Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0149925 (small cell lung cancer)
 6,491 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Strategies to block the effects of tumor growth factors, such as estrogen, and to recruit other regulatory elements, such as with retinoids, have focused interest on the possibility of successful tumor intervention approaches. Approaches that neutralize the effects of critical molecules that drive tumor promotion are attractive targets for evaluation as new intervention agents. Clinical intervention trials with early stage patients or with subjects from "high risk" populations impose stricter types of constraints than conventional chemotherapy approaches in advanced stage patients. The potential for short-term toxicity has to be considered, as it may affect subject accrual or compliance. The longer expected survival of intervention subjects mandates closer attention to the possibilities of unexpected long-term toxicities with chronic administration of an intervention agent. As part of a Phase I clinical trial evaluating the utility of a monoclonal antibody directed against the autocrine growth factor, gastrin-releasing peptide to block the growth of small cell lung cancer, we developed a mathematical model to predict the requisite amount of antibody to neutralize growth factor effect. This model requires knowledge of the equilibrium concentration of the secreted growth factor, specific receptor, and bioavailability of the antibody in the tumor interstitium. A range of possible target doses of antibody can be developed to address the potential for heterogeneity frequently encountered in such systems, including a range of levels for peptide production and specific receptor expression. This approach could be applied to rationally derive treatment or intervention in which specific information regarding the relevant binding parameters is available. Through refinement of this modeling approach more context-specific dosing of agonist/antagonists could be determined which may decrease side effects associated with the drug administration.
 ...
PMID:The correct dose: pharmacologically guided end point for anti-growth factor therapy. 131 37

In a European joint project carried out in 6 laboratories a disease-oriented program was set up consisting of a panel of 7 tumor types, each represented by 4 to 8 different human tumor lines, for secondary screening of promising anticancer drugs. Human tumor lines were selected on the basis of differences in histology, growth rate, and sensitivity to conventional cytostatic agents. Xenografts were grown s.c. in nude mice, and treatment was started when tumors reached a mean diameter of 6 mm in groups of mice where at least 6 tumors were evaluable. Drugs were given at the maximum tolerated dose. For evaluation of drug efficacy, median tumor growth curves were drawn, and specific growth delay and treated/control x 100% were calculated. Doxorubicin (8 mg/kg i.v. days 1 and 8) was effective (treated/control < 50%, and specific growth delay > 1.0) in 0 of 2 breast cancers, 1 of 3 colorectal cancers, 2 of 5 head and neck cancers, 3 of 6 non-small cell lung cancers, 4 of 6 small cell lung cancers, 0 of 3 melanomas, and 3 of 6 ovarian cancer lines. Amsacrine (8 mg/kg i.v. days 1 and 8) was not effective, while datelliptium (35 mg/kg i.p. days 1 and 8) was active against 2 of 6 small cell lung cancer lines. Brequinar sodium (50 mg/kg i.p. days 1-5) showed efficacy in 4 of 5 head and neck cancers, 5 of 8 non-small cell lung cancers, and 4 of 5 small cell lung cancer lines. The project has been shown to be a feasible approach. Clinical activity for doxorubicin and inactivity for amsacrine against solid tumor types was confirmed in the human tumor xenograft panel. Additional anticancer drugs will be studied in the European joint project to further define the reliability of this novel, promising screening approach.
 ...
PMID:Phase II preclinical drug screening in human tumor xenografts: a first European multicenter collaborative study. 139 20

In this study, we show that bispecific hetero-F(ab')2 enhances cytolytic activity in human lymphokine activated killer (LAK) cells derived from peripheral blood mononuclear cells against human small cell lung cancer (SCLC) cell lines. We used two types of bispecific F(ab')2 (anti-CD3-LU246mAb, anti-CD16-LU246mAb) which play different roles in the enhancement of cytolytic activity in LAK cells against the human SCLC cell lines N231, H69 and Lu135. Anti-CD3 Fab' or anti-CD16 Fab' were coupled with LU246 Fab' that recognized the antigen on human SCLC cells for reproducing bispecific F(ab')2. Anti-CD16 (3G8) Fab' conjugated with LU246 Fab' targeted NK-LAK cells to SCLC cells to mediate cytolysis, but NK-LAK cells induced by LGL-enriched fraction did not display enhanced cytotoxicity even when bispecific antibody was used in 51Cr release assay. Anti-CD3 (OKT3) Fab' conjugated with LU246 Fab' cross-linked T-LAK cells to SCLC cells activated T-LAK cells through the CD3 complex, and enhanced the cytolytic activity of T-LAK cells against SCLC lines. Although OKT3-LU246 F(ab')2 was not so potent in enhancing cytolytic activity in 51Cr release assay, it played a greater role in enhancing the inhibitory effect on tumor growth than 3G8-LU246 F(ab')2 in human tumor clonogenic assay and in vivo tumor neutralization assay. In addition, the enhancement of target cell lysis by bispecific antibodies was generally more potent than antibody dependent cellular cytotoxicity (ADCC) using LU246 monoclonal antibody.
 ...
PMID:[The enhancement of cytolytic activity in lymphokine activated killer cells using bispecific F(ab')2]. 166 20

