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

The clinical and electrophysiological data of 18 consecutive adult patients with paraneoplastic Lambert-Eaton myasthenic syndrome (LMES) have been reviewed. The cancer associated with LEMS was small-cell lung carcinoma (SCLC) in 15 cases and epidermoid lung carcinoma in 3 cases. The main clinical neurological features were proximal lower limb weakness (100%), depressed tendon reflexes (94%) and dryness of the mouth (66%). The results of repetitive nerve stimulation (RNS) were not statistically different in the paraneoplastic LEMS group and in a group of 6 LMS patients in whom no carcinoma had been detected. Low-amplitude compound muscle action potential (CMAP) was present in all cases; decremental response at low stimulation rates was present in 13/15 cases. An abnormal incremental response at high stimulation rates was observed in all cases. A close correlation between CMAP amplitude and clinical condition was found in 4 cases during the long-term follow-up. In one patient the RNS electrical pattern could be misinterpreted as myasthenia gravis in only one muscle tested. We underline the usefulness of a 50 Hz stimulation during 4 seconds to establish the diagnosis unequivocally, and that of post-exercise facilitation in routine detection among an SCLC population. Our results suggest that CAMP amplitude and RNS test could be used to evaluate the short-term improvement of LMS under treatment and, in some cases, for the long-term follow-up. The infraclinical axonal neuropathy detected in 8 patients probably was another associated autoimmune paraneoplastic complication.
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PMID:[Lambert-Eaton syndrome: clinical and electrophysiological study of 18 cases associated with lung cancer]. 144 71

Lewis lung carcinoma (LLC) clones were used in in vitro models for dissemination to identify mechanisms regulating the stimulation of metastatic LLC-LN7 migration by prostaglandin E2 (PGE2) or forskolin plus 3-isobutyl-I-methylxanthine (IBMX), and the lack of responsiveness to generated cAMP in non-metastatic LLC-C8 cells. The regulatory subunits of protein kinase A (PKA) from LLC-LN7 cells bound more 8-N3-32P-cAMP, even though production of regulatory subunits was equal to that in LLC-C8 cells. Protein kinase C (PKC) differentially regulated PKA activation in the LLC variants. PKC activation inhibited PGE2-stimulated migration by LLC-LN7 cells. Inhibition of PKC with staurosporine stimulated LLC-LN7 cell migration to a level comparable with that induced by PGE2. However, PGE2 did not further stimulate the migration of staurosporine-treated cells. The PGE2 or staurosporine stimulation of LLC-LN7 cell migration was dependent on PKA activation. The effects that modulation of PKA and PKC had on LLC-LN7 cell migration paralleled the effects on endogenous protein phosphorylation. LLC-LN7 cell autophosphorylation was stimulated to a similar degree by PGE2, forskolin plus IMBX, staurosporine, or the combination of staurosporine and forskolin plus IBMX. In contrast, neither migration nor autophosphorylation was stimulated in non-metastatic LLC-C8 cells by cAMP elevation or by PKC inhibition. Autophosphorylation, although not migration, of LLC-C8 cells was stimulated by forskolin plus IBMX when PKC activity was inhibited. These results suggest that the increased PKA response of metastatic LLC-LN7 cells is contributed by an increased binding of cAMP by the PKA regulatory subunits and a reduced level of regulation by PKC.
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PMID:Regulation of protein kinase A activation and prostaglandin E2-stimulated migration of Lewis lung carcinoma clones. 165 7

