Bulletin

Issue: June 2006

Research in Action

Quest for improved anti-cancer drugs

La Trobe University is helping to develop more effective drugs for the treatment of a range of cancers.

Professor Phillips and Dr Cutts: decreasing
the level of unwanted side-effects.

Professor of Biochemistry, Don Phillips, and Australian Research Council Fellow, Dr Suzanne Cutts, recently received a $208,000 National Health and Medical Research Council Development Grant to improve the performance of the commonly used anti-cancer drug doxorubicin - also known by the trade name Adriamycin.

The grant was one of only nine awarded this year in Australia, of which only two were awarded in Victoria.

Doxorubicin is used to treat a wide spectrum of tumours. It remains the benchmark against which all new anticancer drugs are compared.

However, says Professor Phillips, greater use of doxorubicin remains limited by several factors which need to be reduced or eliminated for the drug to be more effective. It is cardiotoxic which means that it can damage heart muscle and the total drug received by individual patients must therefore be minimised. It also produces side effects common to most anticancer drugs, and patients can develop resistance to its use over time.

The latest research aims to reduce or eliminate these factors, enabling its more widespread use.

Professor Phillips says that previous research in his laboratory has shown it is possible to activate doxorubicin by interaction with formaldehyde, a simple but highly reactive chemical that links doxorubicin to DNA.

Doxorubicin-DNA linkages are termed 'covalent adducts'. Tumour cells have elevated levels of formaldehyde which originate from within the cells themselves.

These levels can be enhanced substantially by treatment with formaldehyde-releasing prodrugs such as AN-9 developed by Israeli scientists, Professor Abraham Nudelman of Bar Ilan University and Dr Ada Rephaeli of the University of Tel Aviv, with whom the La Trobe team works in close collaboration.

By treating tumour cells in culture with doxorubicin and a formaldehydereleasing prodrug, a massive increase of doxorubicin-DNA adducts was observed.

Dr Cutts says that cancer cells treated with this combination of doxorubicin and formaldehyde-releasing prodrug undergo more widespread cell death compared to conventional doxorubicin treatment.

Details of research illustrating this were published with Dr Lonnie Swift, a research Fellow in Professor Phillips' laboratory, in the May 2006 issue of the journal Cancer Research. Importantly, cancer cells that were previously resistant to doxorubicin also undergo cell death.

By designing and testing a new series of formaldehyde-releasing prodrugs, Professor Phillips and Dr Cutts have identified a new formaldehyde-releasing prodrug called AN-193 that is even more efficient at activating doxorubicin than AN-9. Several important potential advantages arise from the ability to form these more cytotoxic doxorubicin-DNA adducts.

Because doxorubicin is more cytotoxic when in the form of drug-DNA adducts, it may be possible to administer it at a lower dose than doxorubicin alone. This would decrease the level of unwanted side-effects.

New prospects for tumour-localised treatments

Doxorubicin adduct formation also offers new prospects for tumour-localised treatments because the activating agent, being a small, chemically simple compound, can be localised in high concentrations within tumours, hence localising the cytotoxic response to the tumour.

There is now considerable interest in the possible clinical advantages to be gained by the co-administration of doxorubicin, together with a formaldehyde-releasing activating agent.

Professor Phillips says that as a result of the new grant, this concept is now able to be tested on human tumours in an animal model. The objective is to demonstrate improved responses in both doxorubicin sensitive and resistant human breast tumours in mice in order to establish whether this is a viable treatment option for future clinical development.

The tumour volume will be measured in response to single agent doxorubicin treatments, and compared to combinations with the prodrug AN-9 and the improved prodrug AN193, to establish if the doxorubicin plus AN-193 combination is more effective in reducing tumour growth.

The bio-distribution of doxorubicin- DNA adducts will also be assessed in different tissues to demonstrate whether adduct levels are associated with tumour responses in both doxorubicin sensitive and resistant breast cancers, as well as to identify the extent of formation in other potentially critical tissues such as heart and liver.

A successful outcome to this study would confirm the molecular understanding of the doxorubicin activation process developed over the last five years by Professor Phillips and Dr Cutts, and will provide new avenues for the development of tumour-targeted responses to doxorubicin.

The new grant is critically important because it now enables Professor Phillips and Dr Cutts to obtain the necessary proof-of-principal required to attract a commercial partner to help commercialise this technology.