Response of Small-Cell Lung Cancer Xenografts to Chemotherapy: Multidrug Resistance and Direct Clinical Correlates

Poupon, Marie‐France; Arvelo, Francisco; Goguel, A; Bourgeois, Y.; Jacrot, M.; Hanania, Nicole; Arriagada, R.; Chevalier, T. Le

doi:10.1093/jnci/85.24.2023

Cited by 53 publications

(24 citation statements)

References 17 publications

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“…Tumor material was placed in collecting medium (DMEM supplemented with 10 mmol/L HEPES, 1 mmol/L pyruvate sodium, 200 units/mL penicillin, 200 Ag/mL streptomycin, 200 Ag/mL gentamicin, 5 Ag/mL ciprofloxacine, 20 Ag/mL metronidazole, 25 Ag/mL vancomycin, and 2.5 Ag/mL fungizone), as described (32). Five-week-old Swiss nu/nu (nude) male mice were used as xenograft recipients; they were bred in the animal facilities of the Institut Curie and maintained in specified pathogen -free conditions.…”

Section: Establishment Of Primary Culturesmentioning

confidence: 99%

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Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

Falguières

Maak

Weyhern

et al. 2008

Molecular Cancer Therapeutics

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The targeting of solid tumors requires delivery tools that resist intracellular and extracellular inactivation, and that are taken up specifically by tumor cells. We have shown previously that the recombinant nontoxic B-subunit of Shiga toxin (STxB) can serve as a delivery tool to target digestive tumors in animal models. The aim of this study was to expand these experiments to human colorectal cancer. Tissue samples of normal colon, benign adenomas, colorectal carcinomas, and liver metastases from 111 patients were obtained for the quantification of the expression of the cellular STxB receptor, the glycosphingolipid globotriaosyl ceramide (Gb 3 or CD77). We found that compared with normal tissue, the expression of Gb 3 was strongly increased in colorectal adenocarcinomas and their metastases, but not in benign adenomas. Short-term primary cultures were prepared from samples of 43 patients, and STxB uptake was studied by immunofluorescence microscopy. Of a given tumor sample, on average, 80% of the cells could visibly bind STxB, and upon incubation at 37°C, STxB was transported to the Golgi apparatus, following the retrograde route. This STxB-specific intracellular targeting allows the molecule to avoid recycling and degradation, and STxB could consequently be detected on tumor cells even 5 days after initial uptake. In conclusion, the targeting properties of STxB could be diverted for the delivery of contrast agents to human colorectal tumors and their metastases, whose early detection and specific targeting remains one of the principal challenges in oncology. [Mol Cancer Ther 2008;7(8):2498 -508]

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Section: Establishment Of Primary Culturesmentioning

confidence: 99%

“…Poupon). Subcutaneous tumor implantation procedures were done as described in detail elsewhere (32).…”

Section: Establishment Of Primary Culturesmentioning

confidence: 99%

Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

Falguières

Maak

Weyhern

et al. 2008

Molecular Cancer Therapeutics

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“…39 Transplanted tumors were dissected and suspended in culture medium. After filtration, cells were grown in DMEM (Sigma, St. Louis, MO) supplemented with 10% FCS (Dutscher, Brumath, France), and Penicillin G (10 2 IU/ml) ϩ streptomycin (50 g/ml; Sigma).…”

Section: Cell Lines Culture Conditions and Quantification Of Prolifementioning

confidence: 99%

In vivo efficacy of STI571 in xenografted human small cell lung cancer alone or combined with chemotherapy

