An Auckland University "stealth" drug that targets lung tumours and preserves healthy tissue has been picked up for clinical development in a Japanese-American deal.

The drug, called PR509, is among a pioneering class of anti-cancer medicines from scientists at the university-based Auckland Cancer Society Research Centre and the Maurice Wilkins Centre.

Designed by Dr Jeff Smaill and Dr Adam Patterson, these "pro-drugs" are activated by the low-oxygen or hypoxia within many solid tumours and act against a variety of cancer types.

"Our drugs can be seen as stealth pro-drugs, hiding in inactive form until hypoxia arises," said Dr Patterson.

PR509 is part of a "pipeline" of hypoxia-activated pro-drugs previously licensed to San Diego biotechnology company Proacta.

Under an agreement between Proacta and Japanese pharmaceutical company Yakult Honsha, PR509 will now be developed for non-small-cell lung cancer and is likely to be tested on gastric, breast and pancreatic cancers.

"Standard treatments for cancer are indiscriminate in their attack against both cancer cells and healthy cells," said Dr Patterson, a cancer biologist, "and this toxicity in normal tissues limits the dose that can be safely administered to patients.

"Creating a pro-drug that only becomes active once it reaches the tumour is an efficient way of overcoming this problem.

"About two-thirds of tumours contain zones not reached by oxygen," said Dr Smaill, a medicinal chemist.

"The cancer cells in these hypoxic zones are more resistant to treatment, making them an important cause of treatment failure and relapse. Scientists have been searching for a way to eliminate these cells for many years."

The new pro-drugs target human epidermal growth factor receptors, or HERs, which are involved in normal cell growth and are overactive or mutated in many cancers. The process converting the pro-drugs to their active, toxic form can't occur in oxygen, so healthy tissue is protected.

Unlike the anti-HER drugs in use at the moment, the new pro-drugs inhibit all members of the HER family of receptors once activated, so they may work against more tumour types. They also stay in tumours for a longer time.

"By preventing toxicity in healthy cells, and achieving long residency and slow release within cancerous tissue, we can deliver much more drug to a tumour than is possible with standard chemotherapy, " said Dr Smaill.

"This is associated with far greater efficacy against tumours."

Dr Patterson said scientists had known for more than 50 years that the parts of a tumour distant from blood vessels were continuously hypoxic.

"There is now growing evidence that tumour zones that appear to be well oxygenated also cycle through periods of hypoxia, which can last from minutes to hours or even days.

"These fluctuations in oxygenation are unpredictable and nearly impossible to target with conventional agents. However, they are thought to be an important cause of cancer aggression and spread, as well as treatment failure."

'HIDDEN' PRO DRUGS
* PR509 and its relatives are activated by low oxygen levels found inside many tumours.

* The drugs therefore harm only the tumours, not healthy tissue.

* They can also "hide" in oxygenated parts of a tumour, becoming toxic only when these areas go through a low-oxygen cycle.