Article on Drug that acts on Enzymes

Rush is on to develop new wave of cancer drugs

Studies to assess the safety of a new cancer drug called phenoxodiol are underway in Australia.

The astounding success of the cancer pill Gleevec, approved for marketing in the United States this month, proves it's possible to selectively destroy cancer cells without harming normal, healthy cells. As a result, many patients who were at death's door are now in remission. Now other similar drugs now are in the pipeline, ready to enter clinical trials.

"Clearly this has to be the new direction for cancer drug development because the old way of injuring cells non-selectively doesn't work," said Graham Kelly with Novogen Pharmaceuticals.

Among the new wave of therapies is a drug called phenoxodiol, which is already showing hints that it could work in a broad range of cancers without causing serious side effects. Two small studies designed to assess safety are underway in Australia.

"We have not seen any drug-associated toxicity to date, which is great because even at low doses you often see some toxicity," said Kelly.

Phenoxodiol is being tested in patients with a range of cancers including kidney, pancreatic, lung, prostate, colon and melanoma. Administered intravenously, the drug apparently works by targeting enzyme systems that are fundamental to the survival of all cells, both normal and cancerous, but are only inhibited in cancer cells.

Kelly says this is an entirely new approach, since there is no existing evidence that it is possible to selectively switch off enzymes in cancer cells that are also active in normal cells. Although the scientists did not deliberately set out to achieve this, it appears this is how phenoxodiol works.

The first U.S. study of phenoxodiol is set to begin at the Cleveland Clinic by the end of June and will include 20 to 30 cancer patients who have failed standard therapies. An Australian renal cancer patient has thus far been on the drug the longest of any testers and is showing continued improvement after seven months.

"It's an intriguing class of drugs and there appear to be some hints that phenoxodiol is having some effects," said Dr. Ronald Bukowski, Director of Experimental Therapies at Cleveland Clinic Taussig Cancer Center. "Gleevec is the tip of the iceberg and everyone hopes we can translate it to larger malignancy populations."

The question is, will phenoxodiol and similar agents produce the same dramatic results seen in Novartis Pharmaceutical's Gleevec?

"It's my prediction that many patients with chronic myelogenous leukemia will be cured with Gleevec and patients with some other types of cancers will be helped, but not totally cured," said Dr. Harmon Eyre, chief medical officer with the American Cancer Society.

"Other enzyme-inhibiting agents in trials will represent a major step forward, but I doubt they'll have the same magnitude of results seen with Gleevec."

Traditional chemotherapy attacks all cells -- cancerous and normal. Gleevec stops the action of an enzyme known to drive the growth of a type of leukemia. The drug also has been successful in treating a type of stomach cancer known as gastrointestinal stromal tumor (GIST), which is driven by an enzyme similar to the one seen in leukemia.

While Gleevec helps as many as 90 percent of some leukemia patients enter remission, the drug also has produced remission in about 60-percent of patients with the intestinal cancer. Meanwhile, other agents under development appear to interfere with pathways that signal growth, but may not be absolutely specific to cancer.

"As a class of agents there is potential for a greater response rate and, long-term, they will need to be tried with other therapies like standard chemotherapy and radiation," said Eyre. "But these newer agents will be relatively nontoxic and we'll see a flood of them."

Other agents in the final stages of testing include a drug called C225, made by ImClone, which helps about 20 percent of patients with advanced colon cancer. The drug is also being tested in patients with advanced head and neck cancers. A drug made by Astra Zeneca, known as ZD1839, has shown encouraging results in patients with non-small cell lung cancer.

"Because of tremendous interest, this whole category of development will speed up dramatically," predicted Eyre "In the next 3 to 5 years we may see a number of these drugs on the market, if not sooner."

Thanks to Rhonda Rowland CNN Medical Unit

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