Phenoxodiol is a sphingosine kinase inhibiting compound, the first of its kind to reach human clinical trials. (See the following background notes).

The clinical trial was conducted by Dr Paul de Souza, Medical Oncologist at the Cancer Care Centre, at Sydney’s St. George Hospital.

The Phase I study was a dose-escalating safety trial in patients with late-stage solid cancers and was intended to identify the drug’s toxicity, if any, and the highest tolerable dose.

In 17 patients treated intravenously with phenoxodiol to date, the drug was generally well tolerated with only minimal evidence of drug-related toxicity being detected.

Three of the 17 patients showed stabilisation of their cancer over three months of therapy, with two patients (pancreatic carcinoma and prostatic carcinoma) continuing therapy beyond three months. One patient (renal carcinoma) continued therapy for eight months.

Dr Graham Kelly, the phenoxodiol Program Director at Novogen said the study was designed primarily to test the safety of phenoxodiol.

“Because of the unknown consequences of blocking sphingosine kinase, we deliberately used a low intensive treatment regime, and therefore an anti-tumour response was not an expectation. Also, we must remember these patients had advanced cancers,”, Dr Kelly said.

“This evidence of disease stabilisation with such a low intensity dosing schedule makes us very optimistic, but obviously we remain cautious. We still have a lot to learn about this novel-acting compound.”

On the basis of these data, three additional Phase I clinical studies have commenced, two in Australia and one at the Cleveland Clinic in the US, using more intensive dosage regimes of phenoxodiol.

Dr Kelly added that the data was significant because phenoxodiol was the first sphingosine kinase inhibitor to reach the clinic.

“Sphingosine kinase is a normal body enzyme which presents the challenge of switching this enzyme off in cancer cells without doing significant harm to the rest of the body,” Dr Kelly said.

“We designed phenoxodiol to be selective and the results of this study show that this is possible.”

The presentation was made at the “Molecular Targets and Cancer Therapeutics” International Conference sponsored by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer (EORTC) in Miami, Florida.

Phenoxodiol was granted Investigational New Drug (IND) status by the US Food and Drug Administration (FDA) on 29 January 2001.

Novogen is a world leader in the field of phenolic drug research.

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FOR FURTHER INFORMATION : PROFESSOR ALAN HUSBAND, RESEARCH DIRECTOR OR MR CHRISTOPHER NAUGHTON, MANAGING DIRECTOR, NOVOGEN LIMITED, TEL (02) 9878 0088 http://www.novogen.com

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BACKGROUND NOTES ON PHENOXODIOL

Phenoxodiol belongs to a novel class of drugs called signal transduction inhibitors.

Signal transduction refers to the process by which a cell transmits signals from its genome (DNA) to the end target in the cell. These signals normally are in the form of proteins known as enzymes.

In cancer, mutations of the genome can lead to faulty signalling through abnormally high expression of a particular enzyme.

If mutations occur in genes regulating whether a cell can divide or die by the process of apoptosis, then the outcome might be excessive production of particular enzymes that result in the cell dividing uncontrollably, migrating into neighbouring tissues, and failing to die naturally by apoptosis (natural cell death).

Signal transduction inhibitors aim to block these effects either by stopping the abnormal enzymes being made in the first place, or by blocking their activity.

By specifically targeting these abnormal signalling processes, it is hoped that the cancer process can be more effectively and more specifically contained without harming non-cancer cells.

Phenoxodiol is distinguished in the family of signal transduction inhibitor drugs in targeting the enzyme, sphingosine kinase. Sphingosine kinase has recently been identified as being fundamental to the cancer process.

This enzyme is involved in signal transduction processes regulating cell division, cell migration and cell survival.

Sphingosine kinase is important to the survival and function of all cells in the body, but is over-expressed in cancer cells.

Inhibition of this enzyme has been suggested as a potentially valuable new tool in the fight against cancer, given its hypothesized key role in the cancer process and the belief that it is over-expressed in most forms of human cancer.

In the laboratory, phenoxodiol is a potent inhibitor of sphingosine kinase, resulting in cancer cells being blocked from dividing and then undergoing rapid cell death by apoptosis.

Phenoxodiol is the first sphingosine kinase inhibitor to reach the clinic.

In view of the fundamental importance of sphingosine kinase to normal health, a cautious treatment regime was adopted in the reported trial where the drug was injected only once weekly for 12 weeks. The doses being tested were 1,2,5,10, 15,20, 25 and 30 mg/kg per injection.

Pre-clinical studies had confirmed that phenoxodiol could be administered at doses that would yield significant anti-cancer effect without toxicity, but caution was still required in this first use in humans.

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