Innovative Chemotherapy: Investigation of the Multidrug Resistant PhenotypeInvestigation of the Multidrug Resistant Phenotype
Multidrug resistance is a common clinical problem in lung cancer. In SCLC, most tumors recurring after chemotherapy manifest this phenotype, while some demonstrate it prior to therapy. In contrast, most NSCLC and carcinoid tumors demonstrate de novo resistance. While there are many possible reasons for chemoresistance to multiple agents including those that the tumor cells have not been exposed to, one of the best studied mechanisms is over-expression of a 170,000 dalton membrane protein (F-glycoprotein) encoded by the MDRl gene. F-glycoprotein functions as an energy-dependent efflux pump, removing many (but not all) cytotoxic drugs from the cell before they can exert their cytotoxic effects. The MDRl gene is expressed as a 4.5 kb mRNA in some normal tissues, including colonic mucosa, renal proximal tubules, biliary ducts and adrenal cortex and medulla. Click Here
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We have focused on the semiautomatic MTT assay, a tetrazolium dye method. Large numbers of samples can be tested at many drug concentrations and the results obtained within a few days. The major disadvantage of such assays is that they are unable to discriminate between normal and tumor cells if applied to fresh tumor samples. We are attempting to adapt the assay for clinical use by combining it with short-term selective culture of tumor cells in defined media as well as differential adhesiveness. By these methods, a relatively pure tumor cell sample can be obtained within a few days. add comment
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Innovative Chemotherapy: In vitro Drug Sensitivity TestingIn vitro Drug Sensitivity Testing
Selection of individualized chemotherapy based on in vitro drug sensitivity testing (DST) has been a goal of clinicians for more than 3 decades. Despite intense interest and research, and the development of multiple assay methods, this goal has remained theoretic for the most part. In applying such procedures, the following points must be carefully considered: How do you test?; What do you test?; How do you interpret and apply the data?; and (most important of all), What is its clinical relevance? While a detailed discussion of these points is beyond the scope of this report, certain aspects will be considered, in particular those that impact on lung cancer. website
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The former results in higher take rates and rapid fatality. Of interest, the intracranial tumors selectively locate in meningeal and ventricular sites. Thus, it represents a useful model of meningeal carcinomatosis. While only a few tumors can be transplanted intraperito-neally, widespread dissemination may result, with frequent involvement of pleural and pericardial spaces. Thus, these inoculation routes may provide useful models for pleural and pericardial involvement. Other occasionally utilized sites include intrathoracic, intrasplenic and intravenous inoculations. The recently described technique of intrabron-chial inoculation offers a unique orthotopic model for studying the biology of peripheral airway tumors. other
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Innovative ChemotherapyXenografts and In vitro Drug Sensitivity Testing
Over 150,000 cases of lung cancer occur in the USA annually, nearly 90% of whom will die of their disease with a median life expectancy of less than 1 year. Obviously, we need both new drugs as well as new therapeutic concepts. While the latter ideas are discussed by other contributors to this issue, this report will focus on the use of animal and cell culture models for the selection of individualized chemotherapy as well as for the identification of new therapeutic agents. add comment
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C. “Natural killer cell” antigens: In 1984 Ruff and Pert reported the presence of reactive sites on SCLC shared by specific markers for macrophages. They suggested a hemopoietic stem cell origin for SCLC. Later, the expression of certain natural killer cell antigens such as Leu-725 and NKH-l were identified. Leu-7 was demonstrated in 16/20 SCLC tumors, in occasional non-SCLC tumors (7/33) and in all the carcinoids (6/6). These antibodies seem to react with a number of neuroendocrine cells, but are apparently quite suggestive of SC IX when present in malignant lung tumors. Read the rest of this entry »

The Clinical Relevance of Recent Developments in Pathology and Biology of Small Cell Lung Cancer: Specific peptidesB. Specific peptides: Multiple peptides have been demonstrated in SCLC tumors based on immunohistochemistry. At present the literature is loaded with studies using different antibodies, which hampers an interpretation of the results. Bombesin or the mammalian homologue, gastrin-releasing peptide (GRP), has attracted considerable interest. It acts apparently as an autocrine growth factor for SCLC, and it is noteworthy that the growth of SCLC cells in vitro and in xenografts can be inhibited by a monoclonal antibody to GRP” While GRP has been demonstrated frequently in experimental models, it has been difficult to identify this peptide on formalin-fixed surgical material. Read the rest of this entry »

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