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1.
Cancer Res ; 69(8): 3364-73, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19351829

RESUMO

Traditional approaches to the preclinical investigation of cancer therapies rely on the use of established cell lines maintained in serum-based growth media. This is particularly true of small-cell lung cancer (SCLC), where surgically resected tissue is rarely available. Recent attention has focused on the need for better models that preserve the integrity of cancer stem cell populations, as well as three-dimensional tumor-stromal interactions. Here we describe a primary xenograft model of SCLC in which endobronchial tumor specimens obtained from chemo-naive patients are serially propagated in vivo in immunodeficient mice. In parallel, cell lines grown in conventional tissue culture conditions were derived from each xenograft line, passaged for 6 months, and then reimplanted to generate secondary xenografts. Using the Affymetrix platform, we analyzed gene expression in primary xenograft, xenograft-derived cell line, and secondary xenograft, and compared these data to similar analyses of unrelated primary SCLC samples and laboratory models. When compared with normal lung, primary tumors, xenografts, and cell lines displayed a gene expression signature specific for SCLC. Comparison of gene expression within the xenograft model identified a group of tumor-specific genes expressed in primary SCLC and xenografts that was lost during the transition to tissue culture and that was not regained when the tumors were reestablished as secondary xenografts. Such changes in gene expression may be a common feature of many cancer cell culture systems, with functional implications for the use of such models for preclinical drug development.


Assuntos
Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Animais , Carcinoma de Células Pequenas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Reprodutibilidade dos Testes , Transplante Heterólogo , Células Tumorais Cultivadas
2.
Cancer Res ; 68(7): 2321-8, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18381439

RESUMO

Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line-based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line-based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nitrofenóis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos de Bifenilo/administração & dosagem , Carcinoma de Células Pequenas/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Etoposídeo/administração & dosagem , Etoposídeo/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Nitrofenóis/administração & dosagem , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Sulfonamidas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
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