RESUMEN
The metastasis dissemination is a process which leads to a primary tumor cells to migrate, infiltrate host tissues and form a secondary tumor focus at distance. This clinic evolution is a consequence of the cancer natural history and is due to the appearance of new potentialities in tumoral cells, providing to a small quantity of them an invasive and metastatic capability. This dissemination is possible by many factors; among them the lack of cohesion in tumor tissue cells, forming new blood vessels, resistance to anoikis and posterior implantation of tumoral cells in a heterotypic site. The change of cohesion in cell systems, synthesis of proteolytic enzymes, cell motility, modification of signals induced by growth factors, or the substratum for environment adhesion, and lack immune recognition by the immunologic system, are the main contributors to the appearance of metastasis. A permissive ecosystem is necessary to implant tumoral cells in target organs such as: liver, lung and bone marrow. This special environment, which is more favorable to metastasis, supplies an stroma, adhesive systems, growth factors and neo-vascularization. It is important to point out that the development of a metastasis is preceded by some genetic changes which make possible the adaptation of malign cells to a new microenvironment.
Asunto(s)
Metástasis de la Neoplasia , Neoplasias Óseas/secundario , Adhesión Celular , Movimiento Celular , Endopeptidasas/metabolismo , Humanos , Invasividad Neoplásica , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Proteínas de Neoplasias/metabolismo , Células Neoplásicas CirculantesRESUMEN
Small cell lung carcinomas (SCLC) are characterised by chemosensitivity to diverse antitumoral compounds. However, responses are transitory and relapses are commonly observed. We examined the ability of verapamil, a reverser of P-glycoprotein (Pgp)-related resistance, to improve the efficacy of CyCAV combined chemotherapy (Cy, cyclophosphamide (CPA); C, cisplatin (CDDP); A, doxorubicin (ADM);V, etoposide (VP16)), as currently administered to SCLC patients at Institut Gustave-Roussy, France, and adapted to the treatment of nude mice implanted with these tumours. Although Pgp encoded by the MDR1 (multidrug resistance) gene is not the only mechanism for multidrug resistance (MDR), and not all drugs included in this regimen are recognised by Pgp, we anticipated a therapeutic benefit. Four different SCLC lines, expressing the MDR1 gene and recently grafted into nude mice, were used. SCLC-75, SCLC-6 and SCLC-41 originated from untreated patients, and SCLC-74T was derived from a patient treated with a combination of ADM, CPA and VP16. SCLC-41% and SCLC-6T tumours were used after having undergone, respectively, five and nine cycles of in vivo passage and CyCAV treatment of the tumour-bearing nude mice, to reinforce their chemoresistance. The efficacy of the CyCAV regimen, associated with or without verapamil (given 24 h before CyCAV on days 1-5), was tested on the growth of these SCLC. Verapamil (25 mg/kg) improved the antitumour effect of CyCAV in mice bearing SCLC-6T, SCLC-41T and SCLC-75 tumours, although toxicity was observed. Verapamil modestly delayed the plasma clearance of ADM. Two daily injections of 10 mg/kg of verapamil, administered at a 3 h interval, proved to be effective, whereas the same total dose administered as a bolus was not. These results indicate that the association of some reversers of MDR, including drugs possibly interacting with Pgp, might potentiate SCLC combined chemotherapy.