The new drug -- called AQ4N -- has just gone into clinical trials in England.

The drug works by destroying only the oxygen-starved (hypoxic) cells that exist within tumors. These cells are difficult to destroy by conventional treatment methods -- yet form up to 30% of any tumor.

And the higher the percentage of hypoxic cells in a tumor, the worse the prognosis for the patient.

AQ4N is the result of ten years of work by Dr. Stephanie McKeown of the University of Ulster's Radiation Science Research team, based at the Jordanstown campus.

"Laboratory tests indicate that AQ4N is likely to be effective against hypoxic cells in any solid tumor," said Dr. McKeown. "We are confident that AQ4N will enhance the effectiveness of contemporary anti-cancer treatments, as it can reach and destroy hypoxic tumor cells that are resistant to radiation and existing chemotherapy techniques."

And there is a double advantage: according to Dr. McKeown, the oxygen-starved cells targeted by AQ4N are also prime suspects in the development of more malignant and aggressive cancers -- including secondary cancers.

"When oxygen-rich cancer cells are killed using radiotherapy or conventional chemotherapy, the previously dormant hypoxic cells may then cause regrowth of the tumor into a more malignant, aggressive and treatment-resistant tumor. That's why it's so important to kill off hypoxic cancer cells, and why we're so excited about the potential of AQ4N," she said.

AQ4N was originally designed by Professor Laurence Patterson of the University of London (previously based at De Montfort University, Leicester). Development and implementation of the new drug was carried out by the Bioreductive Development group (part of the Radiation Science Research Unit led by Prof. David Hirst) at the University of Ulster, Jordanstown.

Dr. McKeown's R&D effort was primarily funded by the Ulster Cancer Foundation and has recently received a funding commitment from the UK Cancer Research Campaign.

Clinical trials are now under way, organized by the Cancer Research Campaign and funded by BTG plc (British Technology Group). The initial trials are being carried out by Prof. Will Steward, (Leicester Royal Infirmary) and Dr. Dennis Talbot (Imperial Cancer Research Fund's unit at Churchill Hospital, Oxford).

AQ4N is fundamentally different from other standard chemotherapy agents since it is administered as the non-toxic prodrug (AQ4N) and only becomes toxic when reduced in hypoxic cells.

This allows specific targeting of tumor tissue since hypoxic cells are rarely found in normal tissue. Indeed, they are only found in tumors, due to the poorly formed chaotic vessels which develop inadequately in the tumor to meet the needs of the fast growing tumor cells.

This specific difference provides an opportunity to target a therapy directly to tumors while sparing normal tissues.

The presence of a significant proportion of hypoxic cells in a wide range of human tumors has only recently been confirmed with the development of sensitive oxygen electrodes.

The importance of tumor hypoxia is twofold. First, it is known to protect cells from the cytotoxic effects of standard chemotherapy drugs (hypoxic cells are dormant (i.e., non-cycling) and therefore are less susceptible to cytotoxic agents. Also, oxygen significantly enhances the cytotoxic effects of radiation.

Secondly, it has recently been shown that increasing levels of hypoxia can predict for poor prognosis and may also be instrumental in selecting cells within the tumor which are stress-resistant and of a more malignant phenotype.

Dr. McKeown's group has shown that the inclusion of AQ4N in a range of treatment regimens, both radiation and standard chemotherapy, enhances the anti-tumor effect of these agents. Standard therapies primarily target better oxygenated cells, leaving the hypoxic cells to repopulate the tumor; for complete tumor control, it may be essential to kill this more malignant subpopulation.

The current Phase I clinical trial is being funded by British Technology Group and organized by the Cancer Research Campaign. It is being carried out by Prof. Will Steward, University of Leicester, at the Leicester Royal Infirmary, and Dr. Dennis Talbot at the Churchill Hospital Oxford.

It is designed to evaluate the toxicity of the drug and its efficacy with palliative radiotherapy for head and neck tumors. It is hoped to start a second trial in the near future of AQ4N in combination with a standard cytotoxic agent.

(Review article: Patterson LH and McKeown SR. AQ4N: a new approach to hypoxia-activated cancer chemotherapy (2000) Br J Cancer, 83 (12) , 1589 - 93.)

19-Jul-2001