Transforming growth factor-beta 1 (TGF-beta 1), a regulator of growth and differentiation of many cell types, has previously been purified from the human placenta, and the messenger (m) RNA is abundantly expressed there. We found that the approximate 2.5-kilobase TGF-beta 1 mRNA is expressed in JEG-3 human choriocarcinoma cells, which have been widely used as a model system for studying the regulation of trophoblast hormone secretion. Cholera toxin (CT) elevates the cellular levels of the second messenger cAMP and increases the secretion of CG and steroids in these cells, thus being a potent inducer of trophoblast-differentiated functions. We show that CT also stimulates TGF-beta 1 mRNA levels in JEG-3 cells in a concentration- and time-dependent manner as studied by Northern and dot blotting. The maximal effect (about 5-fold increase above basal levels) occurs within 12-48 h of induction with a CT concentration of 1.0 ng/ml. The cell-permeable cAMP-analog 8-bromo-cAMP stimulates the accumulation of TGF-beta 1 mRNA in JEG-3 cells as well. Furthermore, this cAMP analog also induces TGF-beta 1 mRNA levels in normal cultured term placental cytotrophoblasts. 12-O-Tetradecanoyl phorbol-13-acetate, an active phorbol ester protein kinase C regulator and inducer of TGF-beta 1 mRNA in many cells, increases TGF-beta 1 mRNA accumulation in JEG-3 cells with a similar time course as cAMP analogs but to a lesser extent. Human HT-1080 fibrosarcoma and A-549 lung carcinoma cells exhibit up-regulation of TGF-beta 1 mRNA in response to TGF-beta 1 itself, but we show that activation of the cAMP-dependent pathway does not affect TGF-beta 1 mRNA levels in these cells. Cycloheximide, an inhibitor of protein synthesis, prevents the effect of CT and 12-O-tetradecanoyl phorbol-13-acetate on TGF-beta 1 mRNA expression in JEG-3 cells, suggesting that a protein mediator may be involved in the transduction of their effects. Our finding of a cAMP-dependent induction pathway for TGF-beta 1 mRNA expression in JEG-3 cells provides a new mechanism for the regulation of the synthesis of this ubiquitous growth and differentiation factor and suggests that TGF-beta 1 may have a role in trophoblast differentiation.
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PMID:Adenosine 3',5'-monophosphate and phorbol ester induce transforming growth factor-beta 1 messenger ribonucleic acid levels in choriocarcinoma cells. 165 96

The role of glucocorticoids and second messenger systems in the regulation of the vasopressin (VP) gene was studied in the human small cell lung carcinoma cell line GLC-8. Small cell lung carcinoma GLC-8 cells express VP mRNA and contain both glucocorticoid and mineralocorticoid receptors. Treatment with the synthetic glucocorticoid dexamethasone when added alone at 10(-8) M had no effect on the VP mRNA level and decreased the level by 30% at 10(-6) M. However, the effect of dexamethasone changed to positive when cells were simultaneously treated with cAMP-enhancing agents. VP mRNA levels, which were elevated by 1.5- to 2-fold by the cAMP-enhancing agents alone, increased a further 1.5- to 3-fold by dexamethasone. Thus, the combined effect of dexamethasone and cAMP stimulation was a 3- to 7.5-fold increase in VP mRNA levels. Long term treatment with the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) reduced the VP mRNA level by 75%. The TPA-suppressed VP mRNA levels could be up-regulated about 6-fold by simultaneous treatment with 8-bromo-cAMP. Dexamethasone did not alter the TPA-suppressed VP mRNA levels. These results indicate that both cAMP and protein kinase-C pathways as well as glucocorticoid receptors are involved in the regulation of VP mRNA levels and that these factors interact. This leads to a negative or positive response of VP gene expression to glucocorticoids in a state-dependent manner. The interactions may be of significance in a physiological context and relate to the different regulation of VP-expressing systems in the brain.
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PMID:Regulation of vasopressin messenger RNA levels in the small cell lung carcinoma cell line GLC-8: interactions between glucocorticoids and second messengers. 171 34

The effects of prostaglandin E1(PGE1), prostaglandin synthesis inhibitor and indomethacin (IN) on the growth and metastasis of Lewis lung carcinoma (LLC) were studied and their mechanisms of action were investigated. Seventy-five C57BL mice of both sexes were utilized in the experiment. It was found that both PGE1 and IN could significantly retard the growth of transplanted LLC and reduce the number of pulmonary metastatic foci. PGE1 obviously decreased the acid phosphatase (ACP) activity of LLC cells while IN showed no such effect. Besides, PGE1 could markedly elevate the plasma cAMP level of LLC-bearing mice, but not normal controls. Meanwhile, it could decrease plasma cGMP concentration of both normal and tumor-bearing mice. IN, like PGE1, could increase plasma cAMP and decrease plasma cGMP levels of LLC-bearing animals. TEM observation revealed that tumor cells treated with PGE1 and IN presented a series of degenerative and destructive changes. In addition, PGE1 and IN exhibited a different effect on several cell-mediated immune responses of the tumored hosts, the former inhibitory and the latter stimulatory. The possible mechanisms of action of the two chemicals are discussed.
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PMID:The inhibitory effects of prostaglandin E1 and indomethacin on the growth and metastasis of transplanted Lewis lung carcinoma in C57BL mice. 216 65

