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PubMed1995

Prospective multimodality treatment of SCLC--experience during the past 18 years.

Lung cancer has been one of the leading malignancies in China. Since 1989 it has ranked first among common malignancies in the male population, and second in females. In 1975, a multimodality treatment study group for lung cancer was organized in our institute. The group has since expanded to 15 institutions in the Beijing and Tianjin area during the past four years. The present communication is based on our experiences and data, and tries to explain the treatment strategy of our study group.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Antigenic phenotype and biological characteristics of two distinct sublines derived from a small cell lung carcinoma cell line.

Two sublines, SCLC-MOA1 (MOA1) and SCLC-MOA2 (MOA2), were established from the SCLC-MO cell line, which was originally derived from an oat cell type of small cell lung carcinoma (SCLC). SCLC-MO showed typical culture morphology of SCLC, growing as tightly packed floating aggregates, while both MOA1 and MOA2 grew as a monolayer. MOA2 showed markedly shorter culture doubling time and higher colony forming efficiency than SCLC-MO and MOA1. When transplanted into nude mice, both SCLC-MO and MOA1 showed intermediate cell type histology, while MOA2 showed a picture of large cell carcinoma as non-SCLC. As for biomarkers, SCLC-MO showed a transitional state between the classic and the variant types, while MOA1 was the variant type. In contrast, MOA2 lost the biomarker characteristic of SCLC, showing rather non-SCLC type. SCLC-MO expressed NE-150 neuroendocrine antigen, but lacked PE-35 panepithelial antigen which is generally present on SCLC. It lacked also OE-130 epithelial antigen which is generally absent from SCLC. Thus, the phenotype was NE-150+/PE-35-/OE-130-, which was different from the major phenotype of SCLC, NE-150+/PE-35+/OE-130-. MOA1 was weakly positive for PE-35, showing NE-150+/PE-35 +/- /OE-130-, while MOA2 was positive for OE-130, but lost NE-150, i.e., NE-150-/PE-35+/OE-130+, showing a non-SCLC phenotype. Thus, a good concordance was observed between the antigenic phenotype and the biological characteristics of these SCLC lines. The results altogether suggested that a part of large cell carcinoma in the tumor of the patient may be derived from SCLC. Karyotype analysis showed that there were several marker chromosomes including deletion of chromosome 3p shared by these three cell lines, supporting the belief that MOA1 and MOA2 originated from SCLC-MO. Southern blot analysis showed the amplification of the L-myc related gene, probably rearranged L-myc, in the primary SCLC tumor as well as in SCLC-MO and MOA1. Northern blot analysis showed the 2.2-kilobase transcripts hybridized with a L-myc probe were observed in SCLC-MO and MOA1, but not in MOA2. In contrast, the c-myc transcript was detected only in MOA2. The activity of the myc gene family may contribute to certain biological characteristics of SCLC.

Animals↗
PubMed1986

Discrimination of human small cell and non-small cell lung tumors by a panel of monoclonal antibodies.

The immunohistochemical reactivity of biopsy specimens from different human lung tumor cell types was examined with 4 human small cell lung carcinoma (SCLC)-reactive monoclonal antibodies (MoAbs) (SCLC 1096, SCLC 2051, SCLC 3121, and SCLC 5023) generated in this laboratory, with the use of Formalin-fixed, paraffin-embedded tissue sections. Each MoAb reacted preferentially with SCLC tumors (62-97% of 29 cases tested), with low-to-moderate cross-reactivity with non-SCLC tumors (SCLC 1096, 13.7%; SCLC 2051 and SCLC 3121, 9.8% each; SCLC 5023, 41%, of 51 cases tested). None of the 4 MoAbs reacted with nonmalignant lung biopsy specimens. SCLC tumors were characterized by their collective immunoperoxidase reactivity with the MoAb panel of SCLC 2051, SCLC 3121, and SCLC 5023. Based on unequivocal positive reactions with at least 2 of the 3 MoAbs, this MoAb panel correctly identified 97% (28/29) of SCLC cases of 80 lung tumor cases tested. By contrast, only 4 of 51 (7.8%) non-SCLC cases were positive by the same criterion. These observations suggest that immunohistochemical analysis with these SCLC-reactive MoAbs could help in discriminating small cell from other human lung carcinoma cell types.

Antibodies, Monoclonal↗
PubMed1987

Characterization of two cell lines with distinct phenotypes established from a patient with small cell lung cancer.