Small cell lung cancer (SCLC) is a fatal malignancy due to its propensity to metastasize widely and to reoccur after chemotherapy in a drug-resistant form. While most SCLC cell lines are anchorage independent for growth, laminin induced the attachment of five of six SCLC cell lines tested (NCI-N417, NCI-H345, NCI-H146, NCI-H187, NCI-H510, and NCI-H209). NCI-N417 SCLC cells adopted a flattened morphology on laminin, and a classic SCLC cell line (NCI-H345) demonstrated a neuron-like appearance while the other SCLC cell lines except NCI-H187 cells, attached but did not spread. Adhesion to laminin was associated with increased resistance to several cytotoxic drugs. Matrigel, an extract of basement membrane proteins, greatly accelerated tumor growth when coinjected with SCLC cells in athymic mice. A synthetic peptide from the B1 chain of laminin, cyclic-YIGSR (Tyr-Ile-Gly-Ser-Arg), inhibited laminin-induced SCLC cell adhesion and migration in vitro and reduced the size of the tumors they formed when coinjected with matrigel and YIGSR. These results suggest that the interaction of SCLC cells with laminin and possibly with other basement membrane proteins can enhance their tumorigenicity and drug resistance.
 ...
PMID:Reconstituted basement membrane (matrigel) and laminin can enhance the tumorigenicity and the drug resistance of small cell lung cancer cell lines. 216 54

An immunotoxin was made by conjugating a murine monoclonal antibody (B4G7) that recognizes the human epidermal growth factor (EGF) receptor with gelonin, a ribosome-inactivating protein. This B4G7-gelonin conjugate was shown to be specifically cytotoxic for EGF receptor-hyperproducing cells. The conjugate was tested in nude mice and shown to be capable of suppressing the growth of an EGF receptor-hyperproducing squamous carcinoma cell (A431) solid tumor. Nude mice bearing an A431 cell tumor that were given injections i.p. for 5 consecutive days with at least 10 micrograms of the conjugate showed significant suppression of tumor growth for about 7 days. On the other hand, an unconjugated mixture of B4G7 and gelonin showed no specific antitumor activity against the A431 cell tumor. The growth of an EGF receptor-deficient small cell lung cancer cell (H69) tumor was not suppressed by injection of the conjugate. No toxic effects were observed in histological examination of nontumorous tissues of mice treated with at least 250 micrograms of conjugate per mouse. These results suggest that the conjugate may be useful for targeting therapy to EGF receptor-hyperproducing squamous carcinoma.
 ...
PMID:Suppression of an epidermal growth factor receptor-hyperproducing tumor by an immunotoxin conjugate of gelonin and a monoclonal anti-epidermal growth factor receptor antibody. 255 59

Bombesin-like peptides are found in many different human tumors and are thought to function as an autocrine growth factor for small cell lung cancer in humans. In this study, a human small cell lung carcinoma (NCI-H69) was s.c. implanted bilaterally into the flanks of 12 nude mice. The mice were randomized and divided into two groups and given either bombesin (20 micrograms/kg) or saline i.p. 3 times a day. Tumor areas were measured twice weekly for 6 wk. At sacrifice, the tumors and normal pancreas were excised, weighed, and assayed for DNA, RNA, and protein content. Significant stimulation of tumor growth was observed at weeks 4, 5, and 6. Tumor weight at sacrifice was significantly elevated (77%) above the control, as was DNA content (78%). Bombesin significantly increased the weight (42%), DNA (48%), and protein (61%) contents of the normal mouse pancreas. We conclude that bombesin may act as an autocrine growth factor, or indirectly through the release of other growth factors, on human small cell lung carcinoma.
 ...
PMID:Effects of bombesin on growth of human small cell lung carcinoma in vivo. 283 Sep 65

Treatment-resistant, chronically hypoxic tumor cells have been assumed to exist in some solid human tumors, limiting their curability. To date, six patients with different types of tumors have been studied using radioactive labelled electron affinic compounds that bind to hypoxic cells. Although the gross clinical appearance of the tumors in all six patients was of a large and fixed mass which might on clinical grounds be expected to contain hypoxic cells, we have observed drug binding to hypoxic regions in only two, a rapidly growing small cell lung cancer (SCLC) and a malignant melanoma. The hypoxic fraction of the malignant melanoma was found to be 6% and the SCLC tumor approximately 10%. We have observed that areas of maximum adduct formation can be found in tumor cells immediately adjacent to blood vessels, suggesting that blood flow over the labelling interval was restricted. These preliminary studies suggest that sensitizer adduct formation in human tumor tissue may be a useful measure of tissue pO2 at the cellular level and that tumor hypoxia might be more related to the rate of tumor growth and histological grading than to tumor size.
 ...
PMID:Binding of 3H-misonidazole to solid human tumors as a measure of tumor hypoxia. 301 5

