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PubMed2004

Identification of a novel collagen-like protein, SclC, in Streptococcus equi using signal sequence phage display.

Strangles is a serious disease in horses caused by Streptococcus equi subspecies equi. In this study, genes encoding putative extracellular proteins in this subspecies have been identified using signal sequence phage display. Among these, one showed similarities to the SclB protein, a member of the collagen-like proteins of Streptococcus pyogenes. The novel gene denoted sclC encodes a protein, SclC, of 302 amino acids, containing typical features found in cell wall-anchored proteins in Gram-positive bacteria. Based on similarities to the S. pyogenes collagen-like proteins the mature SclC protein can be divided into various domains: an N-terminal non-repetitive region (A), a highly repetitive collagen-like region (CL), and a C-terminal proline-rich wall-associated region (W). Using PCR, the sclC gene was detected in all studied strains of S. equi subsp. equi and S. equi subsp. zooepidemicus. Further, antibodies against recombinant SclC were detected in a collection of sera from horses with no history of strangles as well as horses previously infected with S. equi subsp. equi. Interestingly, the sera from convalescence horses were found to have significantly increased antibody titers against the SclC protein indicating that this protein is expressed during infection of S. equi subsp. equi.

Amino Acid Sequence↗

PubMed1998

Transition from SCLC to NSCLC phenotype is accompanied by an increased TRE-binding activity and recruitment of specific AP-1 proteins.

Transitions from small cell (SCLC) to non-small cell lung cancer (NSCLC) cells have been documented both in vitro and in vivo and are thought to be an important step during tumor progression of human small cell lung cancer towards a treatment-resistant tumor state. We have screened NSCLC and SCLC cell lines for differences in the composition of nuclear transcription factors using consensus oligonucleotide sequences (SRE, Ets, TRE, CRE, B-motif, GAS, E-box). We found NSCLC cells to exhibit significantly higher AP-1 binding activity than SCLC cells consistent with the increased expression of CD44, an AP-1 target gene. To gain more insight into the molecular mechanisms underlying these differences, we analysed SCLC cell lines (NCI-N592 and NCI-H69) which were phenotypically transformed into NSCLC-type cells by transfection with activated H-ras and c-myc oncogenes. In these cells, ras-induced transition is accompanied by a strong induction of AP-1-binding activity along with increased expression of CD44 mRNA and protein. When analysing the composition of the AP-1 complex in more detail and comparing ras-induced versus phorbol ester-induced changes, we found Fra-1 to be the major component induced in ras-transfected but not in phorbol-ester treated or non-treated parental SCLC cells. This finding is paralleled by the observation that among the various members of the Fos and Jun family analysed (c-Fos, FosB, Fra-1, Fra-2, c-Jun, JunD, JunB) fra-1 is the only gene to be exclusively expressed in NSCLC cells but not in cells of SCLC origin. Our data, thus, point to a histiotype-related mechanism of recruitment among AP-1 proteins which may have bearings on the fate of lung cancer development.

Carcinoma, Non-Small-Cell Lung↗

PubMed1992

Splicing of the VASE exon of neural cell adhesion molecule (NCAM) in human small-cell lung carcinoma (SCLC).

Expression of the neural cell adhesion molecule (NCAM) on small-cell lung carcinoma (SCLC) cell lines and tumour tissue has been investigated. Cell lines were found to express highly sialylated NCAM. Neuraminidase treatment revealed the presence of the 140- and 120-kDa isoforms with differential expression of a 95-kDa protein. Similar data were obtained with SCLC tumour tissues. These results were corroborated by Northern blotting where mRNA of 6.7 and 5.5 kb coding for the 140- and 120-kDa isoforms, respectively, were identified. In a few tumours, a weaker band of 7.4-kb mRNA coding for the 180-kDa NCAM was also identified. This result could not be confirmed biochemically due to shortage of material. Finally, a 5-kb transcript was identified in all SCLC samples examined. The NCAM isoform coded by this mRNA remains unknown. Using the polymerase chain reaction (PCR), we have demonstrated the presence of the VASE mini-exon in some isoforms of SCLC NCAM. The VASE mini-exon sequence in human SCLC differs from the published murine sequence by only one base change. This substitution does not result in altered amino-acid sequence.