Two small cell lung cancer (SCLC) cell lines were established from pericardial and pleural effusions of a patient with histopathologically proven SCLC of the oat cell type. Chemotherapy was administered without response during the 148-day period prior to the establishment of the first cell line, SCLC-22H, and some of the same drugs were administered in the 15 days prior to the establishment of the second cell line, SCLC-21H. Both cell lines differed markedly in their biochemical, kinetic, and morphological properties. Although the biomarkers L-Dopa decarboxylase, bombesin, carcinoembryonic antigen, and neurotensin were detectable in SCLC-22H, they were undetectable or low in SCLC-21H. The population doubling time was twice as fast and the colony forming efficiency higher in SCLC-21H than in SCLC-22H. They both expressed high concentrations of the SCLC marker enzymes neuron-specific enolase and the creatine kinase isoenzyme BB and showed no significant differences in their chromosomal characteristics. c-myc was amplified and expressed in both cell lines, and SCLC-21H had an additional rearranged and amplified EcoRI c-myc fragment. Morphological differences were apparent in liquid culture, cytology, and xenograft histology; SCLC-21H grew much more loosely than SCLC-22H, and had more prominent nucleoli and more abundant cytoplasm. Ultrastructurally dense core granules were present in both cell lines. SCLC-21H thus expressed properties of the variant cell type of SCLC, whereas SCLC-22H had mixed classic/variant features. An in vivo progression of the patient's tumor from a pure small cell to a mixed small cell/large cell morphology could be demonstrated, which suggests that cell line SCLC-22H represents a cell type characteristic for the transitional phase of the tumor. The features of this cell line therefore define a new subclass of SCLC called transitional cell type. SCLC-22H may be of use to study the mechanisms involved in the classic to variant transition, which probably has a considerable impact on the prognosis and response to therapy.

Carcinoma, Small Cell↗
PubMed1992

Antitumoral activity of bombesin analogues on small cell lung cancer xenografts: relationship with bombesin receptor expression.

Gastrin releasing peptide (GRP), the human homologue of bombesin (BN), is an autocrine growth factor for small cell lung cancer (SCLC) cells. The synthetic octapeptides [D-cpa1-beta-Leu8-des-Met9]litorin (BIM 26182) and [D-Phe6-Leu13-CH2NH-Cpa14]bombesin(6-14)NH2 (BIM 26189) are potent GRP/BN antagonists of the proliferation of 3T3 and rat pancreas cells. The effect of these analogues on the proliferation of four SCLC cell lines (SCLC 6, SCLC 41, SCLC 75, SCLC 74R) was tested in vitro and in vivo. Two of these SCLC lines (SCLC 41M and SCLC 75) had receptors for BN/GRP and expressed the prepro-GRP mRNA. BIM 26182 and BIM 26189 inhibited [3H]thymidine incorporation into the DNA of SCLC 41 cells, stimulated [3H]thymidine incorporation in SCLC 6, and had no effect on the two other cell lines. The SCLC implanted s.c. in nude mice were treated with either BIM 26182 or BIM 26189. BIM 26182 and BIM 26189 injected at the doses of 50 micrograms twice a day (s.c.) around the tumor for 10 to 21 days delayed the growth of SCLC 41 and of SCLC 75. The maximal effect was observed during the treatment period, after which the tumors regrew, suggesting a cytostatic effect of these peptides. No inhibitory effect of the peptides on SCLC 74R or SCLC 6 growth was observed. These data suggest that GRP antagonists are able to inhibit the in vitro and in vivo growth of BN/GRP receptors-positive SCLC.

Animals↗
PubMed2000

Differential expression of the LAMB3 and LAMC2 genes between small cell and non-small cell lung carcinomas.