Decaudin

Crémoux

Sastre

et al. 2004

Intl Journal of Cancer

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Tyrosine kinase proteins play a crucial role in the transduction of intracellular signals, leading to various cellular responses, such as proliferation, apoptosis and differentiation. 1,2 These enzymes are therefore becoming new targets in antitumor therapies designed to block tumor growth, metastasis and neoangiogenesis and to trigger tumor cell apoptosis. 3,4 The tyrosine kinase inhibitor, STI571, belonging to the 2-phenylaminopyrimidine class, formerly known as CGP57148B, selectively inhibits BCR/ABL, 5 platelet-derived growth factor receptor (PDGFR) and c-kit kinase activity. 6 Numerous publications have shown preclinical and clinical efficacy of STI571 on these 3 identified targets: (i) via inhibition of ABL kinase activity in chronic myeloid leukemia (CML) in chronic phase or acute lymphoblastic leukemia with t(9;22)(q34;q11); 7,8 (ii) via PDGFR, CML with PDGFR␣ rearrangement, 9 idiopathic hypereosinophilic syndrome, 10 dermatofibrosarcoma protuberans, [11][12][13] SCLC appears to be an appropriate target for STI571 therapy, as 36% to more than 70% of SCLC tumors and cell lines express c-kit transcript or protein. 29 -38 The growth and viability of a number of SCLC cell lines were inhibited in a dose-dependent fashion by STI571 27,28 and by adenovirus vectors expressing antisense c-kit transcript; 26 in vitro data have shown that STI571 inhibits cell growth and viability via a mechanism involving inactivation of the tyrosine kinase c-kit. 28 This effect appears to be cytostatic because no increase in apoptosis was observed. 27 In contrast with in vitro data reported in CML, STI571 failed to enhance the cytotoxicity of either carboplatin or etoposide when coadministered with these agents. 27 No data are available concerning the efficacy of STI571 in in vivo xenografted human SCLC tumors or on the therapeutic potential of combined administration of chemotherapy and imatinib in these tumors. We therefore investigated the therapeutic efficacy of STI571, alone or combined with chemotherapeutic agents, on various human SCLC cells or tumors xenografted into nude mice. We found that STI571 induced tumor growth inhibition to a variable extent that was not dependent on c-kit expression level, and a synergistic efficacy of concomitant chemotherapy was observed, associated with increased toxicity. Material and methods Cell lines, culture conditions and quantification of proliferation and apoptosisThe SCLC6 human small cell lung cancer cell line was obtained from tumor that was previously xenografted into nude mice. 39 Transplanted tumors were dissected and suspended in culture medium. After filtration, cells were grown in DMEM (Sigma, St. Louis, MO) supplemented with 10% FCS (Dutscher, Brumath, France), and Penicillin G (10 2 IU/ml) ϩ streptomycin (50 g/ml; Sigma). Cells were cultured in medium containing stem cell factor (SCF, Amgen, Nevilly sur Seine, France) or medium alone in the presence or absence of STI571 (Novartis, Basel, Switzerland) and/or etoposide (Pierre Fabre, Boulogne, France) or topotecan (GlaxoSmit...

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“…Several chemotherapeutic agents active in SCLC patients (as doxorubicin, etoposide, or vincristine) are P-gp substrates, raising the question of the impact of ABCB1 expression in these types of tumours. In patient samples, good correlations have been reported between increased ABCB1 expression, lack of response to chemotherapy, and shorter survival (Holzmayer et al, 1992;Poupon et al, 1993;Savaraj et al, 1997), suggesting that ABCB1 gene expression may play a significant role in drug resistance in SCLC.…”

mentioning

confidence: 99%

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

et al. 2007

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Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drugsensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drugsensitive cells, but strongly decreased it in drug-resistant cells. These up-and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter À50GC, À110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment.

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Response of Small-Cell Lung Cancer Xenografts to Chemotherapy: Multidrug Resistance and Direct Clinical Correlates

Abstract: Failure of chemotherapy to control SCLC seems to be related to an acquired multidrug resistance involving the MDR1-mediated mechanism. Therapeutic benefit could therefore be expected from chemotherapy combined with inhibitors of MDR1.

Cited by 53 publications

References 17 publications

Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

In vivo efficacy of STI571 in xenografted human small cell lung cancer alone or combined with chemotherapy

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

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