Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A patient with heavy hypokalaemia is described: hypokalaemia and its effects were the unique clinical manifestations of small cell carcinoma of the lung, associated with ACTH ectopic secretion. The rapid unfavourable evolution denotes the explosive behaviour of the syndrome.
 ...
PMID:Hypokalaemia as the only clinical symptom of ACTH ectopic secretion in a case of small cell carcinoma of the lung with very rapid evolution. 739 47

We developed a 24 hour intravenous dexamethasone suppression test for the differential diagnosis of Cushing's syndrome. Basal ACTH and cortisol levels were measured at 8 and 9 AM; a bolus of 8 mg dexamethasone phosphate (in children 5 mg/m2) was administered intravenously, and cortisol levels were measured hourly until 3 PM, then every 2 hours until midnight, and the next morning at 8 and 9 AM. We studied 13 patients with an ACTH-secreting pituitary adenoma, four with an autonomous adrenal adenoma, a 10 year-old girl with primary adrenocortical nodular dysplasia, one male with an ACTH-secreting medullary carcinoma of the thyroid, and one male with an ACTH-secreting non-small cell carcinoma of the lung, and compared their results to those obtained in 8 lean and 12 obese normal individuals (controls). The clinical diagnosis was first ascertained by the response to the oral administration of dexamethasone in low and high doses (standard Liddle test), then by the intravenous dexamethasone suppression test, and finally confirmed surgically. Although both controls and patients with an ACTH-secreting pituitary adenoma significantly suppressed their cortisol levels within hours after the injection (50% reduction of basal value at 2 hours, and 75% at 4 hours, p < 0.0001), levels remained suppressed the next morning only in the controls, while in the patients they returned to basal values. No suppression was observed in any of the patients with an adrenal adenoma and the child with primary adrenocortical nodular dysplasia (whose ACTH levels were low), or in the patients with ectopic ACTH secretion tumors (whose ACTH levels were high).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Single intravenous bolus of dexamethasone for the differential diagnosis of Cushing's syndrome. 758 93

POMC processing is frequently altered in ACTH-secreting nonpituitary tumors in which intermediate lobe-like peptides such as corticotropin-like intermediate lobe peptide (CLIP) are occasionally generated. In rodent pituitaries, the exclusive presence of prohormone convertase PC2 in the melanotrophs of the intermediate lobe is responsible for the specific conversion of ACTH to alpha MSH and CLIP, by contrast with corticotrophs of the anterior lobe, which do not contain PC2 and, therefore, only produce ACTH. The goal of our study was to look for PC2 expression in ACTH-secreting nonpituitary tumors in man. Using Northern blot analysis, PC2 transcripts were detected in five nonpituitary tumors that contained large proportions of CLIP (from 40-95% of the total C-terminal immunoreactive ACTH). A predominant PC2 messenger ribonucleic acid migrated with an apparent mol wt of 5 kilobases, and a minor signal at 3 kilobases was also detected. No PC2 messenger ribonucleic acid could be detected in the small cell carcinoma of the lung-derived DMS-79 human cell line, which produces unprocessed POMC, or in three pituitary tumors responsible for Cushing's disease or Nelson's syndrome, which produced intact ACTH, but no CLIP. These data strongly suggest that, as in rodents, PC2 is responsible for the production of smaller POMC end products, such as CLIP, frequently observed in ACTH-secreting nonpituitary tumors in man.
 ...
PMID:Expression of the prohormone convertase PC2 correlates with the presence of corticotropin-like intermediate lobe peptide in human adrenocorticotropin-secreting tumors. 796 50

In the normal pituitary, glucocorticoids are the principal negative regulatory of the pro-opiomelanocortin (POMC) gene which gives rise to the biologically active peptides ACTH and beta-endorphin. In Cushing's syndrome, ACTH-secreting pituitary tumours show a degree of glucocorticoid resistance, whilst ACTH-secreting extra-pituitary tumours have an even greater resistance to glucocorticoid excess. In an attempt to understand the mechanism of this phenomenon, we have compared the effects of glucocorticoids on POMC mRNA and peptide secretion in human and mouse corticotroph adenoma cells and in small cell lung carcinoma (SCLC) cells. ACTH precursor peptides were inhibited within 24 h by 25-50 nM hydrocortisone in primary cultures from a human corticotroph adenoma. In the mouse corticotroph adenoma cell line (AtT20), inhibition of both ACTH precursors and ACTH was not observed after 24 h but, by 10 days, glucocorticoids suppressed peptide levels with a concentration causing 50% inhibition of 50 nM hydrocortisone and maximal inhibition at 500 nM hydrocortisone. In marked contrast, there was no response to 500 nM hydrocortisone in the five SCLC cell lines (COR L103, COR L42, COR L24, COR L31, DMS 79) all of which secrete ACTH precursors. However, two of the five SCLC cell lines (COR L31 and DMS 79) were responsive to 1000 nM hydrocortisone. POMC mRNA, quantitated by slot-blot analysis, gave similar results for the five SCLC cell lines, implying that the abnormality may occur at the level of gene expression. When one of the three resistant cell lines (COR L103) was incubated with 2000 nM hydrocortisone or 2000 nM dexamethasone a clear suppression of precursor peptides and POMC mRNA was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Glucocorticoid inhibition of ACTH peptides: small cell lung cancer cell lines are more resistant than pituitary corticotroph adenoma cells. 838 76

