Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma

Our plain-English summary of Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma, by S.K. Lam, S. Yan, S. Xu, et al (Lung Cancer, 2020).

The study

• Authors: S.K. Lam, S. Yan, S. Xu, J.C. Ho
• Journal: Lung Cancer
• Published: 2020;148:138-148
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Inhalation of asbestos fibers is the key culprit in malignant pleural mesothelioma (MPM). Although the import and use of asbestos have been restricted, the incidence of MPM continues to increase globally due to the prolonged lag time in malignant transformation. The development of a novel adjuvant therapy for the minority of individuals with resectable early-stage disease and effective treatment for those with unresectable MPM are urgently needed. Our preliminary data revealed that ornithine decarboxylase (ODC) is highly expressed in MPM xenografts. This study aimed to determine the treatment effects of α-difluoromethylornithine (DFMO), a specific ODC inhibitor, in MPM xenografts.

Results: In an "extended adjuvant DFMO treatment" setting, nude mice were fed with DFMO for 7 days prior to inoculation of 200,000 cells. DFMO suppressed tumor growth and increased median survival in both xenografts. In H226 xenograft, 43 % of treated mice had not reached the humane endpoint by day 132, mimicking long-term survival. DFMO decreased spermidine, increased nitrotyrosine and activated apoptosis in both xenografts. Furthermore, increase in nitrosocysteine, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesion and inhibition of the Akt/mTOR pathway were induced by DFMO in H226 xenograft. In "DFMO treatment" setting, 107 cells were inoculated into nude mice and DFMO treatment commenced when tumor size reached ∼50-100 mm3. DFMO also suppressed tumor growth by similar mechanisms. Supplementation with spermidine reversed the therapeutic effect of DFMO. DFMO increased actin nitration at tyrosine 53 and inhibited actin polymerization.

Conclusion: DFMO is preclinically effective in treating MPM.

Copyright © 2020 Elsevier B.V. All rights reserved.

In plain English

This laboratory experiment in mice did not study asbestos exposure. The authors tested DFMO, which blocks the enzyme ornithine decarboxylase (ODC). They implanted two human malignant pleural mesothelioma cell lines, MSTO-211H (biphasic) and H226 (epithelioid), under the skin of female nude mice. ODC was undetectable in normal mesothelial cells but high in both tumor models and four patients' tumor samples. Some mice got DFMO in drinking water from a week before tumor cells were injected. In the 211H model, median survival was 65 days in the pooled 1% and 2% DFMO arms versus 49.5 days for controls (p = 0.08, not statistically significant). In the H226 model, median survival was 120 days with 2% DFMO versus 44 days for controls (p less than 0.0001). Of these, 43% had not reached the humane endpoint (a set tumor size) by day 132. DFMO started after tumors formed also slowed growth and lengthened median survival in both models. Adding cisplatin or pemetrexed gave no extra benefit. Spermidine reversed DFMO's effect. The authors concluded DFMO might serve as a new treatment in early and metastatic MPM.

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: Animal experiment (mouse xenograft models of human mesothelioma), with supporting cell-culture tests and staining of four patient tumor samples
• Who was studied: Female nude mice (4 to 6 weeks old) injected with two human mesothelioma cell lines: MSTO-211H (biphasic) and H226 (epithelioid). Groups had 8 mice (7 in the 2% DFMO H226 group) in the extended adjuvant setting and 6 in the other experiments. Tumor sections came from four mesothelioma patients. University of Hong Kong.
• Exposure: The drug DFMO (α-difluoromethylornithine), given orally in drinking water at 0.5%, 1% or 2%. It was given either from one week before tumor cells were injected (extended adjuvant setting) or after tumors had formed (treatment setting). It was also tested combined with cisplatin or pemetrexed and with spermidine supplementation. Asbestos exposure was not studied.
• Main results:
  • ODC was undetectable in normal mesothelial MeT-5A cells but highly expressed in both xenograft models and in tumor sections from four mesothelioma patients.
  • 211H model, extended adjuvant setting: the 1% and 2% DFMO arms were pooled for analysis. Median survival was 49.5 days (range 39 to 75) in controls and 65 days (range 46 to 68) in the pooled arm (p = 0.08).
  • H226 model, extended adjuvant setting: median survival was 44 days (range 37 to 63) in controls and 120 days (range 55 to more than 132) in the 2% DFMO group (p less than 0.0001).
  • In the H226 model, 43% of treated mice had not reached the humane endpoint by day 132.
  • DFMO lowered spermidine but not putrescine in tumors of both models.
  • In the treatment setting (DFMO started after tumors formed), DFMO suppressed tumor growth and increased median survival in both models.
  • Combining DFMO with low or high doses of cisplatin or pemetrexed gave no added benefit in either model.
  • High-dose DFMO combined with cisplatin made the mice hypothermic and underweight, which the authors described as severe adverse effects.
  • Spermidine supplementation reversed the anti-tumor effect of DFMO in both models.
  • DFMO increased nitration of actin at tyrosine 53, and actin staining was weaker in DFMO-treated tumors of both models. The authors interpreted this as inhibition of actin polymerization.
  • In cell culture, combining DFMO with cisplatin or pemetrexed did not reduce cell viability more than single treatments.
• The authors' conclusion: The authors concluded that DFMO might serve as a new therapeutic agent, other than standard cisplatin and pemetrexed chemotherapy, in both early and metastatic stage MPM.
• Limitations the authors state:
  • The adjuvant model imitated residual disease by injecting a small number of cells before tumors formed. It involved no surgery.
  • Combination treatments were not tested in the extended adjuvant setting, partly because of the limited number of animals for ethical reasons.
  • Only two cell lines were used, because they were the only ones available in the lab that could form xenografts.
  • The authors stated that DFMO's safety has not been directly compared with that of pemetrexed and cisplatin.
  • The ratio of DFMO's two enantiomers (forms that may differ in strength) was not known for the supplier's product. The authors suggested this may explain differences from an earlier study.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Malignant Transformation, Adjuvant Therapy, Unresectable, Median Survival, Apoptosis.

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