New drug may cure more chemo-resistant cancers

Three years of research at the Yale School of Medicine have uncovered a drug that increases the potency of chemotherapy treatment 100-fold in clinical trials.

The drug, Phenoxodiol, is developed by Marshall Edwards, Inc., a subsidiary of the Australian biotechnology company Novogen. According to Novogen, when Phenoxodiol was used with the anti-cancer drug docetaxel on resistant ovarian cancer cells, only a hundredth of the amount of docetaxel was necessary to match the effects of docetaxel alone.

In November 2004, the FDA granted “fast track” status to Phenoxodiol in its intravenous form intended for use in recurrent ovarian cancer patients, and an oral form of the drug for hormone-refractory prostate cancer was granted the same status Jan. 26.

This status ensures that the FDA will facilitate the drug’s development and expedite its review process.

While Phenoxodiol may be on the FDA “fast track” now, it has taken years of testing and research to reach this point. Dr. Guillermo Mor, a professor of gynecologic oncology at the Medical School, has played a crucial role in the development of Phenoxodiol. He said this drug resulted from studies of tumor cells which had become resistant to chemotherapy.

“Current understanding suggests that apoptosis, or programmed cell death, is the key mechanism for most anti-tumor therapies,” according to the Yale study.

However, Mor said cancer cells often become resistant to drugs, such as docetaxel, which treat cancer by apoptosis.

To solve this problem, Mor said his team searched for compounds, called chemosensitizers, that make cells more sensitive to chemotherapy treatments. The researchers screened a number of compounds and eventually discovered what would become Phenoxodiol. The chemical is a synthetic version of an aromatic compound produced by plants, said Ayesha Alvero, a member of the Yale research team.

Researchers said this particular plant derivative attracted their interest for two main reasons.

“It is able to remove the blocking to apoptosis, therefore making cancer cells sensitive to apoptosis signals,” Mor said.

Equally important as its sensitizing capability, the compound is not toxic to normal cells. This means that Phenoxodiol enables chemotherapy treatments to successfully kill cancer cells while leaving healthy cells unharmed.

“Drugs like Phenoxodiol represent a new class of drugs aimed at the machinery that controls the cell cycle,” Dr. Vincent DeVita, a professor at the Yale Cancer Center and Medical School. “They are likely to be useful, but only when combined with other similar drugs, so that multiple defects in the control of the cancer cell cycle can be attacked at the same time.”

Alvero said clinical studies began after the drug passed preliminary in-vitro testing. The drug is now being tested on prostate cancer patients in Australia and on ovarian and cervical cancer patients here at Yale. Mor said the preliminary results from these tests are all promising. Given their recent success, Mor said researchers are hopeful that Phenoxodiol will prove to be an effective treatment for a vast array of cancer types.

Yale’s collaboration with Novogen is just one example of the University’s ongoing involvement in the advancement of cancer treatment.

“Yale Cancer Center physician-scientists have always been involved in testing new drugs that open new horizons, going back to the 1940s when nitrogen mustard, the first anti-cancer drug, was tested here,” DeVita said. “The first section of medical oncology in the country was established at Yale.”

Mor and Alvero said Phenoxodiol has the potential to significantly impact the lives and treatments of cancer patients by increasing the effectiveness of chemotherapy while decreasing its side effects.

“It means a new drug that can provide a cure for otherwise chemo-resistant patients,” Alvero said. “More importantly, it does not seem to affect normal cells, so side effects won’t be a major problem — unlike other drugs used for chemotherapy.”

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