiotherapy for a locally advanced head and neck cancer; in his most recent follow-up notes, he was described as a "complete remission." Nonetheless, he apparently died peacefully in his sleep from a cardiac arrest one night and was found the next day by a concerned neighbor. In our absence, after Mr. B. expired, his death certificate was filled out by a physician who didn't know him in detail, but did know why he recently was treated in our department. The cause of death was listed as head and neck cancer. It wasn't long after his death before we began to receive those notorious "requests for additional information," letters from the statistical office of a well-known cooperative group. Mr. B., as it turns out, was on a clinical trial, and it was "vital" to know further details of the circumstances of his passing. Perhaps this very large cancer had been controlled and Mr. B. succumbed to old age (helped along by the tobacco industry). On the other hand, maybe the residual "fibrosis" in his neck was actually packed with active tumor and his left carotid artery was finally 100% pinched off, or maybe he suffered a massive pulmonary embolism from cancer-related hypercoagulability. The forms and requests were completed with a succinct "cause of death uncertain," adding, "please have the Study Chairs call to discuss this difficult case." Often clinical reports of outcomes utilize and emphasize the endpoint "disease specific survival" (DSS). Like overall survival (OS), the DSS can be calculated by actuarial methods, with patients who have incomplete follow-up "censored" at the time of last follow-up pending further information. In the DSS, however, deaths unrelated to the index cancer of interest are censored at the time of death; thus, a death from intercurrent disease is considered a "success" (to the investigator, that is; obviously, not to the patient and his or her family). The DSS rate will always be superior to the OS rate. Obviously, for any OS curve, if one waits long enough it will ultimately come to zero. There is thus a very logical rationale for reporting the DSS separately, particularly in diseases where death from intercurrent disease is expected to be common. Analyzing the DSS allows researchers to better compare the biologic efficacy of two or more cancer treatments, since it does not necessarily come to zero. Unlike some other endpoints, including local-regional control or freedom from progression, it takes into account the possibility of salvage therapy. DSS also focuses on an endpoint of interest to the public-death from cancer. In a recent popular media survey in which people were asked how they would choose to die if they could, 0% selected cancer. However, there are two serious potential problems with heavy dependence on the DSS. First, since patients who die from intercurrent disease are considered "cured," it seriously inflates the apparent effectiveness of a cancer treatment. Given the same biologic disease and the same treatment, the DSS as calculated in an old, sick population at high risk of intercurrent death will be better than the DSS in a younger, healthier population whose major risk is from their cancer. This problem has been discussed with respect to early stage prostate cancer, in which the conservative approach of observation has been criticized. The studies at issue rely heavily on the DSS, suggesting a comparable DSS (90% at 10 years) with "watchful waiting" to other researchers' results with aggressive therapy. The problem is that these series of conservative management focus on a patient population (as opposed to individuals) with a high risk of competing causes of mortality, which is very different from the population of patients generally treated with aggressive therapy (in which some have shown overall survivals superior to age-matched controls). It is fallacious and illogical to compare nonrandomized series of observation to those of aggressive therapy. In addition to the above problem, the use of DSS introduces another potential issue which we will call the bias of cause-of-death-interpretation. All statistical endpoints (e.g., response rates, local-regional control, freedom from brain metastases), except OS, are known to depend heavily on the methods used to define the endpoint and are often subject to significant interobserver variability. There is no reason to believe that this problem does not occasionally occur with respect to defining a death as due to the index cancer or to intercurrent disease, even though this issue has been poorly studied. In many oncologic situations-for example, metastatic lung cancer-this form of bias does not exist. In some situations, such as head and neck cancer, this could be an intermediate problem (Was that lethal chest tumor a second primary or a metastasis?.Would the fatal aspiration pneumonia have occurred if he still had a tongue?.And what about Mr. B. described above?). In some situations, particularly relatively "good prognosis" neoplasms, this could be a substantial problem, particularly if the adjudication of whether or not a death is cancer-related is performed solely by researchers who have an "interest" in demonstrating a good DSS. What we are most concerned about with this form of bias relates to recent series on observation, such as in early prostate cancer. It is interesting to note that although only 10% of the "observed" patients die from prostate cancer, many develop distant metastases by 10 years (approximately 40% among patients with intermediate grade tumors). Thus, it is implied that many prostate cancer metastases are usually not of themselves lethal, which is a misconception to anyone experienced in taking care of prostate cancer patients. This is inconsistent with U.S. studies of metastatic prostate cancer in which the median survival is two to three years. It is possible that many deaths attributed to intercurrent disease in "watchful waiting" series were in fact prostate cancer-related, perhaps related to failure to thrive, urosepsis, or pulmonary emboli. We will not know without an independent review of the medical records of individual patients; in some cases, even the most detailed review, sometimes even an autopsy, will not be conclusive. There are only a few data available describing the problems created by cause-of-death-interpretation bias. One small study, presented only in abstract form, assessed the cause of death in 50 randomly selected prostate cancer patients who died. Five experts in prostate cancer were asked to assign the cause of death as due to or not due to prostate cancer. The DSS varied from 21% to 35% among the five reviewers, a relative difference of 66%. Studies of autopsies, which are now rarely done in the U.S., have shown that fatal malignant tumors were occasionally missed by clinicians and-even more sobering-an occasional patient thought to have died from metastatic cancer is found to have no tumor but to have died from a "benign" cause such as TB. One study suggested an error rate of approximately 8%. Clearly the use of DSS is here to stay and is a useful adjunct to OS in analyzing randomized trials. There needs to be more research on the validity and interobserver reproducibility of the DSS. In the meantime, researchers should not report DSS without reporting OS and the reasons for intercurrent deaths should be described-peer reviewers should enforce this. As with so many other problems with statistics in the medical literature, it is the job of the reader to remain skeptical. The rate of intercurrent deaths in a study should reflect the age and demographics of the study population. If the DSS is far superior to the OS, the population being studied may be unusually sick (and thus unrealistic), or there may be a bias in classifying the causes of death. Similarly, if the DSS and OS are identical (unless a highly virulent malignancy is being studied), it may suggest the researchers have only included an unusually healthy (and thus unrealistic) patient population. Finally, we would also be a bit suspicious of a sizeable series that did not have any deaths that were considered of "uncertain" cause, unless the researchers specifically included them as being due to the cancer. We honestly think that everybody has a few patients like Mr. B.
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PMID:"Just Another Statistic" 1038 5

The cellular and molecular mechanisms of radiation-induced lung cancer are not known. In the present study, alterations of p53 in tumorigenic human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells induced by a single low dose of either alpha-particles or 1 GeV/nucleon (56)Fe were analyzed by PCR-single-stranded conformation polymorphism (SSCP) coupled with sequencing analysis and immunoprecipitation assay. A total of nine primary and four secondary tumor cell lines, three of which were metastatic, together with the parental BEP2D and primary human bronchial epithelial (NHBE) cells were studied. The immunoprecipitation assay showed overexpression of mutant p53 proteins in all the tumor lines but not in NHBE and BEP2D cells. PCR-SSCP and sequencing analysis found band shifts and gene mutations in all four of the secondary tumors. A G-->T transversion in codon 139 in exon 5 that replaced Lys with Asn was detected in two tumor lines. One mutation each, involving a G-->T transversion in codon 215 in exon 6 (Ser-->lle) and a G-->A transition in codon 373 in exon 8 (Arg-->His), was identified in the remaining two secondary tumors. These results suggest that p53 alterations correlate with tumorigenesis in the BEP2D cell model and that mutations in the p53 gene may be indicative of metastatic potential.
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PMID:Alterations of p53 in tumorigenic human bronchial epithelial cells correlate with metastatic potential. 1042 2

A 59-year-old man was given a diagnosis of lung cancer (moderately differentiated tubular adenocarcinoma) with left adrenal gland and bone metastases in January 1997, and received chemotherapy and irradiation therapy. In late May, anemia and occult blood were detected, with a marked increase in serum CA 19-9. In August, the patient was admitted to our department complaining of melena. His serum CA 19-9 level on admission was significantly elevated (18,960 U/ml). After admission, symptoms of ileus developed. Radiographs of the small intestine and abdominal computed tomographic scans suggested the presence of a tumor in the small intestine. Therefore, surgery was performed, revealing a tumor in the jejunum, which was histologically diagnosed as metastasis of lung cancer to the small intestine. Immunohistochemical staining for CA 19-9 was more intense in specimens from the small intestine tumor than from lung cancer specimens. Serum CA 19-9 decreased significantly after resection. The clinical course and results of CA 19-9 staining suggested that CA 19-9 production by the metastatic lesion in the small intestine was the major cause of the patient's high serum CA 19-9 level. This appears to be a rare case because, to our knowledge, there are no previous reports in the Japanese literature on patients with small intestine metastasis from lung cancer showing an exceptionally high level of serum CA 19-9.
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PMID:[Lung cancer with small intestine metastasis characterized by exceptionally high levels of serum CA 19-9]. 1048 66

The occurrence of primary lung cancer is rare in childhood. The case of an 11-year-old boy with primary lung cancer is presented in this report. He had a substantial family history of cancer. His chief complaint was coughing with right chest pain. A chest radiograph showed a coin lesion in the right lower lung. A right lower lobectomy revealed a squamous cell carcinoma (stage IIIA at Japanese TNM classification). Systemic chemotherapy using cisplatin, vindesine, THP-adriamycin and cyclophosphamide was performed. Six months after surgery, a recurrent tumor occurred. An analysis of the familial cancer related genes (p53 gene and mismatch repair gene) showed no abnormality.
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PMID:Lung cancer in a child with a substantial family history of cancer. 1066 54

We reported an autopsy case of cerebral infarction with primary lung cancer. The patient was a 50-year-old man. Despite having been treated with warfarin potassium and ticlopidine hydrochloride, he relapsed cerebral infarction. His laboratory data on admission showed that lupus anticoagulant was positive, together with a high value of beta-thromboglobulin, thrombin-antithrombin III complex, markers of platelet and coagulation activation, CEA and CA 19-9. The autopsy finding revealed a primary papillary adenocarcinoma in the right lower lung, multiple cerebral infarction, renal infarction, pulmonary infarction and splenic infarction. The atherosclerotic changes were mild in the whole tissues and findings of vasculitis were not observed. Recurrence of cerebral infarction was effectively suppressed with the addition of steroid therapy to antithrombotic therapy. This case was considered as catastrophic antiphospholipid syndrome. It is necessary to differentiate antiphospholipid syndrome in case of the abnormal coagulation and fibrinolytic factors with recurrent cerebral infarction. Moreover, systemic examinations are important, because malignant tumor may exist on the background of the case.
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PMID:[An autopsy case of catastrophic antiphospholipid syndrome presenting with recurrent multiple cerebral infarction associated with lung cancer]. 1068 94

A 47-year-old male, a heavy smoker, was referred to our hospital after Class IV was detected by screening of sputum cytology. His chest X-ray film showed no abnormalities, but bronchoscopy revealed a small nodular lesion at the orifice of right B2. Squamous cell carcinoma was diagnosed by transbronchial biopsy. The clinical stage was I (T1N0M0), and S2 sleeve segmentectomy with lymph node dissection (R 2 b) was performed. The pathological stage was I (T1N0M0), and it was confirmed as early hilar lung cancer. There were no post operative complications and he is well without any evidence of recurrence 5 months after surgery. It may well be considered that this segmental bronchoplastic procedure is useful for cases with early stage squamous cell carcinoma of the segmental bronchus to preserve pulmonary function.
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PMID:[A case of right B2 hillar lung cancer treated by sleeve segmentectomy]. 1077 65

Human lung epithelial cells and many other cell lines are hypersensitive to low doses of ionizing radiation (<0.2 Gy). However, above a threshold dose of 0.4-0.6 Gy, an induced radioprotective response is triggered that protects cells at higher radiation doses. At 4 h, when maximal induced radioprotection is seen in these cells after low-dose priming, the two-dimensional gel protein expression pattern in 0.5-Gy-exposed cells is subtly altered, with seven proteins being 2- to 5-fold down-regulated and one being 2-fold up-regulated. They include: (a) the protein kinase C inhibitor 1, or histidine triad nucleotide-binding motif (HINT) protein; (b) substrates for protein kinase C activity including the chloride intracellular channel protein 1; and (c) a cytoskeletal protein degraded during apoptosis. In addition, a lung cancer-specific protein that binds to both telomeres and nascent mRNA molecules is down-regulated, as is interleukin 1alpha. Therefore, at least in human lung epithelial cells, radioprotection may be the result of signaling pathway switching, which results in the removal of damaged cells and the preparation for enhanced general transcription in surviving cells during a period in which cell proliferation is repressed. This combination of events may be cell-type-specific and may have implications for the protection of normal lung tissue during unavoidable radiation exposure such as in radiotherapy.
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PMID:Expression of proteins coincident with inducible radioprotection in human lung epithelial cells. 1078 77


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