Imbalance in Postdiscontinuation Chemotherapy and Mesothelioma Disease

Imbalance in Postdiscontinuation Chemotherapy and Mesothelioma Disease

Another interesting study is called, “Antisense therapy for malignant mesothelioma with oligonucleotides targeting the 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.  Here 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 and the proapoptotic proteins Bax and Bak. We have previously shown pharmacologic inhibition of bcl-xl expression in malignant pleural mesothelioma can lead to apoptosis, so we sought to determine 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 exposed to modified bcl-xl antissense oligonecleotides directed near the messenger RNA initiation sequence with and without 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 in both cell lines relative to sense oligonucleotides (>65%). Significant cellular killing in both the I-45 and REN cell lines was achieved with antisense oligonucleotides (compared with sense oligonucleotides) without (P = .003 and .006, respectively) and with (P = .006 and .0005, respectively) liposomal delivery. Hoechst staining and sub-G1 fluorescence-activated cell sorter analysis demonstrated apoptosis to be the mechanism of cellular death. Use of a liposomal delivery system increased therapeutic effect and allowed lower doses of antisense oligonucleotides.

Conclusion: Antisense oligonucleotides directed at the bcl-xl gene product engender apoptosis in esothelioma cell lines. The therapeutic potential of inhibiting expression of this protein in mesothelioma should be evaluated.”

Another study is called, “Phase III Trial of Pemetrexed Plus Best Supportive Care Compared With 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.  Here 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), time to tumor progression (TTP), time to treatment failure (TTF), and toxicity.   Patients and Methods Patients with relapsed MPM after first-line chemotherapy were randomly assigned to receive pemetrexed 500 mg/m2 plus BSC (P+BSC) every 21 days or BSC alone.   Results – The study enrolled 243 patients (123 on P+BSC arm and 120 on BSC arm). Median OS time was not significantly different between 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 responded to 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 < .0001), and a disease control rate (partial response plus stable disease) was achieved in 59.3% and 19.2% of patients in P+BSC and BSC arms, respectively (P < .0001). Use of postdiscontinuation chemotherapy was significantly greater among BSC patients compared with P+BSC patients (51.7% v 28.5%, respectively; P = .0002), with more BSC patients receiving pemetrexed (18.3% v 3.3%, respectively; P = .0001). Postdiscontinuation therapy was initiated earlier for BSC than P+BSC patients (median time to initiation, 4.3 v 15.7 months, respectively; log-rank P < .0001). Chemotherapy was well tolerated, with expected modest (4% to 7%) grade 3 and 4 hematologic toxicities.

Conclusion Second-line pemetrexed elicited significant tumor response and delayed disease progression compared with BSC alone in patients with advanced MPM. Improvement in OS was not seen in this study, possibly because of the significant imbalance in postdiscontinuation chemotherapy between the arms.”

Another interesting study is called, “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 Medicine, University of Texas Health Science Center at Tyler 75710, USA. Am J Physiol Lung Cell Mol Physiol 268: L972-L982, 1995.  Here is an excerpt: “Urokinase (uPA) interacts with its receptor (uPAR) to promote proteolysis and tumor migration, functions of potential importance in the pathogenesis of malignant mesothelioma. Immunohistochemistry of human malignant mesothelioma tissue and mesothelioma cells (MS-1) showed that mesothelioma cells express uPAR. We isolated uPAR from MS-1 cells by metabolic labeling and showed that it could be 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 with a mean dissociation constant (Kd) of 5.4 +/- 1.1 nM. Binding was inhibited by a blocking antibody to uPAR and by the uPA amino-terminal fragment (ATF), but 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 of the receptor from the cell surface. Stimulation of subconfluent MS-1 cells by high molecular weight or recombinant uPA, but not ATF or low molecular weight fragment, caused concentration-dependent incorporation of [3H]thymidine. These data indicate a novel mechanism by which malignant mesothelioma cells localize pericellular proteolysis and concurrently regulate tumor cell proliferation.”

Monty Wrobleski is the author of this article.  For more information please click on the following links

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