Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy

Our plain-English summary of Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy, by T. Riedel, S. Cavin, H. van den Bergh, et al (Scientific Reports, 2018).

The study

• Authors: T. Riedel, S. Cavin, H. van den Bergh, T. Krueger, L. Liaudet, H.B. Ris, P.J. Dyson, J.Y. Perentes
• Journal: Scientific Reports
• Published: 2018;8(1):10263
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.

In plain English

This was a laboratory and animal study, not a study of asbestos exposure. The authors tested RAPTA-T, an experimental ruthenium compound, on human pleural mesothelioma tumors grown in female nude mice. In cell culture, RAPTA-T inhibited the enzyme PARP-1 and caused a two-fold drop in release of the growth factor VEGF-A. In mice, a daily dose of 50 mg per kg made tumor blood vessels less dilated and less twisted. Higher doses caused weight loss and deaths. By day 8, fluid pressure inside treated tumors averaged 5.7 mmHg, compared with 13.2 mmHg in untreated tumors. Treated tumors also had more supporting cells (pericytes) around their vessels and less low-oxygen tissue. After pre-treatment, tumors held more platinum from the drug cisplatin: 0.16 versus 0.05 ng per mg of tissue. RAPTA-T alone did not significantly slow tumor growth. In mice with tumors in the pleural cavity, pre-treatment before liposomal cisplatin (Lipoplatin) gave a tumor growth delay of 11 days, compared with 6 days for Lipoplatin alone (4 mice per group). The authors concluded that combining RAPTA-T with chemotherapy may be a new option for mesothelioma.

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 (cell culture) and animal experiments using human mesothelioma cells grown as tumors in mice (xenografts), both under the skin and in the pleural cavity
• Who was studied: Six-week-old female Swiss nude mice implanted with the human mesothelioma cell lines MSTO-211H and H-Meso-1, at the University of Lausanne. Group sizes were small, for example 5 per group in the under-the-skin model and 4 per group in the pleural model.
• Exposure: No asbestos exposure was studied. The mice received the experimental ruthenium compound RAPTA-T daily (50, 75 or 100 mg per kg; 50 mg per kg in the main experiments), followed by a single dose of cisplatin (4 mg per kg) or liposomal cisplatin (Lipoplatin, 18 mg per kg).
• Main results:
  • In cell culture, RAPTA-T inhibited PARP-1 activity with an IC50 of 400 micromolar.
  • In cultured MSTO-211H mesothelioma cells, RAPTA-T at 400 micromolar caused a two-fold drop in VEGF-A levels.
  • The low dose (50 mg per kg) was tolerated by the mice. Higher doses caused weight loss and spontaneous deaths.
  • At day 8, tumors treated with RAPTA-T had lower interstitial fluid pressure than control tumors: 5.7 plus or minus 3.5 mmHg versus 13.2 plus or minus 1.1 mmHg (6 to 7 mice per group, p less than 0.0001).
  • Pericyte coverage of tumor vessels was higher in RAPTA-T treated tumors than in controls: 34.6 plus or minus 19.2% versus 21.5 plus or minus 16.3% of vessels positive for alpha-SMA.
  • Tumor hypoxia (low-oxygen tissue) was significantly reduced after RAPTA-T treatment (3 mice per group, P = 0.037).
  • Vessel density in tumor sections did not change significantly with RAPTA-T compared with controls on day 11: 260 versus 318 vessels per square mm (P = 0.56).
  • Tumors pre-treated with RAPTA-T contained more platinum after cisplatin than tumors given cisplatin without pre-treatment: 0.16 plus or minus 0.05 versus 0.05 plus or minus 0.03 ng Pt per mg of tumor tissue (P = 0.005).
  • RAPTA-T alone had no significant effect on tumor growth by day 21 compared with control.
  • In the pleural (orthotopic) model, RAPTA-T before Lipoplatin gave a growth delay of 11 plus or minus 1 days, compared with 6 plus or minus 2 days for Lipoplatin alone (4 mice per group). The rate of tumor re-growth was very similar in both groups.
• The authors' conclusion: The authors concluded that their results suggest chemotherapy combined with RAPTA-T as a possible new option for resectable mesothelioma (before surgery) and advanced mesothelioma (palliative), or for other solid tumors.
• Limitations the authors state:
  • The authors note that an effect of RAPTA-T on cancer-associated fibroblasts cannot be excluded.

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, Interstitial, Cisplatin, Mesothelioma.

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