Anti-tumour activity in non-small cell lung cancer models and toxicity profiles for novel ruthenium(II) based organo-metallic compounds

Authors

Sylvie M. Guichard, University of EdinburghFollow
Roderick W. Else, Department of Veterinary Pathology, School of Veterinary Studies, Summerhall, Edinburgh
Benjamin David Zeitlin, University of the PacificFollow
Morwenna Muir, University of Edinburgh, Western General HospitalFollow
Michael Dodds, University of Edinburgh
Heinz-Herbert Fiebig, Institute for Experimental Oncology, Oncotest GmbH, Am Flughafen 12-4, D-79108 Freiburg, Germany
Peter J. Sadler, University of EdinburgFollow
Duncan I. Jodrell, Western General Hospital, Department of Medical Oncology, Crewe Road, EdinburghFollow

ORCiD

Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188

Department

Biomedical Sciences

Document Type

Article

Publication Title

Biochemical Pharmacology

ISSN

0006-2952

Volume

71

Issue

4

DOI

10.1016/j.bcp.2005.10.053

First Page

408

Last Page

415

Publication Date

Winter 2-14-2006

Abstract

Novel ruthenium(II) organo-metallic compounds are active in ovarian cancer models [Aird RE, Cummings J, Ritchie AA, Muir M, Morris RE, Chen H, et al. In vitro and in vivo activity and cross resistance profiles of novel ruthenium(II) organometallic arene complexes in human ovarian cancer. BrJ Cancer 2002;86(10):1652-7]. [(eta(6)-C6H5C6H5)Ru(en)Cl](+) (as a PF6 salt, where en = ethylenediamine (RM175)) has been evaluated in a 13-cell line panel. Particular sensitivity (similar to 10-fold lower than mean IC50) was noted in breast cancer and non-small cell lung cancer cell lines. In addition, IC50 in the A549 was 2 mu M and RM175 (25 mg kg(-1), days 1 and 5, i.p.) caused a significant (p = 0.004) growth delay in a xenograft model. HC11 [(eta(6)-tetrahydroanthracene)Ru(en)Cl]PF6 was more potent in the A549 cell line (IC50 0.5 eta M). HC11 (25 mg kg-1, days 1, 8 and 15, i.p.) was also active in vivo. Following RM175 25 mg kg-1, days 1 and 5, and 15 mg kg(-1), days 1-5, HC11 25 and 40 mg kg(-1), day 1, elevated alanine transaminase levels were detected, suggesting hepatotoxicity. No changes were observed in kidney or haematological parameters. In liver sections, multi-focal hepatic necrosis was seen, becoming confluent at high doses of HC11. In vitro studies confirmed that HC11 was more toxic than RM175 to fresh human hepatocytes and equitoxic to mithramycin. Liver toxicity may be related to the arene ligand and modification may reduce the potential for hepatic toxicity, while maintaining the anti-tumour activity seen. (c) 2005 Elsevier Inc. All rights reserved.

Recommended Citation

Guichard, S. M., Else, R. W., Zeitlin, B. D., Muir, M., Dodds, M., Fiebig, H., Sadler, P. J., & Jodrell, D. I. (2006). Anti-tumour activity in non-small cell lung cancer models and toxicity profiles for novel ruthenium(II) based organo-metallic compounds. Biochemical Pharmacology, 71(4), 408–415. DOI: 10.1016/j.bcp.2005.10.053
https://scholarlycommons.pacific.edu/dugoni-facarticles/395