Plenary Lecture

Plenary Lecture

Platinum Drugs, Still Essential in our Fight Against Cancer

Associate Professor Janice Aldrich-Wright
Nanoscale Organisation and Dynamics Group
School of Biomedical and Health Sciences
College of Health & Science
University of Western Sydney
Locked Bag 1797, Penrith South DC
N.S.W. 1797 Australia

In order to overcome the toxic side-effects of cisplatin and its analogues and the acquired resistance many cancers develop to platinum treatment1 my group has been developing two new families of platinum based anticancer agents, as well as new drug delivery vehicles (DDVs).

We have developed a family of over 70 structurally related metallointercalators based on phenanthroline and phenanthroline-derivatives and chiral ancillary ligands which display cytotoxicity at levels up 10-fold lower than cisplatin in many different cancer cells lines which are sensitive or resistance to cisplatin.2-5 In in vivo trials the maximum tolerated dose was found to be around 16 mg/Kg compared to cisplatin (6 mg/kg). We are currently conducting further in vitro and in vivo trials which include efficacy trials in rats with HCT8 colon cancer and nude mice with human breast, lung and colon tumour xenographs.

Sequence Selective Agents
We have been developing a range of platinum-based drugs which include ligands that are capable of binding to specific DNA sequences.6-7 These agents bind to their target sequences with greater affinity than other sequences, are able to prevent RNA synthesis in vitro and unwind DNA helices by up to 13o. We are currently synthesising more soluble forms of these cationic complexes that we hope will have sufficient sequence specificity to selectively bind to telomere regions or mutant p53 genes of DNA.

Drug Delivery Vehicles (DDV)
Cationic lipids have been widely studied for their ability to deliver genes and DNA vaccines for therapeutic purposes. These lipids provide a DNA delivery vehicle into the cell and protect DNA from extracellular degradation. In the 1990ís, CSIRO developed a platform drug and gene delivery technology by using a very common buffer, 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris).8-10 It was recognised that Tris could provide a straightforward yet novel method for attaching one, two or three fatty acids to amino acids or peptides to alter their physicochemical properties. Tris cationic lipids (DDV) offer chemical flexibility, readily allowing generation of a range of conjugates with one, two or three different fatty acyl substituents, which can then be tailored, for different functions. Although there has been a lot of interest in the application of cationic lipids for gene delivery, their usage for delivery of anticancer drugs has remained relatively unexplored.

Brief Biography of the Speaker:
Associate Professor Janice Aldrich-Wright; (B.App.Sc., University of Technology Sydney; Ph.D, Macquarie University) is currently based at the University of Western Sydney. She is a Royal Australian Chemical Institute Fellow and her research has been the subject of patent application and more than sixty peer reviewed publications. Over the past 20 years she has established a research group at UWS that focuses on metal complex-DNA interactions with numerous local and international collaborations. Importantly, she has established anticancer compounds which operate under a mode of action different to current clinical alternatives. Innovative bioinorganic molecular design, elegant synthesis and the biophysical and biological testing of these compounds are at the heart of her research drive.



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