Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines

Our plain-English summary of Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines, by M. Kitazono-Saitoh, Y. Takiguchi, S. Kitazono, et al (Oncology Reports, 2012).

The study

• Authors: M. Kitazono-Saitoh, Y. Takiguchi, S. Kitazono, H. Ashinuma, A. Kitamura, Y. Tada, K. Kurosu, E. Sakaida, I. Sekine, N. Tanabe, M. Tagawa, K. Tatsumi
• Journal: Oncology Reports
• Published: 2012;28(1):33-40
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Although cisplatin and pemetrexed are key drugs in the treatment of malignant pleural mesothelioma, their drug-drug interactions, cross-resistance and resistance mechanisms in malignant pleural mesothelioma are not well understood. In the present study, the interaction of these 2 agents was determined by clonogenic assays followed by isobologram analysis of 4 human malignant pleural mesothelioma cell lines. The cell lines were exposed to the agents using a stepwise dose-escalation method to establish drug-resistant sublines. Thymidylate synthase mRNA expression was evaluated in the drug-resistant sublines. As a consequence, cisplatin and pemetrexed had synergistic effects in 3 cell lines and an additive effect in the fourth cell line. The former 3 cell lines showed similar pemetrexed sensitivity in the parental cells and their cisplatin-resistant sublines, whereas the fourth cell line exhibited cross-resistance. In contrast, cisplatin had diverse effects on pemetrexed-resistant sublines. High thymidylate synthase expression did not correlate with natural pemetrexed resistance. Elevated thymidylate synthase expression correlated with acquired pemetrexed resistance in 2 sublines. In conclusion, cisplatin and pemetrexed showed synergistic activity and no cross-resistance in 3 of the 4 malignant pleural mesothelioma cell lines, suggesting the clinical relevance of their combination in chemotherapy. Thymidylate synthase expression did not necessarily correlate with pemetrexed resistance. The information together with the experimental model presented here would be useful for further investigating therapeutic targets of malignant mesothelioma.

In plain English

This laboratory study used four human malignant pleural mesothelioma cell lines (H2452, H28 and H226, described as epithelial, and 211H, described as biphasic), not patients. The authors tested the chemotherapy drugs cisplatin and pemetrexed, alone and together, by counting surviving cell colonies. Combined, the drugs had an additive effect in H2452 and a supra-additive (synergistic) effect in the other three lines. The authors also grew drug-resistant versions of each line by exposing cells to rising doses for about six months. The cisplatin-resistant version of H2452 was also resistant to pemetrexed; the other three responded to pemetrexed like their original cells. Of the pemetrexed-resistant versions, one became more sensitive to cisplatin, two less sensitive, and one was unchanged. Thymidylate synthase mRNA expression rose significantly in only two pemetrexed-resistant versions, and the most naturally pemetrexed-resistant line had the lowest thymidylate synthase expression of the four lines. The authors concluded that the drugs act synergistically and generally show no cross-resistance in these cells, and that several mechanisms may underlie pemetrexed resistance.

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) cell-line experiment using clonogenic (colony survival) assays, isobologram analysis, and drug-resistant sublines
• Who was studied: Four human malignant pleural mesothelioma cell lines obtained from the American Type Culture Collection: NCI-H2452, NCI-H28 and NCI-H226 (epithelial) and MSTO-211H (biphasic), plus cisplatin-resistant and pemetrexed-resistant sublines derived from each
• Exposure: The chemotherapy drugs cisplatin and pemetrexed, alone and in combination. Resistant sublines were made by stepwise dose escalation over about 6 months, starting at 0.1 µg/ml for both drugs. No asbestos exposure was studied.
• Main results:
  • The combined effect of cisplatin and pemetrexed was additive in H2452 and supra-additive (synergistic) in H28, H226 and 211H.
  • Cisplatin-resistance ratios of the cisplatin-resistant sublines compared with their parental lines were 3.2 for H2452, 2.1 for H28, 3.6 for H226 and 1.7 for 211H.
  • Pemetrexed-resistance ratios of the pemetrexed-resistant sublines were 9.5 for H2452, 2.0 for H28, 17.0 for H226 and 14.3 for 211H.
  • The cisplatin-resistant H2452 subline was also resistant to pemetrexed. The other three cisplatin-resistant sublines had pemetrexed sensitivity similar to their parental lines.
  • Among the pemetrexed-resistant sublines, H2452-P was more sensitive to cisplatin than its parental line, H28-P and H226-P were less sensitive, and 211H-P was indistinguishable.
  • The authors measured mRNA levels by quantitative RT-PCR. Thymidylate synthase (TS) and GARFT mRNA levels were significantly higher than in the parental cells in two pemetrexed-resistant sublines (H2452-P and 211H-P). They were significantly lower in H28-P and not significantly changed in H226-P.
  • The cell line most naturally resistant to pemetrexed, H2452, had the lowest TS expression of the four lines.
• The authors' conclusion: The authors concluded that cisplatin and pemetrexed have a synergistic effect in human malignant pleural mesothelioma cells and in general do not show cross-resistance. They also concluded that low TS expression does not necessarily correlate with pemetrexed sensitivity, suggesting multiple mechanisms may underlie pemetrexed resistance.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Pemetrexed (Alimta), Pleural Mesothelioma, Synergistic Effect, Chemotherapy, Malignant Mesothelioma.

Related studies

• Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed — L. Cortes-Dericks, G.L. Carboni, et al. (2010)
• Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma — O.D. Røe, A. Szulkin, et al. (2012)
• COX-2 specific inhibitors enhance the cytotoxic effects of pemetrexed in mesothelioma cell lines — S.L. O'Kane, G.L. Eagle, et al. (2010)
• Pemetrexed re-challenge in pleural malignant mesothelioma: an option for a subset of patients initially treated with pemetrexed-platinum doublets in the first-line setting? — G. Zalcman, E. Bergot, et al. (2011)
• Pemetrexed for malignant pleural mesothelioma: Is it a standard second-line therapy? — K. Tamura, Y. Fujiwara (2010)
• Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction — K.E. Hwang, Y.S. Kim, et al. (2014)

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