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

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.

• Authors: Tina Riedel, Sabrina Cavin, Hubert van den Bergh, Thorsten Krueger, Lucas Liaudet, Hans-Beat Ris, Paul J Dyson, Jean Y Perentes
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 10263 (07 06 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29980753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organometallic Compounds
• RAPTA-T
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cisplatin (pharmacology)
• Drug Synergism
• Drug Therapy, Combination
• Endothelial Cells (drug effects, pathology)
• Female
• Humans
• Lung Neoplasms (blood supply, drug therapy, pathology)
• Mesothelioma (blood supply, drug therapy, pathology)
• Mesothelioma, Malignant
• Mice
• Mice, Nude
• Organometallic Compounds (pharmacology)
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays