Treatment of Malignant Mesothelioma

Jaklitsch, Michael T.; Grondin, Sean C.; Sugarbaker, David J.

doi:10.1007/s002680020021

Cited by 77 publications

(35 citation statements)

References 49 publications

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“…Mesothelioma is a chemoresistant malignancy. Only multimodality regimens of treatment, based on surgery, radiotherapy and chemotherapy, improve the long-term survival for a very small subgroup of patients (Jaklitsch et al, 2001;Tomek et al, 2003). Furthermore, it has been shown that MM patients have impaired immune responsiveness (Manning et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Rippo¹,

Moretti²,

Vescovi³

et al. 2004

Oncogene

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Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNFrelated apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death. Furthermore, MM cells show resistance to TRAILinduced apoptosis. Caspase-8 (FLICE) is not activated by death receptors triggering in malignant cells whereas it is well activated by nonreceptor stimuli, such as UV radiation. We found that FLIP (FLICE-Inhibitory Protein) is constitutively expressed in all MM cell lines and is more expressed in primary MM cells than in NM cells. Knockdown of FLIP expression in MM cell lines, by a FLIPsiRNA, re-established the normal response to apoptosis induced by Fas or DR4/DR5, which was blocked by pretreatment with the caspase-8 inhibitor z-IETD-fmk. These results indicate that MM cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP.

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Section: Introductionmentioning

confidence: 99%

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Rippo¹,

Moretti²,

Vescovi³

et al. 2004

Oncogene

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“…Multimodality approaches have had a relatively small effect on the majority of the patients and have been associated with toxicity. The survival of patients with mesothelioma ranges between 4 and 12 months (4,5). Clearly, new treatment modalities are needed.…”

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confidence: 99%

Bisphosphonates Inhibit the Growth of Mesothelioma Cells In vitro and In vivo

Wakchoure

Merrell

Aldrich

et al. 2006

Clinical Cancer Research

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Purpose: Bisphosphonates (such as risedronate and zoledronate) are widely used inhibitors of bone resorption. Despite their in vitro antiproliferative effects in various cancer cells, bisphosphonates have not exhibited significant antitumor efficacy in animal models of visceral cancer, which may be due to their poor bioavailability. The diagnostic use of radioactive bisphosphonates has revealed the accumulation of bisphosphonates in mesothelioma, which prompted us to test the antitumor efficacy of bisphosphonates in this disease. Experimental Design and Results: Treatment with either risedronate or zoledronate (2 Â 10 À4 to 2 Â 10 À6 mol/L) inhibited the growth of AB12 and AC29 mouse mesothelioma cells and induced the accumulation of unprenylated Rap1A in these cells. Both these in vitro effects were reversed by geranygeraniol, an end product of the mevalonate pathway that these bisphosphonates inhibit. Both bisphosphonates also induced the phosphorylation of the p38 mitogen-activated protein kinase in AB12 and AC29 cells. The inhibition of p38 augmented bisphosphonate-induced growth inhibition in these cells. Bisphosphonate-induced p38 phosphorylation was not reversible by geranylgeraniol. Risedronate (15 mg/kg) and zoledronate (0.5 mg/kg) inhibited the growth of s.c. tumors and increased the median survival of mice with i.p. mesothelioma tumors in vivo. Discussion: In conclusion, risedronate and zoledronate inhibit the mevalonate pathway and induce p38 activation in mesothelioma cells in vitro. The effects on the mevalonate pathway dominate because the net result is growth inhibition. Both bisphosphonates also inhibit mesothelioma tumor growth in vivo and prolong the survival of mesothelioma-bearing mice. These results support further study of bisphosphonates in the management of mesothelioma.Mesothelioma, an asbestos-related neoplasm of the pleural and peritoneal space, occurs in f10,000 patients worldwide (1). Due to the long latency period for tumor development and the widespread use of asbestos for many years, the incidence is expected to rise until the year 2020 (2). The biological behavior is distinct from other solid tumors in that mesothelioma tends to grow in a sheet-like fashion, covering the surface of the pleura or peritoneum. It shows little tendency to invade, especially early in the course of the disease (3). Mesothelioma typically recurs even after the most aggressive attempts at surgical resection and is poorly responsive to radiotherapy and chemotherapy. Multimodality approaches have had a relatively small effect on the majority of the patients and have been associated with toxicity. The survival of patients with mesothelioma ranges between 4 and 12 months (4, 5). Clearly, new treatment modalities are needed.Bisphosphonates are synthetic analogues of the naturally occurring pyrophosphate. Depending on their molecular structure, these drugs can be divided into pyrophosphateresembling (p-bisphosphonates, such as clodronate) and nitrogen-containing bisphosphonates (n-bisphosphonates, su...

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“…At present, a relatively mature trimodality therapy schedule developed by the Thoracic Surgery Department of Brigham and Women's Hospital in Massachusetts, USA (Antman et al, 1989;Jaklitsch et al, 2001) is generally adopted. First, cytoreductive surgery is received.…”

Section: Discussionmentioning

confidence: 99%

Pleural resection and pleural infusion chemotherapy for therapy of malignant pleural mesothelioma

Zhang¹,

Zhang²,

Zhao³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to evaluate effective treatment methods of malignant pleural mesothelioma (MPM). Twenty-three patients with MPM were cured by pleural infusion chemotherapy after surgery. Median survival time and the 1-, 2-, and 3-year survival rates were analyzed on the basis of follow-up. Median survival time of all patients was 15 months (range: 3 to 89 months); the 1-, 2-, and 3-year survival rates were 69.6, 43.5, and 13.0%, respectively. The 1-year survival rates of patients in stages I, II, and III were 83.3, 62.5, and 33.3%, respectively, the 2-year survival rates were 50, 37.5, and 33.3%, respectively, and the 3-year survival rates were 34, 23, and 0%, respectively. Surgery-oriented comprehensive treatment was adopted for MPM, which could improve the prognosis and life quality of patients to some extent.

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Treatment of Malignant Mesothelioma

Cited by 77 publications

References 49 publications

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Bisphosphonates Inhibit the Growth of Mesothelioma Cells In vitro and In vivo

Pleural resection and pleural infusion chemotherapy for therapy of malignant pleural mesothelioma

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