Amino Acid Sequence↗

PubMed1994

SCLC-cluster-2 antibodies detect the pancarcinoma/epithelial glycoprotein EGP-2.

Analysis of the antibodies submitted to the 3 International Workshops on Small Cell Lung Cancer Antigens has resulted in the identification of 15 clusters of antibody reactivity. One of these clusters, named SCLC cluster 2, is characterized by reactivity against an epithelium-associated 38 kDa membrane glycoprotein. SCLC cluster 2, and a number of other antibodies with reportedly similar reactivities, were shown to recognize a protein encoded by the GA733-2 gene, whereas the newly defined SCLC cluster 13 antibodies react with the GA733-1 gene product. We propose to call the antigen detected by SCLC-cluster-2 antibodies "epithelial glycoprotein 2" (EGP-2), and the epithelium-associated glycoprotein recognized by antibodies clustered in SCLC cluster 13 (see elsewhere in this volume) "epithelial glycoprotein 1" (EGP-1). A short overview of the characteristics of both proteins and the applications of anti-EGP-2 antibodies is presented.

Animals↗

PubMed1993

Molecular cloning of IGFBP-5 from SCLC cell lines and expression of IGFBP-4, IGFBP-5 and IGFBP-6 in lung cancer cell lines and primary tumours.

We showed recently that insulin-like growth factor binding protein (IGFBP)-1, -2 and -3 are differentially expressed in lung cancer and permanent lung cancer cell lines. Elevated levels of IGF binding capacity in serum of lung cancer patients were also reported. The function and tissue specificity of IGFBP are still obscure but they are probably local regulators of IGF action. Here we show the expression of IGFBP-4 transcripts in 11/11 small cell lung cancer (SCLC) cell lines, in nine out of 11 non-small cell lung cancer (NSCLC) cell lines, in 11/11 lung tumour specimens (10 derived from patients with NSCLC and one from SCLC origin) and in normal lung. In addition we isolated IGFBP-5 cDNA from lambda gt10 libraries of SCLC cell lines. With this IGFBP-5 cDNA we detected transcripts of different lengths in seven out of 11 SCLC cell lines, in 11/11 lung cancer specimens but only in one out of 11 NSCLC cell lines and in normal lung. IGFBP-6 was not detected in northern analysis of any tested SCLC cell line but it was expressed in nine out of 11 NSCLC cell lines and in nine out of 11 human lung cancer specimens and in normal lung.

Base Sequence↗

PubMed2004

Soluble Fas and Fas ligand provide new information on metastasis and response to chemotherapy in SCLC patients.

BACKGROUND: The Fas/Fas ligand (FasL) system is a major regulator of apoptosis. Chemotherapeutic drugs have been shown to induce Fas expression on the surface of lung cancer cells, and cancer cell apoptosis. However, this mechanism is not considered to be associated with Fas expressed on lung cancer cells. Soluble Fas and FasL concentrations are reportedly elevated in the peripheral blood of patients with lung cancer, but the roles of circulating soluble Fas and FasL in that disease have not been clarified. MATERIALS AND METHODS: We measured the circulating soluble Fas and FasL levels in 21 patients with small cell lung cancer (SCLC), and 12 healthy matched controls, in order to examine whether such ligands could provide any important information and/or reveal any new clinical features of SCLC. RESULTS: In the CR patients, the neuronal specific enolase (NSE), soluble Fas and soluble FasL concentrations were 21.26+/-3.65 ng/ml, 3.58+/-0.19 ng/ml and 0.50+/-0.15 ng/ml, while in the partial response (PR)/no change (NC)/progressive disease (PD) group of patients they were 33.96+/-7.86 ng/ml, 5.29+/-0.29 ng/ml and 0.59+/-0.07 ng/ml, respectively. The NSE, soluble Fas and soluble FasL concentrations were all elevated in the PR/NC/PD patients, however, significant differences were only seen in Fas concentration between CR and PR/NC/PD patients and CR patients and the controls (p<0.001). CONCLUSIONS: Serum soluble Fas and FasL play important roles in the proliferation and metastasis of SCLC, as well as in the cytotoxic reaction and apoptosis induced by anticancer drugs in SCLC. Further study of the mechanisms and participation of circulating soluble Fas and FasL is necessary to develop treatment strategies for SCLC.