A 25-year-old black homosexual was noted to be hypertensive, hypokalemic, and to have a rectal mass. Histopathology of the biopsied lesion revealed a mixture of poorly differentiated squamous cell and undifferentiated small cell carcinoma. Abdominopelvic CT showed multiple liver metastases, minimal local tumor extension, and normal adrenal glands. Despite aggressive treatment, he remained hypertensive and hypokalemic. Endocrine work-up revealed: normal 24-hr VMA and catecholamines, normal serum aldosterone and renin levels, elevated urinary free cortisol (3360 micrograms/24 hr), elevated serum cortisol (60 micrograms/dl), and elevated serum ACTH (1697 pg/dl). Liver biopsy confirmed metastatic anorectal carcinoma, and immunohistochemical stains of the rectal biopsy were positive for ACTH and neuron-specific enolase. Although many types of neoplasms have been associated with ectopic ACTH production, small cell carcinoma of the lung is the most common. While there are many reports of colorectal and anorectal neuroendocrine small cell carcinomas, few of these tumors have been associated with clinical ectopic hormone production. This case represents the first report of the ectopic ACTH syndrome associated with anorectal carcinoma.
 ...
PMID:Ectopic ACTH syndrome associated with anorectal carcinoma. Report of a case and review of the literature. 838 4

DMS-79 is a human cell line derived from a small cell lung carcinoma (SCLC), which expresses the pro-opiomelanocortin (POMC) gene. We took it as a model in which to study the mechanism of POMC gene expression in these tumors: precursor processing is altered and gene expression is essentially unresponsive to glucocorticoids. POMC gene structure appeared normal by Southern blot analysis, indicating that gene rearrangement was not responsible for its expression in DMS-79. Indeed, using transient expression of human POMC-luciferase fusion genes in DMS-79, we showed that (1) the normal human POMC promoter was functional in DMS-79, and (2) the same proximal promoter region (-417; + 21) produced the full transcriptional activity in DMS-79 and in the mouse pituitary cell line AtT-20. Progressive 5' deletion analysis revealed differences between AtT-20 and DMS-79: region (-611; -376) was active in AtT-20 and not in DMS-79, whereas region (-95; -161) was active in both cell lines and (-376; -417) was only active in DMS-79. The latter partially overlaps a motif homologous to the DE-2 rat element which confers the tissue-specific expression of POMC in AtT-20 cells; however, this motif had no effect in DMS-79. These data suggest that POMC gene transcription is achieved through a different set of transacting factors in DMS-79 and AtT-20. Altogether, our results provide evidence that DMS-79 is a valid model of tumors responsible for the ectopic ACTH syndrome and that the mechanism of POMC gene expression in these SCLC cells is different from that in pituitary cells.
 ...
PMID:Functional analysis of the human pro-opiomelanocortin promoter in the small cell lung carcinoma cell line DMS-79. 880 Jun 43

A specific propiomelanocortin (POMC) immunoradiometric assay was developed using antibodies directed against ACTH and beta-endorphin (beta end). Partially purified standard POMC was prepared from the human small cell lung carcinoma cell line DMS-79 culture medium. Ten units (U) POMC had the same displacement ability as one pg beta end in a C-terminal beta end radioimmunoassay and thus were close if not equal to 10 pg POMC. This POMC assay was used to investigate patients with ACTH-dependent Cushing's syndrome. Plasma POMC was undetectable (< 60 U/mL) in 17 normal controls and in 4 patients with Addison's disease (concomitant ACTH plasma levels between 362 and 1058 pg/mL). Forty-two patients with Cushing's disease were studied, either before (n = 25) or after (n = 17) bilateral adrenalectomy: 7 patients with highly invasive macroadenomas had high POMC plasma levels, between 240 and 4200 U/ml (concomitant ACTH plasma levels between 77 and 5730 pg/mL); 35 patients, including one with an invasive macroadenoma, had undetectable POMC plasma levels (concomitant ACTH plasma levels between 31 and 2820 pg/mL). Among 20 patients with histologically proven ectopic ACTH syndrome, 16 had high POMC plasma levels, between 80 and 8000 U/mL (concomitant ACTH plasma levels between 45 and 9265 pg/mL); all those tumors were malignant, and the highest POMC/ACTH plasma levels ratios (taken as an index of altered POMC processing) were observed in the 3 patients with small cell carcinomas of the lung; in one of these patients, ACTH and POMC plasma levels both decreased during the course of chemotherapy, in parallel with the reduction of the tumoral mass. Four patients with ectopic ACTH syndrome had undetectable POMC plasma levels (concomitant ACTH plasma levels between 78 and 335 pg/mL): they were all typical bronchial carcinoids. These data show that high POMC plasma level is neither specific for nor constant in ectopic ACTH syndrome. Rather it should be considered as a marker of tumor aggressivity, in pituitary- and non-pituitary tumors. Its diagnostic help appears limited for the most frequent cause of occult ectopic ACTH syndrome, the typical bronchial carcinoids.
 ...
PMID:High plasma proopiomelanocortin in aggressive adrenocorticotropin-secreting tumors. 895 27