To identify genes differentially expressed between small cell lung carcinoma (SCLC) cells and non-SCLC cells, mRNA differential display was applied to 3 SCLC cell lines and 6 non-SCLC cell lines. The LAMB3 gene was identified as being expressed only in non-SCLC cells and not in SCLC cells. The LAMB3 gene encodes the laminin beta3 chain, which is a unique component of laminin-5. Laminin-5 is a heterotrimer protein consisting of the alpha3, beta3, and gamma2 chains, and another unique component of laminin-5 is the gamma2 chain encoded by the LAMC2 gene. RT-PCR analysis of the LAMB3 and LAMC2 genes in 45 lung cancer cell lines revealed that both the LAMB3 and LAMC2 genes were co-expressed in 21 of 32 non-SCLC cell lines (66%) but only in one of 13 SCLC cell lines (8%). Coexpression of the LAMB3 and LAMC2 genes was also observed in all 4 cases of primary non-SCLC cells examined but not in the corresponding non-cancerous lung cells. Since alpha6beta4 integrin, the specific laminin-5 binding receptor, is known to be expressed only in non-SCLC cells and not in SCLC cells, it was indicated that laminin-5 is a critical microenvironmental factor for the growth of non-SCLC cells but not of SCLC cells. The differences in the expression of integrins and laminins would be critical factors to distinguish SCLC and non-SCLC cells, and such differences might be associated with the unique biological properties of SCLC cells, including metastatic potential and drug sensitivity.

Carcinoma, Non-Small-Cell Lung↗
PubMed2003

Muscarinic signaling in carcinoma cells.

We previously reported that activation of M(3) muscarinic acetylcholine receptors (mAChR) generates anti-proliferative signals and stimulates cadherin-mediated adhesion in the SCC-9 small cell lung carcinoma (SCLC) cell line. The current study was undertaken to determine the frequency of functional mAChR expression among different SCLC cell lines, and to test the ability of mAChR to generate anti-proliferative signals in different SCLC cell lines. The potential role of Rac1 in SCLC cell-cell adhesion was also investigated. Exposure to the mAChR agonist carbachol induces robust Ca(2+) mobilization (indicated by intracellular fluorescence of the Ca(2+)-binding dye Indo-1) in three SCLC cell lines (SCC-9, SCC-15, and NCI-H146), modest Ca(2+) mobilization in one SCLC cell line (NCI-H209), and no detectable Ca(2+) mobilization in two SCLC cell lines (SCC-18 and NCI-H82). The M(3) mAChR-selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide inhibits Ca(2+) mobilization in all SCLC cell lines responding to carbachol. Incubation with carbachol for four hours significantly inhibits [3H]thymidine uptake in three of the four SCLC cell lines expressing functional mAChR (SCC-9, SCC-15, and NCI-H146 cells), but does not significantly alter [3H]thymidine uptake in the other SCLC cell lines examined. These results indicate that SCLC cell lines often express functional mAChR which elicit anti-proliferative signals when activated. To investigate the role of Rac1 in SCLC adhesion, SCC-9 cells were transiently transfected with cDNA constructs coding for Rac1, constitutively active Rac1(Val-12), or dominant negative Rac1(Asn-17) tagged to green fluorescent protein (GFP). SCC-9 cells expressing GFP-tagged constitutively active Rac1(Val-12) exhibit increased cell-cell adhesion in comparison to cells expressing GFP-Rac1 or GFP-Rac1(Asn-17). Constitutively active GFP-Rac1(Val-12), but not GFP-Rac1 or GFP-Rac1(Asn-17), accumulates at cell-cell junctions in SCC-9 cells. These results indicate that activated Rac1 increases SCLC cell-cell adhesion, consistent with the possibility that Rac1 activation contributes to increased SCLC cell-cell adhesion induced by mAChR stimulation. These findings indicate that activation of mAChR may play a significant role in regulating the proliferation and adhesion of SCLC cells. The demonstration by other investigators that acetylcholine is expressed by a variety of cells in the airways supports the possibility that acetylcholine may activate mAChR expressed by SCLC cells in primary tumors.

Calcium↗
PubMed1999

Standard- and high-dose etoposide, ifosfamide, carboplatin, and epirubicin in 100 patients with small-cell lung cancer: a mature follow-up report.

