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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.
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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
