Bulletin

Issue: April 2005

Research in Action

Mitoxantrone: making it a better anticancer drug

A La Trobe University biochemistry research team is working to make the cancer-fighting drug mitoxantrone more effective.

Following a previous ARC-funded grant involving mitoxantrone’s mechanism of action, Professor Don Phillips and Australian Research Fellow, Dr Suzanne Cutts, have won more ARC funds for a further three-year two-pronged approach to improve the drug.

After achieving significant advances with the anticancer drug Adriamycin, they have turned their attention to two aspects of mitoxantrone—understanding better the processes which occur within cells when the drug fights tumours, and improving it so that it is more efficient in destroying such tumours.

They have received a further ARC Discovery grant of $260,000, over the next three years for their work on the drug which is used mainly against breast and prostate cancer.

The benefits of mitoxantrone derive from its interference with the growth of cancer cells, which are destroyed but it may also effect the growth of normal body cells.

Professor Phillips, who has been involved with this kind of research for more than 20 years, said many cancer patients would benefit if more active derivatives of mitoxantrone could be developed.

He and Dr Cutts developed a molecular model of the drug which revealed that when it penetrates a cell, it becomes lodged between two base pairs of DNA— something like ‘meat in a sandwich’. One side chain of the drug can be covalently attached to the DNA, but the other is not.

‘We want to see if we can make the second side chain of mitoxantrone also attach covalently to the DNA. If it is attached at both ends it can be locked to DNA more securely and therefore is expected to be a much stronger DNA-binding drug,’ Dr Phillips said.

‘We call this a cross linking drug and these are more effective in killing cancer cells because this type of DNA damage is more difficult for tumour cells to repair. If we can do this we will have a new and more effective derivative of mitoxantrone

‘Because mitoxantrone is an existing clinically-active drug, it should take far less time to develop effective derivatives than with an unproved new drug.

‘The ultimate aim is to produce a drug which will have greater capacity to kill tumour cells.

‘There are 30,000 genes in a cell, but in a cancer cell, some critical tumour-suppressing genes are switched off. Mitoxantrone also enables some of these genes to be switched back on—causing them to revert from cancer cells back to normal cells.

‘Because our work may result in one or more patents and possibly commercialisation of new derivatives of mitoxantrone, with both Australian and overseas companies, there are potential commercial benefits to Australia.

‘These more effective derivatives may result in therapies with improved response, reduced drug dosage and reduced side effects,’ Professor Phillips said.•

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