Aged↗

PubMed2005

Enhanced expression of apoptin by the Myc-Max binding motif and SV40 enhancer for SCLC gene therapy.

Apoptin is derived from chicken anemia virus (CAV) and known to induce tumor specific apoptosis but not normal cells. The aim of this study was to use increased expression of apoptin by the Myc-Max response element (MMRE) and SV40 enhancer in small-cell lung cancer (SCLC) gene therapy. To investigate the possibility of the utilization of the MMRE, apoptin, and SV40 promoter/enhancer in targeted cancer gene therapy, adenovirus vector expressing apoptin controlled by the MMRE, and SV40 promoter/enhancer was constructed. Ad-MMRE-apoptin-enh infected SCLC cells were significantly suppressed and induced apoptosis more than those of Ad-apoptin or Ad-apoptin-enh. Infection with Ad-MMRE-apoptin-enh of normal cells did not increase apoptosis. About 85% of SCLC tumors show overexpression of the myc family, so the increased expression of apoptin by MMRE and SV40 enhancer can be used in targeted SCLC gene therapy. These results indicate that apoptin expression was increased by the MMRE and SV40 promoter/enhancer, and that this strategy can be used in SCLC targeted cancer gene therapy.

Adenoviridae↗

PubMed1991

Laminin receptors on SCLC cells.

Several studies have suggested a correlation between the metastatic potential and the expression of adhesion molecules and/or their receptors on tumour cell surface membranes. In this study we investigated the expression of functional laminin receptors on small cell lung cancer (SCLC) cells. To this aim we set up an adherence assay to determine the in vitro binding capability of tumour cell lines to laminin. All of the three SCLC lines tested and cells from a short-term SCLC line adhered to laminin in cell culture plates, and the affinity of cell-matrix adhesion proved to be higher than the cell-cell adhesion. This effect was always laminin dose-dependent. On a laminin affinity chromatography column three major proteins could be eluted with EDTA from soluble extracts of SCLC lines. Their molecular weights of 120, 90 and 30 kDa suggested a possible relationship with the integrin family. This putative integrin laminin receptor expressed on SCLC does not react with fibronectin, vitronectin or collagen.

Carcinoma, Small Cell↗

PubMed1987

Genome analysis of small cell lung cancer (SCLC) and clinical significance.

A chromosome analysis of three cell lines derived from SCLC showed deletions of the short arm of chromosome 3 with bands p21-p23 as the shortest region of overlap. Hybridization of a polymorphic 3p21 probe to DNA from leukocytes of seven SCLC patients revealed heterozygosity for two of them. In the tumours of both these patients the probe detected homozygosity. This suggests the presence of a mutant cancer gene in the short arm of chromosome 3 which might express itself and/or activate some oncogene(s) after deletion of a suppressing normal allele. Amplification of the oncogene C-MYC was found in four cell lines including the ones cytogenetically analyzed. Amplification of C-MYC, though to a lesser degree, was also found in an available pleural effusate from which one of these lines had been established. As shown by in situ hybridization, the amplified oncogene was present in double minutes in three of the cell lines. In the remaining line it was in a homogeneously staining chromosome region. All patients from whom cell lines with C-MYC amplification were obtained had a negative response to chemotherapy. The observed correlation between amplification of C-MYC, occurrence of so-called variant type SCLC-derived cell lines, and negative response to chemotherapy indicates that a genome analysis of SCLC might provide further criteria for the characterization and subdivision of this highly malignant cancer and thereby a base for an optimal selection of therapy for distinct cases of SCLC.

