Adaptation of a chemosensitivity assay to accurately assess pemetrexed in ex vivo cultures of lung cancer

Our plain-English summary of Adaptation of a chemosensitivity assay to accurately assess pemetrexed in ex vivo cultures of lung cancer, by S.L. Suchy, R.J. Landreneau, M.J. Schuchert, et al (Cancer Biology & Therapy, 2013).

The study

• Authors: S.L. Suchy, R.J. Landreneau, M.J. Schuchert, D. Wang, P.R. Ervin, S.L. Brower
• Journal: Cancer Biology & Therapy
• Published: 2013;14(1):39-44
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Pemetrexed is the only FDA approved treatment for mesothelioma and is a second line agent for treatment of non-small cell lung carcinoma (NSCLC). Pemetrexed is inhibited by folate and its analogs, which are components of many culture media, making it challenging to study pemetrexed in vitro. In order to accurately evaluate pemetrexed's effects in vitro, the protocol for a standard chemosensitivity assay, the ChemoFx drug response marker, had to be modified.

Experimental Design: Novel rinse and media change steps were assessed and then added to the assay protocol in order to observe pemetrexed activity. The intraday and interday stability of pemetrexed were also established under the adapted protocol. Then, the modified protocol was used to examine pemetrexed in 65 ex vivo lung cancer specimens.

Results: Substituting 5% RPMI + EGF for BEGM allowed pemetrexed to exert its anticancer activity in the ChemoFx DRM. ChemoFx classified 6.2% of the lung specimens as responsive, 9.2% as intermediate responsive and 84.6% as non-responsive to pemetrexed.

Conclusions: Adapting the ChemoFx protocol allowed for the accurate evaluation of pemetrexed anticancer activity in ex vivo lung specimens. ChemoFx evaluation may provide an indication of a patient's clinical response to the drug prior to pemetrexed treatment. Having this information when treatment options are being considered could avoid wasted time, unnecessary costs and needless side effects that are the result of an inappropriate chemotherapy regimen.

In plain English

This laboratory study did not examine asbestos exposure. The authors adapted a commercial test called ChemoFx, which grows a patient's tumor cells in the lab and grades them as responsive, intermediate responsive or non-responsive to a drug, so that it could measure the cancer drug pemetrexed. In the standard growth medium, pemetrexed showed little effect. When cells were rinsed and switched to a different medium (5% RPMI with epidermal growth factor), the drug killed more cells at higher doses. Adding folic acid weakened that effect. Of 65 lung carcinoma specimens tested, 4 of 65 (6.2%) were graded responsive, 6 of 65 (9.2%) intermediate responsive and 55 of 65 (84.6%) non-responsive. The specimens were described only as lung carcinoma. None were reported as mesothelioma, and the results were not compared with how patients actually did. The authors concluded that ChemoFx may help oncologists judge whether pemetrexed is appropriate for a given non-small cell lung cancer or mesothelioma tumor.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study adapting a chemosensitivity assay, tested on a cell line and on ex vivo tumor cultures
• Who was studied: The lung carcinoma cell line A549 and 65 de-identified lung carcinoma specimens obtained from several US tissue sources and hospitals; tumor type was given only as lung carcinoma, with limited data per specimen; no dates given
• Exposure: The drug pemetrexed at 10 test concentrations for 72 hours; in a separate test, added folic acid up to 501 mg/L. No asbestos exposure was studied
• Main results:
  • In the standard medium (BEGM), pemetrexed showed little cell-killing activity in A549 cells
  • After a rinse and change to 5% RPMI medium, pemetrexed produced a dose-dependent cell-killing effect in A549 cells, and adding epidermal growth factor enhanced it
  • In A549 cells, more folic acid in the treatment medium meant less pemetrexed activity
  • Pemetrexed in the new medium met the assay's quality-control criteria for stability over 8 hours at room temperature and for up to 12 weeks frozen
  • Of the 65 lung carcinoma specimens: 4 of 65 (6.2%) responsive, 6 of 65 (9.2%) intermediate responsive, 55 of 65 (84.6%) non-responsive
  • Of 16 cancer cell lines first evaluated, only A549 was classified as responsive (data not shown)
• The authors' conclusion: The authors concluded that ChemoFx may serve as a tool to help oncologists decide whether pemetrexed is an appropriate treatment to consider for a given NSCLC or mesothelioma tumor
• Limitations the authors state:
  • The folic acid reversal was shown only in a cell line; the authors said it still needs to be confirmed in cultures from patients
  • The standard medium's composition is proprietary, so the authors could not say which folate component causes the difference
  • Only limited data were available for each patient specimen; tumor type was given only as lung carcinoma

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Lung Cancer, Mesothelioma, Carcinoma, Chemotherapy.

Related studies

• Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)
• Survey and biological insights of pemetrexed-related therapeutic improvement in mesothelioma: The Nancy Centre of Biological Resources' Mesothelioma Cohort — F. Vlastos, G. Hillas, et al. (2009)
• Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed — L. Cortes-Dericks, G.L. Carboni, et al. (2010)
• The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)
• "One marker does not fit all": additional translational and validation studies are needed to identify faithful predictors of pemetrexed activity in mesothelioma — E. Giovannetti, G.J. Peters, et al. (2013)
• Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma — D.E. Lustgarten, C. Deshpande, et al. (2013)

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