Anti-tumour activity in non-small cell lung cancer models and toxicity profiles for novel ruthenium(II) based organo-metallic compounds.
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. Br J Cancer 2002;86(10):1652-7]. [(eta6-C6H5C6H5)Ru(en)Cl]+ (as a PF6 salt, where en=ethylenediamine (RM175)) has been evaluated in a 13-cell line panel. Particular sensitivity (approximately 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 microM 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 [(eta6-tetrahydroanthracene)Ru(en)Cl]PF6 was more potent in the A549 cell line (IC50 0.5 microM). 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.
Guichard
S M
SM
Pharmacology and Drug Development Group, Cancer Research UK Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
Else
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Reid
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Zeitlin
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B
Aird
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Muir
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Dodds
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Fiebig
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H
Sadler
P J
PJ
Jodrell
D I
DI
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C501327:RM175; D017975:Ruthenium Compounds; C508979:chloro(eta(6)-tetrahydroanthracene)(ethylenediamine)ruthenium(II); D000410:Alanine Transaminase