Malignant pleural mesothelioma (MPM) is a rare but lethal cancer associated with asbestos exposure. Worldwide, the incidence of MPM is expected to increase over the next 20 years. The molecular and genetic profiling of MPM tumors and patients, and improved understanding of the pathogenesis of MPM may lead to novel diagnostic, preventative and therapeutic strategies. Treatment options for MPM remain limited and no consensus exists at this time. Multimodality therapy that combines surgery, chemotherapy and radiation offers the best chance for long-term survival in select patients.
"Malignant pleural mesothelioma (MPM) is a rare disease with approximately 2000–3000 new cases in the United States diagnosed annually.(Kaufman and Pass 2008) Over the last 20 years, the incidence of MPM has steadily increased, with 70–80% of cases implicating asbestos exposure as the dominate risk factor.(Kaufman and Pass 2008; Robinson and Lake 2005) Management of MPM is predominately with chemotherapy and radiation due its diffuse and invasive nature, which often precludes surgical resection. Consideration for surgery either as an extrapleural pneumonectomy or pleurectomy/decortication is dependent on the disease stage, pulmonary function, and surgeon exper"
[Show abstract][Hide abstract] ABSTRACT: Purpose
Treatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase acts via down regulation of nuclear factor kappa B (NFKβ) by specific microRNAs (miRNA) and that interference of this pathway could have implications for MPM resistance to chemotherapy.
Three immortalized MPM cell lines (H2959, H2373, and H2591) were exposed to Onconase at 0–20 µg/mL. Cell counts were measured at 48 and 72 hours. Gene expression in miRNA-enriched RNA was validated by RT-PCR. The functional implications of miRNA expression were evaluated by transfecting miRNA mimics or inhibitors into MPM cell lines, and performing Matrigel™ invasion, cell proliferation, soft agar colony formation, and scratch closure assays. Effects on NFKβ expression and downstream targets including ABC transporters, BCL-xl, and IAP were assessed by RT-PCR and Western Blotting.
Treatment with 20µg/mL of Onconase significantly decreased cell count and invasion. Hsa-miR-17* was significantly upregulated and hsa-miR-30c significantly down-regulated by Onconase treatment in all cell lines. Forced expression of hsa-miR-17* mimic and hsa-miR-30c inhibitor each significantly decreased functional activity of Onconase in all assays. NFKB1(p50) expression and downstream targets were also decreased with Onconase treatment as well as with forced expression miRNA mimic and inhibitors.
Onconase treatment caused a significant decrease in cell proliferation, invasion, and in expression of certain miRNAs. Recapitulation of the resultant miRNA expression pattern with hsa-miR-17* mimic and hsa-miR-30c inhibitor resulted in downregulation of NFKB1 and reduced malignant behavior in functional assays. Thus, Onconase likely exerts its anti-tumor effect through these miRNAs.
[Show abstract][Hide abstract] ABSTRACT: For more than 30 years, extrapleural pneumonectomy (EPP) has been practiced in suitable patients with diffuse malignant pleural mesothelioma. There has been a general feeling among many surgeons that this prolongs life. However, despite nearly 2000 published patients treated with EPP, no randomized study has ever been performed. This is most unfortunate with a potentially life-threatening, invalidating, and very costly therapy in today's era of evidence medicine. In published materials on PPE, the mean overall survival varies between 9 and 23 months; for almost as many in whom pleurectomy only was performed, it is 9–26 months. Patients subjected to EPP are very heavily selected, and this might explain the better outcome when compared with non-surgical groups of patients. In fact, a recently published study showed an overall survival with chemotherapy only of 22 months in a subgroup filling the criteria usually used for EPP. Thus, it is high time to perform a randomized study to prove the efficiency of EPP.
[Show abstract][Hide abstract] ABSTRACT: Ranpirnase, originally isolated from oocytes of the northern leopard frog (Rana pipiens), is a member of the pancreatic RNase A superfamily of ribonucleases. Ranpirnase exerts antiproliferative and cytotoxic effects in vitro and in vivo and has been shown to act synergistically with different cancer therapeutic agents. The cytotoxic and cytostatic effects of ranpirnase are the consequence of tRNA degradation that results in the disruption of protein translation and the induction of programmed cell death (apoptosis). Ranpirnase has been shown to target malignant cells both in human cancer cell lines and in animal models, and has demonstrated efficacy in the treatment of several human cancers in clinical studies. Most clinical studies have been conducted in patients with malignant mesothelioma, and a confirmatory Phase IIIb trial is currently underway for the treatment of this disease. Owing to its selective destruction of malignant cells and favorable toxicology profile, ranpirnase is a promising antitumor agent with ideal attributes that are generally lacking in conventional cytotoxic drugs.
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