Marrow involvement by small cell lung cancer (SCLC) is detected in 10-23% of patients at initial diagnosis by marrow aspirate and biopsy techniques. To improve the detection and potentially monitor marrow involvement by SCLC we have attempted to concentrate malignant cells with clonogenic potential on a discontinuous density gradient (DDG). The bone marrow from 43 patients with SCLC (36 with histologically negative marrow aspirates and biopsies) were separated on a Ficoll-based DDG. Samples were also separated by conventional Ficoll-diatrizoate (FD) (density, 1.077) gradient sedimentation. The cellular interphase from three fractions (F X) corresponding to specific densities 1.050 (F X 1), 1.055 (F X 2), and 1.060 (F X 3) as well as cells separated by Ficoll-diatrizoate (F X FD) centrifugation were isolated and 2.5 X 10(5) cells from each fraction were cultured in 2 ml of 0.3% agar in McCoy's media with 10% fetal calf serum, 2.5 micrograms transferrin, 1 microgram insulin, and 1% penicillin-streptomycin. Colony growth was assessed after 14 days of culture at 37 degrees C and 6% CO2. Tumor colony growth was seen in eight of 36 (22%) patients with histologically negative marrows as well as in four of seven (57%) patients with known involvement. Mean colony growth per 2.5 X 10(5) cells for all 12 patients was 4.3 colonies for F X 1; 8.8 for F X 2; and 2.7 for F X 3. In contrast mean growth from the F X FD was 1.0 colonies. Cells with clonogenic potential could be demonstrated from F X 2 and F X 3 in seven of 12 and eight of 12 patients, respectively; in F X FD four of 12 patients had tumor growth. We conclude that separation of marrow samples by DDG concentrates malignant cells with clonogenic potential at least 8-fold compared to FD separation and that the sensitivity of the clonogenic assay in detecting marrow involvement by SCLC is enhanced by DDG sedimentation.
 ...
PMID:Detection of small cell lung cancer bone marrow involvement by discontinuous gradient sedimentation. 303 14

Amplified and increased expression of the myc family of protooncogenes (c- and N-myc) has been described to be associated with rapid proliferation in a number of cell lines, including small cell lung cancer (SCLC). In SCLC, c-myc was demonstrated to be amplified in a subset of SCLC cell lines denoted as variant type, which show a more aggressive way of growth in vitro. The N-myc oncogene, which has extensive homology in the second exon with c-myc, has been shown to be implicated in the oncogenesis of several primary tumors, including SCLC. The authors describe, using in situ hybridization, that increased expression of the N-myc oncogenes in primary biopsies from 15 untreated patients with SCLC are strongly associated with poor response to chemotherapy, rapid tumor growth, and short survival.
 ...
PMID:Increased expression of N-myc in human small cell lung cancer biopsies predicts lack of response to chemotherapy and poor prognosis. 303 35

Small cell carcinoma of the lung is frequently associated with a paraneoplastic syndrome or constitutional symptoms. To examine correlations between paraneoplastic syndromes or constitutional symptoms and tumor behavior, the clinical and pathologic features were reviewed in 85 patients with small cell carcinoma of the lung who underwent complete autopsy at The Johns Hopkins Hospital between 1962 and 1983. The 28 (33 percent) subjects with a paraneoplastic syndrome survived significantly longer (10.5 +/- 1.5 months) than those without a paraneoplastic syndrome (7.4 +/- 0.7 months) (p less than 0.05), and they had significantly higher frequencies of tumor invasion into major bronchi (p less than 0.01) and more extensive metastases to bone marrow (p less than 0.05), but significantly lower frequencies of and less extensive metastases to the central nervous system (p less than 0.005). The 35 (41 percent) subjects with constitutional symptoms had markedly increased tumor burdens (p less than 0.005) with significantly more extensive metastases to bone marrow, liver, and lungs (all p less than 0.05). The findings suggest that subjects with small cell carcinoma of the lung associated with a paraneoplastic syndrome tend to have a more benign clinical course with prolonged survival; in addition, the significantly lower frequency of central nervous system metastases in these patients may be due to a paucity of the subpopulations of tumor cells that have the propensity to metastasize to the brain. In contrast, it appears that constitutional symptoms develop in patients with small cell carcinoma of the lung because of rapid tumor growth, coupled with impairment of synthetic activity in the liver due to extensive infiltration of tumor into hepatic parenchyma.
 ...
PMID:Paraneoplastic syndromes and constitutional symptoms in prediction of metastatic behavior of small cell carcinoma of the lung. 609 32


1 2 3 4 5 6 7 8 9 10 Next >>