Another interesting study is called, -Antisense therapy for malignant mesothelioma with oligonucleotides ideal bcl-xl gene product- by W. Roy Smythe, MD, Imran Mohuiddin, MD, Mustafa Ozveran, MD, Xiaobo X. Cao – J Thorac Cardiovasc Surg 2002;123:1191-1198. Is an excerpt: -Objective: Malignant pleural mesothelioma is resistant to conventional therapies and to apoptosis. The bcl-2 family genes are major determinants of apoptotic homeostasis. Malignant pleural mesothelioma lines and tumors rarely express the antiapoptotic Bcl-2 protein but routinely express the antiapoptotic protein Bcl-xl along with the proapoptotic proteins Bax and Bak. We have previously shown pharmacologic inhibition of bcl-xl expression in malignant pleural mesothelioma bring about apoptosis, and now we sought to discover whether antisense oligonucleotides directed at bcl-xl messenger RNA would engender apoptosis, possibly through a “forced imbalance” of bcl-2 family proteins.
Methods: Malignant pleural mesothelioma lines REN (epithelial) and I-45 (sarcomatous) were come across modified bcl-xl antissense oligonecleotides directed near to the messenger RNA initiation sequence with and without having a liposomal delivery system. Untreated cells and bcl-xl sense oligonucleotides were controls. Cell viability was measured by colorimetric assay, and apoptosis was evaluated with Hoechst staining and sub-G1 fluorescence-activated cell sorter analysis. Results: Bcl-xl protein expression after antisense oligonucleotides was downwardly regulated within both cell lines compared to sense oligonucleotides (>65%). Significant cellular killing inside the I-45 and REN cell lines was achieved with antisense oligonucleotides (contrary to sense oligonucleotides) without (P = .003 and .006, respectively) sufficient reason for (P = .006 and .0005, respectively) liposomal delivery. Hoechst staining and sub-G1 fluorescence-activated cell sorter analysis demonstrated apoptosis to generally be the mechanism of cellular death. Using of a liposomal delivery system increased therapeutic effect and allowed lower doses of antisense oligonucleotides.
Conclusion: Antisense oligonucleotides geared towards the bcl-xl gene product engender apoptosis in esothelioma cell lines. The therapeutic potential of inhibiting expression with this protein in mesothelioma should be evaluated.-
Another study known as, -Phase III Trial of Pemetrexed Plus Best Supportive Care In contrast to Best Supportive Care in Previously Treated Patients With Advanced Malignant Pleural Mesothelioma- by Jacek Jassem, Rodryg Ramlau, Armando Santoro, Wolfgang Schuette, Assad Chemaissani, Shengyan Hong, Johannes Blatter, Susumu Adachi, Axel Hanauske, Christian Manegold – Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1698-1704. This is an excerpt: -ABSTRACT – Purpose This multicenter, phase III study compared overall survival (OS) of second-line pemetrexed plus best supportive care (BSC) versus BSC alone in patients with advanced malignant pleural mesothelioma (MPM). Secondary end points included response rate, progression-free survival (PFS), a chance to tumor progression (TTP), time for them to treatment failure (TTF), and toxicity. Patients and techniques Patients with relapsed MPM after first-line chemotherapy were randomly utilized receive pemetrexed 500 mg/m2 plus BSC (P+BSC) every Twenty-one days or BSC alone. Results – The investigation enrolled 243 patients (123 on P+BSC arm and 120 on BSC arm). Median OS time were significantly different relating to the arms (8.4 months for P+BSC and 9.7 months for BSC; P = .74). Cox regression modeling suggested a trending survival benefit for patients who taken care of immediately first-line therapy. Time-to-event measures significantly favored P+BSC (median PFS, TTP, and TTF). Partial response was achieved in 18.7% and 1.7% of patients in P+BSC and BSC arms, respectively (P
Conclusion Second-line pemetrexed elicited significant tumor response and delayed disease progression in contrast to BSC alone in patients with advanced MPM. Improvement in OS were witnessed in this research, possibly because of the significant imbalance in postdiscontinuation chemotherapy amongst the arms.-
Another interesting study is, -Urokinase receptor in human malignant mesothelioma cells: role in tumor cell mitogenesis and proteolysis- by S. Shetty, A. Kumar, A. Johnson, S. Pueblitz and S. Idell – Department of drugs, University of Texas Health Science Center at Tyler 75710, USA. Am J Physiol Lung Cell Mol Physiol 268: L972-L982, 1995. Here’s an excerpt: -Urokinase (uPA) interacts utilizing its receptor (uPAR) in promoting proteolysis and tumor migration, functions of potential importance while in the pathogenesis of malignant mesothelioma. Immunohistochemistry of human malignant mesothelioma tissue and mesothelioma cells (MS-1) indicated that mesothelioma cells express uPAR. We isolated uPAR from MS-1 cells by metabolic labeling and showed that how to attract induced by phorbol myristate acetate (PMA), lipopolysaccharide (LPS), a transforming growth factor-beta (TGF-beta) or tumor necrosis factor-alpha (TNF-alpha). Experiments with MS-1 cells showed that uPA binding was saturable, specific, and reversible which includes a mean dissociation constant (Kd) of 5.4 +/- 1.1 nM. Binding was inhibited with a blocking antibody to uPAR through the uPA amino-terminal fragment (ATF), but is not by low molecular weight uPA. uPAR expression was regulated transcriptionally and translationally; antisense oligonucleotides blocked expression of uPAR protein. Plasminogen activator inhibitor-1 (PAI-1) inhibited PA activity of preformed uPA/uPAR complexes and increased cycling on the receptor from the cell surface. Stimulation of subconfluent MS-1 cells by high molecular weight or recombinant uPA, and not ATF or low molecular weight fragment, caused concentration-dependent incorporation of [3H]thymidine. These data indicate a novel mechanism whereby malignant mesothelioma cells localize pericellular proteolysis and concurrently regulate tumor cell proliferation.-
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