Establishment, growth properties, and morphological characteristics of permanent human small cell lung cancer cell lines

Bepler, Gerold; Jaques, Gabriele; Neumann, Kurt; Aumüller, Gerhard; Gropp, C.; Havemann, K.

doi:10.1007/bf00389964

Cited by 67 publications

(24 citation statements)

References 20 publications

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“…All cell lines were tested for mycoplasma upon arrival in the laboratory. Authentication of the SCLC cell lines was performed years ago prior to arrival in the laboratory (22)(23)(24)(25)(26)(27). The p53 mutation status in the above-mentioned SCLC lines is listed in Table 1 and has previously been evaluated by us (28) and others (29)(30)(31).…”

Section: Cell Linesmentioning

confidence: 99%

PRIMA-1Met/APR-246 Induces Apoptosis and Tumor Growth Delay in Small Cell Lung Cancer Expressing Mutant p53

Zandi

Selivanova

Christensen

et al. 2011

Clinical Cancer Research

122

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Purpose: Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1Met (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1Met to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations. Experimental Design: The therapeutic effect of PRIMA-1Met/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1Met/APR-246 was further evaluated in two different SCLC xenograft models. Results: PRIMA-1Met/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1Met/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1Met/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1Met after i.v. injection in SCLC mouse models with no apparent toxicity. Conclusion: This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1Met/APR-246 for the treatment of SCLC. Clin Cancer Res; 17(9); 2830–41. ©2011 AACR.

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Section: Cell Linesmentioning

confidence: 99%

PRIMA-1Met/APR-246 Induces Apoptosis and Tumor Growth Delay in Small Cell Lung Cancer Expressing Mutant p53

Zandi

Selivanova

Christensen

et al. 2011

Clinical Cancer Research

122

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“…1973), Dartmouth Medical School (Pettengill et al, 1980, the University of Uppsala (Bergh et al, 1985) and the University of Marburg (Beppler et al, 1987). They are listed in Table I.…”

Section: Cell Linesmentioning

confidence: 99%

Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer

et al. 1996

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Female gender is a significant independent favorable prognostic factor in lung cancer. To study the possible role of sex hormones in lung cancer, the expression of sex-steroid receptors and the glucocorticoid receptor was investigated in 29 lung-cancer cell lines stemming from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) by means of immunocytochemistry, ligand-binding assays and RNA expression via polymerase chain reaction. In at least 2 methods of investigation, NSCLC cell lines showed a low expression of estrogen receptor in 6, progesterone receptor in 13 and androgen receptor in I2 out of 17 cases examined; sex-steroidreceptor expression was virtually absent in SCLC cell lines. The glucocorticoid receptor was expressed in all 29 cell lines studied. Additionally, 52 tumor samples from primary lung cancer were investigated for their receptor expression by means of immunohistochernistry. Among patients with primary lung-cancer sex-steroid-receptor expression in tumor biopsies was detected most frequently in female patients (in 69% of I6 cases, vs. 42% of 36 tumors from men) and in patients with adenocarcinoma. Further research will focus on these subgroups. lmmunohistology is a feasible method of studying steroid-receptor expression in lung cancer.o 1996 Wiley-Lhs, Inc.Analyses of large clinical trials have shown that female gender is a significant independent favorable prognostic factor in small-cell lung cancer (Albain et al., 1990;Johnson et al., 1988). Further multivariate analysis of a German multicenter study comprising 766 patients revealed significance only for women under the age of 60 years (Wolf et al., 1991). Two studies of patients with unresectable non-small-cell lung cancer who were treated with chemotherapy also showed a longer survival rate for women (O'Connell et al., 1986;Finkelstein et al., 1986).To determine the influence and possible therapeutical value of sex hormones in lung cancer, we decided to study the expression of their receptors in lung-cancer cell lines and tumor biopsies, since these are a prerequisite for steroid action. There are basically 3 methods for the detection of steroid-hormone receptors: gene expression, binding assays and immunohistochemistry. The gene expression of receptors has not been investigated in lung cancer so far. Binding assays which use radioactive ligands in whole-cell or cytosolic assays are the standard method for studying receptor expression. Immunohistochemistry uses monoclonal antibodies and has been well established for the detection of estrogen receptors and progesterone receptors in breast cancer. Numerous studies have shown a close correlation between immunocytochemical methods and binding assays in mammary carcinoma (Charpin et UL, 1986).The diagnosis of lung cancer is made predominantly on small bronchoscopic biopsies or cytological specimens. Therefore binding assays for which large amounts of fresh tissue have to be provided cannot readily be performed. Immunohistochemistry may overcome this problem, since this method ...

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“…35,36 However, during the latest decades, the clinical relevance of the in vitro variant SCLC cell phenotype has been questioned. Although different cell types can be distinguished within a SCLC tumor, no difference has been observed with regards to survival and chemosensitivity between patients with different combined forms of SCLC and the latest WHO classification of lung tumors does not differentiate between different SCLC variants.…”

Section: Discussionmentioning

confidence: 99%

A chimeric fusion of the hASH1 and EZH2 promoters mediates high and specific reporter and suicide gene expression and cytotoxicity in small cell lung cancer cells

et al. 2008

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Transcriptionally targeted gene therapy is a promising experimental modality for treatment of systemic malignancies such as small cell lung cancer (SCLC). We have identified the human achaete-scute homolog 1 (hASH1) and enhancer of zeste homolog 2 (EZH2) genes as highly upregulated in SCLC compared to a panel of representative normal tissues. Here, we evaluate the use of regulatory regions from the hASH1-and EZH2-promoter regions alone and in combination for suicide gene therapy of SCLC. Two hASH1-promoter regions comprising 0.3 and 0.7 kb immediately upstream of (and including) the transcription start site were tested. Both constructs induced reporter gene activity (up to sevenfold SV40-promoter activity) in all tested classic (hASH1 positive) SCLC and in two hASH1-negative SCLC cell lines, whereas gene activity was low or absent (o4% of SV40 activity) in one hASH1-negative SCLC and in all control cell lines tested. To evaluate its therapeutic potential, the 0.7 kb hASH1 proximal-promoter region was evaluated for cytotoxicity in a suicide gene assay. The construct induced SCLC cytotoxicity at levels equivalent to those observed with the SV40 promoter, while control cells remained unaffected by the treatment. Analogously, a 1.1 kb EZH2-promoter region was evaluated by reporter and suicide gene assays. The EZH2 promoter potently induced reporter gene activity in SCLC (up to 25-fold of SV40 activity) while moderate reporter activity (up to 12% of SV40 activity), was detected in the control cells. However, in the suicide gene assay both control and SCLC cells demonstrated sensitivity indicating lack of promoter specificity. Finally, we fused the 0.7 kb hASH1 promoter to the EZH2 promoter generating a chimeric hASH1EZH2 regulatory construct. The chimeric promoter demonstrated increased activity in SCLC cells compared to the hASH1 promoter alone while retaining specificity in control cells. The hASH1EZH2 promoter thus constitutes a promising transcriptional regulator for SCLC gene therapy.

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Establishment, growth properties, and morphological characteristics of permanent human small cell lung cancer cell lines

Cited by 67 publications

References 20 publications

PRIMA-1Met/APR-246 Induces Apoptosis and Tumor Growth Delay in Small Cell Lung Cancer Expressing Mutant p53

PRIMA-1Met/APR-246 Induces Apoptosis and Tumor Growth Delay in Small Cell Lung Cancer Expressing Mutant p53

Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer

A chimeric fusion of the hASH1 and EZH2 promoters mediates high and specific reporter and suicide gene expression and cytotoxicity in small cell lung cancer cells

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