Asbestos Exposure and Human Mesothelioma Cell Lines

Another interesting study is called, "The emerging role of antifolates in the treatment of malignant pleural Mesothelioma" by Karim Fizazi, William J. John, Nicholas J. Vogelzang - Volume 29, Issue 1, Pages 77-81 (February 2002).  Here is an excerpt: "Abstract - Clinicians have long regarded malignant pleural mesothelioma as a chemoresistant neoplasm and as a result no standard chemotherapy regimen has emerged. Antifolates such as methotrexate are among the most active compounds in mesothelioma, albeit based only on phase II data. Recently two antifolate-based combinations with apparently higher efficacy than older regimens have emerged: the pemetrexed/cisplatin regimen and the raltitrexed/oxaliplatin regimen. In two phase I trials with pemetrexed combined with either cisplatin or carboplatin responses occurred in five of 11 and nine of 29 patients, respectively. In a phase I trial of raltitrexed/oxaliplatin, six of 17 patients (35%) with mesothelioma achieved a partial response. In a phase II trial of raltitrexed/oxaliplatin, 14 objective responses were confirmed in 72 patients (25%) with malignant pleural mesothelioma. Indeed, responses were seen in cisplatin-refractory patients. Based on the promising results from these combination trials, two large phase III studies have begun. The first study was a multicenter, multinational trial sponsored by Eli Lilly and Company, which randomized more than 430 patients with malignant pleural mesothelioma to cisplatin with or without pemetrexed. That trial completed enrollment in February 2001 and is the largest trial ever conducted in mesothelioma. The second trial is being conducted by the European Organization for the Research and Treatment of Cancer (EORTC) and compares cisplatin with or without raltitrexed with planned accrual of 240 patients. In both trials, survival is the main endpoint. These trials will help to define the role of these new antifolates in malignant pleural mesothelioma." Semin Oncol 29:77-81

Another interesting study is called, "Significant augmentation of pro-apoptotic gene therapy by pharmacologic bcl-xl down-regulation in mesothelioma." By Mohiuddin I, Cao X, Fang B, Nishizaki M, Smythe WR. - Cancer Gene Ther. 2001 Aug;8(8):547-54.
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas – Here is an excerpt: "Abstract - The ratio of pro-apoptotic (PAP) and anti-apoptotic (AAP) bcl-2 proteins is important in apoptosis regulation. We sought to determine if inhibition of the AAP bcl-xl by sodium butyrate (SB) would augment apoptotic cellular death in mesothelioma when combined with adenoviral pro-apoptotic gene therapy (PAGT) by simultaneously increasing PAP and decreasing AAP in these cells. Human mesothelioma cell lines were exposed to AdBax, AdBak, Adp53, and SB alone as well as all vectors combined with SB at varying doses and time points. Cell death was assessed, and apoptosis evaluated by morphology and FACS. Isobologram analysis evaluated additive or synergistic effect. Cellular death and apoptosis were augmented by PAGT/SB combinations compared to monotherapy. Following AdBax/SB and AdBak/SB, a decrease of the AAP bcl-xl was noted in combination with increases in PAP bax and bak. By isobologram analysis, additive or synergistic cell killing was noted with both combinations. SB treatment did not significantly augment cell killing or apoptosis in combination with Adp53. PAGT/SB was more effective than monotherapy in induction of apoptotic cell death. Synergy may be due to the ability of SB to decrease bcl-xl with marked increases in PAP engendered by PAGT. Combination therapy with agents that down-regulate AAP in addition to PAGT may prove useful clinically."

Another interesting study is called, "Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): Feasibility and results" - Volume 57, Issue 1, Pages 89-95 (July 2007) by Federico Reaa, Giuseppe Marullia, Luigi Bortolottia, Cristiano Bredaa, Adolfo Gino Favarettob, Lucio Loreggianc, Francesco Sartoria.  Here is an excerpt: "Background - Trimodality therapy seems to be the best treatment for malignant pleural mesothelioma (MPM). A large experience served to evaluate the efficacy of surgery followed by adjuvant chemo-radiotherapy. Trimodality therapy results have led us to test induction chemotherapy followed by EPP and adjuvant radiotherapy in stages I–III of MPM. The aim of our study was to evaluate the feasibility of this protocol and to estimate survival.

Methods - From 2000 to 2003, 21 patients with MPM (14 males and 7 females, median age 59 years) were enrolled in the prospective study. Induction chemotherapy consisted of Carboplatin (AUC 5mg/mL/min on Day 1) and Gemcitabine (1000mg/m2 on Days 1, 8, 15) for three to four cycles. EPP was performed 3–5 weeks after induction therapy, while post-operative RT was given 4–6 weeks after operation.

Results - Ten patients received three cycles of chemotherapy, 10 patients received four cycles and 1 patient had two cycles. Grades 3–4 haematological toxicity occurred in eight (38.1%) patients. Chemotherapy response rate was: complete 0%, partial 33.3% and stable disease 66.7%. Seventeen (80.9%) out of 21 patients underwent EPP with no intra or post-operative mortality with an overall major and minor morbidity rate at 52.4%. Median survival was 25.5 months, with an overall 1, 3 and 5-year survival rate of 71, 33 and 19%, respectively.

Conclusions - In MPM, the combined modality approach using the Carboplatin/Gemcitabine combination as induction chemotherapy is feasible, with good results in terms of survival and morbidity. Our results are similar to those of other studies using a heavier modality treatment."