Carcinoma, Small Cell↗

PubMed1995

[Induction chemotherapy followed by adjuvant surgery (IC-AS) in patients with stage I-II small cell lung cancer (SCLC)].

Ten patients with stage I-II SCLC received IC-AS between 1984 and 1993. As induction chemotherapy, COMP-VAN alternating chemotherapy and CAV-PVP hybrid chemotherapy were administered. The former consisted of a 4-drug combination of cyclophosphamide (CPA), vincristine (VCR), methotrexate (MTX) and procarbazine alternated with a 3-drug combination of etoposide (ETP), adriamycin (ADM) and nimustine every 4 weeks. In the latter, a 3-drug combination of CPA, ADM and VCR given on day 1, and a 2-drug combination of ETP and cisplatin on day 8, were repeated every 4 weeks. All the patients had an objective response, including one complete response by induction chemotherapy. Post-operative pathology revealed SCLC in 4 patients, adenocarcinoma in 2 and no tumor (pathological CR) in 4. Four patients relapsed, and a intrathoracic relapse was experienced in only 2 patients. Six patients have died: 3 from relapsing SCLC, 2 from stomach cancer, and 1 from squamous lung cancer, who was salvaged from relapsing SCLC. The median survival time was 27.5 months, and the 3-year survival rate 37.5%. These results indicate that IC-AS is highly effective for stage I-II SCLC and warrant additional studies comparing IC-AS with chemo-radiotherapy.

Aged↗

PubMedDate not supplied

Are we moving towards continuous treatment in small cell lung cancer (SCLC)?

In the late sixties the first randomized placebo controlled study with cyclophosphamide demonstrated improved survival in patients with extensive small cell lung cancer (SCLC). Since then chemotherapy has become the mainstay of treatment of SCLC. A number of active combination chemotherapy programs for SCLC were developed during the 1970s and early 1980s. Administration of three or four effective drugs simultaneously appeared to be required for optimal results, but the particular regimen selected was of less importance than the delivery of doses that induced moderately severe but not life-threatening myelosuppression. The drugs chosen for a combination were justified on the basis of single agent activity, difference in mechanism of action and non-overlapping toxic effects. The actual doses were usually the result of feasibility studies in which the doses of all except one drug were held constant. Certain combinations became popular quickly, long before it was appreciated that one of the drugs in the combination added more toxicity than benefit. It is therefore not surprising that the old concept that two drugs in combination are better than one, or three drugs in combination are better than two, is being increasingly criticized. There is recognition that at the time of diagnosis SCLC may already be partially resistant to multiple chemotherapeutic agents and that the strategy simulated by Goldie and Coldman may only partly be applicable to SCLC. Moreover, the development of hematopoietic growth factors has provided a reason to re-evaluate the doses of individual cytostatic agents in current combination regimes and to combine drugs that previously were thought to be incompatible. But even without growth factors, recent investigations with the single agent etoposide and the combination of etoposide and cisplatin have provided arguments against the old theories of "more is better". Drug combinations must preferably be selected on the basis of pharmacokinetic studies. Dose intensity has to be revised and fascinating opportunities will arrive as soon as efficient oral formulations of active drugs, such as platinum, ifosfamide and etoposide become available.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1988

Clinical applications of immunocytochemistry in the monitoring of the bone marrow in small cell lung cancer (SCLC).

A panel of monoclonal antibodies (MAbs) has been identified which may be useful in detecting SCLC tumour cells and which does not cross-react significantly with normal marrow elements. Compared with conventional techniques this MAb panel markedly increases detection of micrometastases in the bone marrow especially in limited disease and post-chemotherapy in responding patients. There is a close correlation between immunological positivity and the ability to grow SCLC-like cells for variable periods in serum-free culture. In 4 cases SCLC-like cells have been characterized by electron microscopy or by the establishment of SCLC cell lines in continuous culture. The prognostic importance of pre-treatment detection of marrow involvement is unknown. The implications of post-chemotherapy detection of micrometastases are also uncertain but there may be an association with early systemic relapse which may occur regardless of intervention, including high dose intensification with autologous marrow rescue with primary site and CNS prophylactic irradiation.