BACKGROUND: We conducted a phase I-II trial to assess the feasibility and activity of a combination chemotherapy regimen with etoposide, ifosfamide, cisplatin or carboplatin, and epirubicin in limited-disease (LD, stages I-IIIB) and extensive-stage (ED, stage IV) small-cell lung cancer (SCLC). PATIENTS AND METHODS: Standard-dose chemotherapy (SDC) consisting of etoposide (500 mg/m2), ifosfamide (4000 mg/m2), cisplatin (50 mg/m2) and epirubicin (50 mg/m2) (VIP-E), followed by granulocyte colony-stimulating factor (G-CSF), was given to 100 patients with SCLC. Thirty patients with qualifying responses to VIP-E proceeded to high-dose chemotherapy (HDC) with autologous peripheral blood stem-cell transplantation (PBSCT) after etoposide (1,500 mg/m2), ifosfamide (12,000 mg/m2), carboplatin (750 mg/m2) and epirubicin (150 mg/m2) (VIC-E) conditioning. RESULTS OF STANDARD-DOSE VIP-E: Ninety-seven patients were evaluable for response. The objective response rate was 81% in LD SCLC (33% CR, 48% PR; excluding patients in surgical CR) and 77% in ED SCLC (18% CR, 58% PR). The treatment-related mortality (TRM) of SDC was 2%. Two additional patients in CR from their SCLC developed secondary non-small-cell lung cancers (NSCLC), and both were cured by surgery. The median survival was 19 months in LD SCLC and 6 months in ED SCLC. The five-year survivals were 36% in LD and 0% in ED SCLC. RESULTS OF HIGH-DOSE VIC-E: HDC was feasible in 16% of ED-, and 58% of LD-patients. All HDC patients (n = 30) improved or maintained prior responses. Four patients died of early treatment-related complications (TRM 13%). Two additional patients in CR from their SCLC developed secondary malignancies (esophageal cancer, secondary chronic myelogenous leukemia). The median survivals were 26 months in LD SCLC, and 8 months in ED SCLC. The five-year survival was 50% in LD and 0% in ED SCLC. CONCLUSIONS: Despite high response rates, survival after VIP-E SDC and VIC-E HDC in patients with ED SCLC is not superior to that achieved with less toxic traditional regimens. The high five-year survival rates achieved with these protocols in LD SCLC probably reflect both patient selection (high proportion of patients with prior surgical resection) and the high activity of our chemotherapy regimen in combination with radiotherapy. A study comparing protocols using simultaneous radiation therapy and chemotherapy, and other dose-escalated forms of SDC with HDC is needed to further define the role of this treatment modality in SCLC. Given the high rate of secondary malignancies observed in patients in CR > 2 years in our study, close follow-up and early treatment of these neoplasms may contribute to maintaining overall survival in patients with SCLC.

Adult↗
PubMedDate not supplied

Small cell lung cancer: etiology, biology, clinical features, staging, and treatment.

Lung cancer is the leading cause of cancer death in the United States. Small cell lung cancer (SCLC) accounts for 20% to 25% of all bronchogenic carcinoma and is associated with the poorest 5-year survival of all histologic types. SCLC differs in its etiologic, pathologic, biologic, and clinical features from non-SCLC, and these differences have translated to distinct approaches to its prevention and treatment. Compared with other histologic types of lung cancer, exposures to tobacco smoke, ionizing radiation, and chloromethyl ethers pose a substantially greater risk for development of SCLC. The histologic classification of SCLC has been revised to include three categories: (1) small cell carcinoma, (2) mixed small cell/large cell, and (3) combined small cell carcinoma. Ultrastructurally, SCLC displays a number of neuroendocrine features in common with pulmonary neuroendocrine cells, including dense core vesicles or neurosecretory granules. These dense core vesicles are associated with a variety of secretory products, cell surface antigens, and enzymes. The biology of SCLC is complex. The activation of a number of dominant proto-oncogenes and the inactivation of tumor suppressor genes in SCLC have been described. Dominant proto-oncogenes that have been found to be amplified or overexpressed in SCLC include the myc family, c-myb, c-kit, c-jun, and c-src. Altered expression of two tumor suppressor genes in SCLC, p53 and the retinoblastoma gene product, has been demonstrated. Cytogenetic and molecular evidence for chromosomal loss of 3p, 5q, 9p, 11p, 13q, and 17p in SCLC has intensified the search for other tumor suppressor genes with potential import in this malignancy. Bombesin/gastrin-releasing peptide, insulin-like growth factor I, and transferrin have been identified as autocrine growth factors in SCLC, with a number of other peptides under active investigation. Several mechanisms of drug resistance in SCLC have been described, including gene amplification, the recently described overexpression of multi-drug resistance-related protein (MRP), and the expression of P-glycoprotein. The classic SCLC staging system has been supplanted by a revised TNM staging system where limited disease and extensive disease are equivalent to the TNM stages I through III and stage IV, respectively. Therapeutically, recent strategies have attained small improvements in survival but significant reductions in the toxicities of chemotherapeutic regimens. Presently, the overall 5-year survival for SCLC is 5% to 10%, with limited disease associated with a significantly higher survival rate.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma, Small Cell↗