Cholera toxin (CT) inhibited the in vitro growth of three of four human small-cell lung carcinoma (SCLC) cell lines with a 50% inhibitory concentration of 27-242 ng/ml. Loss of surface membrane ruffling and the capacity of [Tyr4]-bombesin, vasopressin, and fetal calf serum to stimulate increases in intracellular free calcium clearly preceded effects on cellular metabolic activity and cell growth. 125I-[Tyr4]-bombesin binding was unaffected by CT treatment but [Tyr4]-bombesin stimulated phospholipase C activity was decreased in membranes from CT-treated SCLC cells. CT stimulated a rapid but transient increase in intracellular cyclic AMP ([cAMP]i) in SCLC. The effects of CT on susceptible SCLC were not reproduced by elevations of [cAMP]i induced by forskolin or cyclic AMP analogues. GM1 ganglioside, the cellular binding site for CT, was highly expressed in the CT-sensitive but not the CT-resistant SCLC cell lines. In contrast, expression of guanine nucleotide binding protein substrates for ADP-ribosylation by CT was similar. These data demonstrate the existence of a CT-sensitive growth inhibitory pathway in SCLC-bearing GM1 ganglioside. Addition of CT results in decreased responsiveness to several mitogenic stimuli. These results suggest novel therapeutic approaches to human SCLC.
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PMID:Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth of human small-cell lung cancer. 217 11

As an alternative to naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines (e.g., antramycin) which possess properties of DNA alkylation, we have designed several antileukemic chromeno[4,3-b][1,5]benzodiazepine derivatives with potential activity toward leukemia cell membranes and the cyclic nucleotide system. The cis and trans diastereoisomers were characterized by NMR. The absolute configurations of the enantiomers were established by X-ray diffraction and circular dichroism (CD) measurements. By means of absorption spectroscopy and determinations of fluorescence and fluorescence decay, it was found that the cancerostatically active compound (+)(6aR, 13aS)-3,4-dimethoxy-10,11-dimethyl-6,6a,7,8,13, 13a-hexahydrochromeno[4,3-b][1,5]benzodiazepine (ZIMET 54/79) and its biologically inactive (-) enantiomer (ZIMET 55/79) interact with liposomal membranes. At pH values of 6.0 and 7.3 the long-wave absorption bands of these agents showed weak bathochromic and hypochromic effects upon addition of neutral, and positively and negatively charged phosphatidylcholine and phosphatidylcholine/cholesterol liposomes. Such spectral changes are interpreted as resulting from the binding of both agents to phospholipid bilayers. Steady-state determinations using the membrane probe 1-anilino-8-naphthalenesulfonic acid (1,8-ANS) led to the observation of a small decrease in fluorescence intensity in the presence of either agent. Time-resolved measurements demonstrate that the mechanism of action of the agents occurs mainly through the partial displacement of probe molecules from regions of hydrophobic binding to areas of greater solvent accessibility. No significant differences in binding between the cancerostatically active and inactive enantiomers with liposomes (archiral systems) were detectable on the basis of spectrophotometric and fluorescence determinations. Cell membrane bound adenylate cyclase is stimulated by ZIMET 54/79, resulting in an increase of 103% in the level of cAMP in mouse L1210 leukemia cells. On examination of structure-activity relationships, it was found that the biological activity (leukemia L1210, P388, Lewis lung carcinoma, melanoma B16, increase in cAMP) is correlated with the particular configuration (6aR,13aS) and type of substituent at positions 3 and 4 of the benzo ring in the case of alkoxy groups and positions 10 and 11 for methyl groups. No activity was detected toward DNA/RNA using microbial test systems.
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PMID:Physiochemical characterization of substituted chromeno[4,3-b][1,5]benzodiazepine stereoisomers designed as cell membrane active antitumor agents. 239 75

The results are reported of a multidisciplinary diagnostic and therapeutic program applied to 381 patients with lung carcinoma from 1983 through 1985 at Mestre General Hospital. Cytologic and/or histologic diagnosis was established in 95% and staging accomplished in 96% of the patients. One-hundred-twenty-nine patients with non-small cell cancer were primarily treated by surgery (lobectomy or pneumonectomy); 3-year survival of this group was 48%. Of the 45 patients with pN1 or pN2 disease, 23 were treated with postoperative adjunctive mediastinal radiotherapy (50Gy/25 F/5Wk); however, survival showed no significant difference in the two groups. Ninety-seven inoperable patients were treated by radiotherapy alone; among those receiving doses of 50-60 Gy in 5 to 6 weeks, 3-year survival was 10%. Chemotherapy (CAMP), used in 23 cases (22 stage IV, 1 stage III), showed no improvement in survival, as compared with a similar series of patients submitted to symptomatic treatment alone. Of the 27 patients affected by small-cell carcinoma, 14 were treated with an aggressive radiochemotherapy protocol and 13 with palliative radiotherapy or low-dose chemotherapy: median survival in the two groups was respectively 45 and 60 weeks. Our study demonstrates the clinical feasibility of interdisciplinary programs routinely applied to a large population of lung cancer patients, and confirms its rationale in terms of early diagnosis, improved staging, and adequate treatment.
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PMID:[Diagnostic and therapeutic approach to lung neoplasms. Departmental experience at the Mestre Hospital]. 245 97

