School of Medical Sciences


Inhibitors of the enzyme topoisomerase II

TopoII_160px

The ACSRC has made a longstanding contribution to this field, developing the DNA binding drug amsacrine, which is still in clinical use for the treatment of acute leukaemia. Two further inhibitors of this enzyme developed in the ACSRC, asulacrine and DACA, have been tested clinically. 

SN 28049


The Tumour Biology Group is now investigating a new drug, SN 28049, as a potential clinical trial candidate. Existing clinical drugs that target topoisomerase II suffer from the drawback of being susceptible to a phenomenon called multidrug resistance. There are two main types of such resistance, the first mediated by transport proteins on the surface of the cell that remove drug from the cytoplasm, and the second mediated by changes in the topoisomerase II target enzyme, resulting in a lowered response to the drug. We have shown that SN 28049 is highly effective in overcoming resistance mediated by transport proteins. Now, we are currently investigating how SN 28049 can act on forms of the enzyme that have shown resistance to existing drugs such as etoposide.

Selected recent publications


Lukka P, Paxton J, Kestell P, Baguley BC. Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice. Cancer Chemother Pharmacol 2010; 65(6), 1145-52. PMID: 19774378

Lukka PB, Kestell P, Paxton JW, Baguley BC. Development and validation of a liquid chromatography-mass spectrometry (LC-MS) assay for the determination of the anti-cancer agent N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049). J Chrom B 2008; 875: 368-372. PMID: 18926778

Bridewell DJA, Finlay GJ, Baguley BC. The role of topoisomerases and RNA transcription in the action of the antitumour benzonaphthyridine derivative SN 28049. Cancer Chemother Pharmacol 2008; 62: 753-762. PMID: 18175117