The small cell lung carcinoma (SCLC) cell line DMS-79 has been used as a model for studying the molecular mechanism underlying the ectopic ACTH syndrome. We previously showed that two domains of the human Proopiomelanocortin (POMC) gene promoter were specifically active in DMS-79 cells. The present study focuses on the more distal one, Domain IV (-376/-417). DNaseI footprinting experiments identified a single binding site for DMS-79 cell proteins in this domain. Gel-shift and sequence analysis indicated that E2F proteins might bind this site. Indeed, proteins from DMS-79 cells which bind this site (i) have in vitro DNA binding properties indistinguishable from those of E2F proteins (ii) form, like E2F proteins, multiprotein complexes which can be dissociated by sodium deoxycholate and (iii) are recognized by antibodies directed against E2F proteins. Further, we show that the rat POMC distal promoter domain contains a homologous sequence which constitutes a natural mutant of the human POMC E2F binding site, since it does not bind E2F. We show by transient transfection that this natural mutant, in the context of the rat POMC promoter, is not active in DMS-79 cells by contrast to the human POMC E2F binding site. We conclude that E2F binding is required for the activity of Domain IV in DMS-79 cells and contributes to the expression of the POMC gene in SCLC. Further studies are required to elucidate the role of E2F factors in POMC gene transcription in SCLC cells, but our results have identified mechanisms different from those in pituitary corticotroph cells that are used by these SCLC tumor cells.
 ...
PMID:Analysis of the human proopiomelanocortin gene promoter in a small cell lung carcinoma cell line reveals an unusual role for E2F transcription factors. 1035 6

We describe the case of a 56-year-old man with severe muscle weakness due to heavy hypokalemia (serum potassium 1.44 mmol/l) associated with inappropriate kaliuria and alkalemia. Subsequent investigation revealed the presence of ectopic ACTH hypersecretion due to a small-cell lung carcinoma. A significant clinical/laboratory improvement was achieved following chemotherapy-induced regression of the primary tumor. The profound hypokalemia was probably the result of cortisol hypersecretion, which in concert with the ACTH-induced decreased 11beta-hydroxysteroid dehydrogenase activity can exhibit an increased mineralocorticoid activity. In addition, other ACTH-dependent mineralocorticoids may play a contributory role in the development of severe hypokalemia.
 ...
PMID:Severe muscle weakness due to hypokalemia as a manifestation of small-cell carcinoma. 1036 46

Melatonin (MEL) may counteract tumors through a direct oncostatic role. MEL is also an antistress agent with immunoenhancing properties against tumors due to a suppressive role of MEL on corticosterone release. Rotational stress (RS) (spatial disorientation) facilitates metastasis progression in mice. Also, MEL counteracts tumors because of its influence on immune responses via the metabolic zinc pool, which, is reduced in tumors and stress. Zinc is required for normal thymic endocrine activity (i.e. thymulin) and interleukin-2 (IL-2) production. Because in vivo data is still controversial, exogenous MEL treatment (22 days in drinking water) in both intact and pinealectomized (px) mice bearing Lewis lung carcinoma leads to significant decrements of metastasis volume, restoration of the negative crude zinc balance, recovery of thymulin activity and increment of IL-2 exclusively in intact and px tumor bearing mice subjected to RS. Significant inverse correlations are found in both stressed intact and px tumor bearing mice after MEL treatment between zinc and corticosterone (r = 0.78, P < 0.01; r = 0.80, P < 0.01, respectively). Positive correlations between zinc and IL-2 (r = 0.75, P < 0.01; r = 0.73, P < 0.01, respectively) or thymulin (r = 0.75, P < 0.01; r = 0.82, P < 0.01, respectively) are observed in same models of mice. These findings suggest a MEL action to decrease metastasis mediated by a possible interplay between zinc and MEL, via corticosterone, with consequent restoration of thymic efficiency and IL-2 production. MEL as an antistress agent with immunoenhancing properties in cancer deserves further consideration.nuclear factor-kb; POMC, proopiomelanocortin; Px, pinealectomized mice; RIA, radioimmunoassay; RS, rotational stress; SDI, stressed intact mice; SDPx, stressed pinealectomized mice; TNF-alpha, tumor necrosis factor-alpha; ZnFTS, active zinc-bound thymulin; ZnFTS + FTS, total thymulin.
 ...
PMID:Melatonin administration in tumor-bearing mice (intact and pinealectomized) in relation to stress, zinc, thymulin and IL-2. 1041 Dec 80


<< Previous 1 2 3 4 5 6 Next >>