Antibodies, Monoclonal↗

PubMed1992

Prevalence of the Rhesus-negative phenotype in Caucasian patients with small-cell lung cancer (SCLC).

We report that the Rhesus (Rh)-negative phenotype is more prevalent in patients with small-cell lung cancer (SCLC) than in the normal Caucasian population (SCLC: 25% Rh-negative vs. 15% expected, p less than 0.0001). This finding has been validated for a Central and a Northern European population (Switzerland and UK). In contrast, the Rh-negative phenotype is no more frequent in non-small-cell lung cancer patients or in heavy smokers with coronary heart disease than in the general population. There was a normal distribution of the ABO blood group phenotype in all patients studied. Whilst the significance of this observation is unclear, we hypothesize that a genetic predisposition to the development of SCLC may be linked to a hitherto unidentified gene on chromosome 1p near the Rh locus. Our observation may perhaps allow further progress to be made in understanding genetic mechanisms of SCLC carcinogenesis.

ABO Blood-Group System↗

PubMed1994

Detection of the neural cell adhesion molecule (NCAM) in serum of patients with small-cell lung cancer (SCLC) with "limited" or "extensive" disease, and bone-marrow infiltration.

The neural cell adhesion molecule (NCAM) is a tumour-related antigen found on the surface of small-cell lung cancer (SCLC). NCAM exists in several molecular forms, including a soluble isoform. We have measured serum levels of NCAM using an enzyme immunoassay with 2 antibodies, NCC-LU-246 and NCC-LU-243, that react with different epitopes on the NCAM molecule. NCAM activity from 83 patients with active SCLC, either pre-treatment, progressing or in relapse was significantly higher than in 70 patients on follow-up. Overall, 40% of patients with active SCLC and 7% patients on follow-up had serum levels of NCAM > 2SD above controls; 61% of patients with relapsed SCLC had elevated levels of NCAM. Pre-treatment NCAM levels were significantly higher in 35 patients with "extensive" disease than in 19 patients with "limited" disease. Serum NCAM activity was also significantly higher in patients with tumour infiltration of the bone marrow. This difference could not be explained solely by the presence of "extensive" disease. Serum NSE levels in these patients were correlated with NCAM activity. The presence of raised serum NCAM in active disease and in patients in relapse suggests that this antigen could be used as a target for antibody-directed therapy of micrometastases.

Antibodies↗

PubMed1996

Interferon alpha-2a and combined chemotherapy as first line treatment in SCLC patients: a randomized trial.

BACKGROUND: Interferons (IFNs) are known to act synergistically with antineoplastic agents when applied to SCLC cell cultures. This study was conducted in order to detect the clinical benefits, if any, of the addition of IFN-alpha in the induction chemotherapy (CT) of SCLC patients. PATIENTS AND METHODS: Ninety previously untreated patients with SCLC were randomly assigned to receive either CT alone (arm A) or CT plus IFN alpha-2a in a dose of 3 MU/m2 twice weekly (arm B). CT for both arms consisted of carboplatin 420 mg/m2, etoposide 200 mg/m2 and ifosfamide 3.5 g/m2 or epirubicin 80 mg/m2 every 28 days for a total of eight cycles. Responding patients received primary site and prophylactic cranial irradiation and then had maintenance CT with cyclophosphamide 100 mg/m2/day for 20 days every month. Patients in arm B received IFN throughout these treatments. RESULTS: Eighty-one patients were evaluable for response, 39 in arm A and 42 in arm B. Both arms were comparable in terms of age, performance status and extent of disease. Overall response rates were not significantly different between the two arms (90% vs. 86%), although complete response rate was higher in arm B (38% vs. 28%). More importantly, Kaplan-Meier analysis disclosed a clear survival benefit in the arm receiving IFN-alpha (P < 0.05). For limited disease the difference was even more significant (P < 0.0067), while for extensive disease no significant difference was found (P < 0.35). Fever, fatigue and anorexia were more frequent in arm B (P < 0.001), as also leukopenia (P < 0.01). CONCLUSION: The addition of IFN-alpha to induction CT appears to confer a survival benefit to SCLC patients but optimal dosing schedule has yet to be defined.

Adult↗

PubMed2003

Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumour specimens.

Previous studies have shown that STI571, a selective tyrosine kinase inhibitor of c-KIT, is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumours (GIST), especially those that have activating mutations in the c-kit exon 11 that encodes the juxtamembrane (JM) domain of the c-KIT oncoprotein. We examined the prevalence of activating exon 11 c-kit mutations in 26 small-cell lung cancer (SCLC) cases in order to explore whether this disease is also a potential target for treatment with STI571. Expression of c-KIT, estimated by immunohistochemistry, was demonstrated in 14 out of 22 SCLC samples (64%); nine samples showed moderate to strong staining (41%), five samples were weakly positive (23%), whereas eight samples (36%) were negative for CD117. Next, we examined the mutational status of exon 11 of the c-kit gene, by single-stranded conformational polymorphism (SSCP) and sequencing in all of the cKIT/CD117-positive tumours. However, no activating mutations in the c-kit exon 11 were found by either technique. Apparently, c-KIT oncoprotein expression in SCLC was not correlated with activating mutations in c-kit exon 11. In analogy to GISTs, our results could imply that SCLC patients would not benefit from treatment with STI571.

Carcinoma, Small Cell↗

PubMed2000

Asymptomatic brain metastases (BM) in small cell lung cancer (SCLC): MR-imaging is useful at initial diagnosis.

PURPOSE: In this study we evaluated the usefulness of MR-imaging in the detection of asymptomatic brain metastases (BM) at the initial diagnosis in patients with small cell lung cancer (SCLC) and studied the follow-up of these patients. PATIENTS AND METHODS: One-hundred and twenty-five patients with SCLC were investigated with MR-imaging. RESULTS: In 112 patients with normal neurological findings, MR-imaging of the brain demonstrated BM in 17 patients (15%). Six of these 17 patients were therefore upgraded to extensive disease (ED). Two of these 17 patients died during chemotherapy because of progressive disease and 3 patients became neurologic symptomatic with progressive disease on MR-imaging of the brain. After completion of chemotherapy a repeated MR-imaging of the brain in the remaining 12 patients showed 1 complete remission, 4 partial remission and 7 progressive disease of the BM. CONCLUSION: This study showed that at presentation an unexpectedly high percentage of SCLC patients had asymptomatic BM on MR-imaging. We propose that MR-imaging of the brain should be included in the staging of SCLC patients as well for staging, prognosis and therapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Long-term survival of a patient with small-cell lung cancer (SCLC) following treatment with thalidomide and combination chemotherapy.

Thalidomide, an angiogenesis inhibitor is currently used in clinical trials in the US and Europe in combination with chemotherapy for the treatment of various solid tumors. The prognosis of patients suffering from small-cell lung cancer (SCLC) is poor. A 73-year-old female with extensive disease of SCLC was given six courses of chemotherapy with adriamycine, cyclophasphamide and oncovine, which led to complete remission of the disease. Following written informed consent, the patient has been treated with thalidomide 200 mg orally on a daily basis for 2 years and 5 months. There has been no sign of tumor recurrence during the follow-up. This case underlines the possible role of additional treatment with angiogenesis inhibitors in combination with traditional chemotherapy in the therapy of SCLC. Although there is no proof that thalidomide contributed to this good outcome and no conclusions can be drawn from this treatment in a single patient, further studies may determine the role of thalidomide as an adjuvant antiangiogenic agent in the therapy of SCLC.

Aged↗