Characterization and drug sensitivity profiling of primary malignant mesothelioma cells from pleural effusions

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Abstract

Background

Patients with malignant mesothelioma have a poor prognosis and only 40% respond to first line treatment; a combination of pemetrexed and cisplatin or carboplatin. We used primary malignant mesothelioma cells and an ex vivo chemosensitivity assay with future purpose to predict best choice of treatment. The clinical outcome of these patients might be predicted by measuring drug sensitivity.

Methods

Pleural effusions containing primary malignant mesothelioma cells were received from the diagnostic routine. We characterized and tested the chemosensitivity of 18 malignant samples and four benign samples from 16 different patients with pleural effusions. Cells were seeded in a 384-well plate for a robotized ex vivo testing of drug sensitivity to 32 different drugs. The primary cells were further characterized by immunocytochemistry to evaluate the proportion of malignant cells and to study the RRM1 and ERCC1 reactivity, two proteins associated with drug resistance.

Results

We observed great individual variability in the drug sensitivity. Primary cell isolates were affected by between one and ten drugs, and resistant to the remaining tested drugs. Actinomycin D and daunorubicin were the two drugs effective in most cases. Adjusting efficiency of individual drugs for varying proportion of tumor cells and to the average effect on benign cells correlated with effect of pemetrexed, cisplatin and survival time. General drug sensitivity, proportion of malignant cells and reactivity to RRM1 correlated to each other and to survival time of the patients.

Conclusions

The proportion of malignant cells and RRM1 reactivity in the pleural effusions correlate to drug sensitivity and survival time. The variability in response to the commonly used chemotherapies emphasizes the need for tests that indicate best individual choice of cytotoxic drugs. The efficiency of the obtained results should preferably be corrected for admixture of benign cells and effects of given drugs on benign cells.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2407-14-709) contains supplementary material, which is available to authorized users.

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Most cited references 41

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Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

Nicholas Vogelzang, James J Rusthoven, James T Symanowski … (2003)

Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P =.020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P =.001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P <.0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

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Mesothelin: a new target for immunotherapy.

Raffit Hassan, Tapan Bera, Ira Pastan (2004)

Mesothelin is a differentiation antigen present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The mesothelin gene encodes a precursor protein that is processed to yield the 40-kDa protein, mesothelin, attached to the cell membrane by a glycosylphosphatidyl inositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor. The biological function of mesothelin is not known. Mesothelin is a promising candidate for tumor-specific therapy, given its limited expression in normal tissues and high expression in several cancers. SS1(dsFv)PE38 is a recombinant anti-mesothelin immunotoxin that is undergoing clinical evaluation in patients with mesothelin-expressing tumors. There is evidence that mesothelin is an immunogenic protein and could be exploited as a therapeutic cancer vaccine. A soluble mesothelin variant has been identified and could be a useful tumor marker for malignant mesotheliomas.

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Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma.

Armando Santoro, P Zucali, Raffaele Cavina … (2006)

This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM). Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2 and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12 supplementation. Pemetrexed was provided within the Expanded Access Program. A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible. Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.

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Author and article information

Contributors

Adam Szulkin: adam.szulkin@gmail.com

Rita Ötvös: rita.otvos@ki.se

Carl-Olof Hillerdal: carl-olof.hillerdal@ki.se

Aytekin Celep: aytekin.celep@karolinska.se

Eviane Yousef-Fadhel: eviane.yousef-fadhel@karolinska.se

Henriette Skribek: henriette.skribek@ki.se

Anders Hjerpe: anders.hjerpe@ki.se

László Székely: laszlo.szekely@ki.se

Katalin Dobra: katalin.dobra@ki.se

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 24 September 2014

Publication date PMC-release: 24 September 2014

Publication date Collection: 2014

Volume: 14

Issue: 1

Electronic Location Identifier: 709

Affiliations

[ ]Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital F-46, SE-141 86 Stockholm, Sweden

[ ]Karolinska Institutet, Department of Microbiology Tumor and Cell Biology (MTC), Nobels väg 16, KI Solna Campus Karolinska Institutet, Box 280, SE 171 77 Stockholm, Sweden

Article

Publisher ID: 4896

DOI: 10.1186/1471-2407-14-709

PMC ID: 4190467

PubMed ID: 25253633

SO-VID: 506bbffd-d07f-4b0c-9149-eac2aeb55df4

License:

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 16 April 2014

Date accepted : 27 August 2014

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: malignant mesothelioma,pleural effusions,primary cells,chemotherapy,ex vivo chemosensitivity,cytotoxic drugs,rrm1,ercc1 and individualized treatment

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: malignant mesothelioma, pleural effusions, primary cells, chemotherapy, ex vivo chemosensitivity, cytotoxic drugs, rrm1, ercc1 and individualized treatment

Characterization and drug sensitivity profiling of primary malignant mesothelioma cells from pleural effusions

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Abstract

Background

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Results

Conclusions

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Karger: Oncology

Most cited references 41

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

Mesothelin: a new target for immunotherapy.

Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma.

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