Gastrin-releasing peptide (GRP), the mammalian homolog of the amphibian peptide bombesin, is encoded in man by a single gene located on chromosome 18. Restriction enzyme and DNA sequence analyses establish that the gene is 10 kilobases in size with two introns of 4.8 and 3.9 kilobases. Exon 1 encodes the 5'-untranslated region, the signal peptide, and the first 23 amino acids of GRP. Exon 2 encodes the remaining three complete amino acids of GRP and the first 74 amino acids of the GRP carboxy-terminal extension peptide. Hence, intron 1 interrupts the coding region of the bioactive portion of GRP between the first and second nucleotides for Gly, the 24th amino acid of GRP. Exon 3 encodes the remainder of the GRP-extension peptide and the 3'-untranslated region. Two GC-rich, potential regulatory sequences and a sequence associated with regulation by cAMP lie between the CAAT and TATA boxes; the primary transcriptional start site is located 30 bases downstream from the TATA box. The second intron has an alternate donor site at its 5'-end and an alternate acceptor site at its 3'-end. S1 nuclease mapping demonstrates that differential RNA splicing using these sites results in the similar expression of three GRP mRNAs in GRP-containing neurons (in stomach and brain) as well as in GRP-containing neuroendocrine cells (fetal lung). In addition, the pattern of RNA splicing is similar between normal tissue and neoplastic tissue (small cell carcinoma of the lung and medullary carcinoma of the thyroid).
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PMID:Analysis of the gene and multiple messenger ribonucleic acids (mRNAs) encoding human gastrin-releasing peptide: alternate RNA splicing occurs in neural and endocrine tissue. 284 May 64

All consecutive eligible patients with non-small-lung carcinoma seen at Centro di Riferimento Oncologico and Istituto Nazionale per la Ricerca sul Cancro were entered into a randomized chemotherapy study. Conditions of eligibility included advanced stage (stage III not amenable to radiation therapy or i.v.), measurable or evaluable lesions, age less than 70 years, performance status (PS) greater than 40, and no previous chemotherapy. Patients were randomized to either CAMP (cyclophosphamide 300 mg/m2 i.v., adriamycin 20 mg/m2 i.v., methotrexate 15 mg/m2 i.v. days 1 and 8, procarbazine 100 mg/m2 orally from day 1 to day 10, every 4 weeks) or DE (cisplatin 20 mg/m2 i.v. for five consecutive days and etoposide 75 mg/m2 i.v. on the same days, every 3 weeks). Treatment was continued until progression. Out of the 136 patients randomized, 133 were eligible (CAMP 62, DE 71) and 108 evaluable. Patient characteristics included male/female ratio 57/5 (CAMP) and 61/10 (DE), median age of 60 years (CAMP) and 59 years (DE), PS greater than or equal to 70 for 39 (CAMP) and 50 (DE), PS less than 70 for 23 (CAMP) and 21 (DE), stage III for 18 (CAMP) and 15 (DE), and stage IV for 44 (CAMP) and 56 (DE). DE was superior to CAMP in terms of response rate, defined as responding/evaluable patient ratio (38.2% versus 20.8%); however, the responding/eligible patient ratio was not significantly different in the two groups. The superiority of DE tended to be more marked in stage III patients, in patients with PS greater than or equal to 70, and in the squamous histological type. Toxicity was acceptable (one toxic death) and evenly distributed in the two treatment groups; only renal toxicity was prevalent in the DE group. Survival (all eligible patients) was significantly better in the DE than in the CAMP group. Whether DE chemotherapy is superior to a no-chemotherapy approach has not been evaluated in this study and remains to be determined.
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PMID:Chemotherapy of advanced non-small-cell lung cancer with cyclophosphamide, adriamycin, methotrexate, and procarbazine versus cisplatin and etoposide. A randomized study. 284 69


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