Chemo-Hormone Combo Curtails Toxic Side Effects

Research with mice offers hope for ovarian, breast and prostate tumors

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By Alan Mozes
HealthDay Reporter

TUESDAY, Aug. 23, 2005 (HealthDay News) -- Aiming to minimize the harsh side effects of chemotherapy, researchers have fashioned a treatment that combines cancer drugs with a specific hormone to target cancer cells without attacking healthy tissue.

The treatment approach -- which combines luteinizing hormone-releasing hormone (LHRH) with the anti-cancer drug camptothecin (CPT) -- has so far only been tested in mice implanted with human ovarian cancer tumors.

However, in this week's issue of Proceedings of the National Academy of Sciences , the researchers expressed enthusiasm for the potential of such an engineered delivery system for humans suffering from ovarian, prostate, and breast cancers.

"With this delivery system we have what we want," said study co-author Tamara Minko, an associate professor in the department of pharmaceutics at Rutgers University in New Jersey. "We can deliver a drug to the cancer cells that will kill the tumor but not be toxic to the normal organs."

Minko and her associates decided to test the hormone-drug combination after observing that receptors for LHRH appeared to be overly abundant in breast, ovarian and prostate cancer cells.

In normal circumstances, LHRH helps to regulate the reproductive system in both mice and humans. But the hormone is not present in large quantities in most healthy organs such as the liver, kidney, spleen, heart, lung, brain, or skeletal muscle, the researchers said.

They studied 12 female mice to see whether LHRH-receptors would draw LHRH -- and the chemotherapy attached to it -- directly to the cancer cells without creating toxic side effects in the surrounding non-cancerous organs.

Half the mice were implanted with ovarian cancer cells, and all 12 were treated with the LHRH-CPT combination therapy four times daily, every other day, for a two-week period.

Tumor size in the cancerous mice and overall weight changes in all the mice were measured throughout treatment, as was uptake of the drug combination in healthy tissue throughout the body.

Minko and her colleagues found that only trace amounts of the chemotherapy drug accumulated in healthy tissue -- such as the brain and pituitary gland -- in both cancerous and non-cancerous mice. At the same time, the drug delivery system appeared to increase the anti-tumor effect of the chemotherapy.

The researchers also report that the LHRH-CPT combination reduced the incidence of toxic side effects typically associated with chemotherapy. No healthy mouse organs were adversely affected by the treatment, and the mice were ultimately able to produce healthy offspring.

The researchers believe the hormone-chemotherapy combination might offer an opportunity to administer chemotherapy at lower doses than current norms -- maximizing chemotherapy's cancer-killing properties while minimizing side effects.

"This drug delivery system does not have the side effects typical of cancer chemotherapy in mice, so we're excited," said Minko. She added that the next step is to harness the same treatment technology to attack the problem of chemotherapy resistance.

"Most cancer drugs are not very effective in the second step of chemotherapy, because the cancer cells develop resistance," she said. But, Minko noted, she and her colleagues have already identified another chain of molecules that appear to have resistance-inhibiting properties when combined with cancer medications.

David C. Ward, deputy director of the Nevada Cancer Institute in Las Vegas, said he was enthusiastic about the Rutgers findings.

"A lot of the new cancer treatments are targeted, and anything that will improve the specificity of delivery is good," he said. "Targeting chemo directly to the tumors without the side effects of general therapeutic agents -- targeting cancer cells over normal cells -- is extremely useful. So this approach gets closer to the magic bullet we would like to have."

In related news, researchers at the University of Texas M.D. Anderson Cancer Center say they have identified a gene they believe is a trigger for the onset of ovarian cancer.

Reporting in the same issue of the journal, the researchers analyzed more than 400 ovarian tumor samples and found that high levels of the gene -- known as atypical protein kinase C iota (PKCi) -- were present in all cases of serous ovarian cancer, which accounts for 60 percent of all ovarian cancer cases in the United States.

They also found that high levels of PKCi in combination with a second protein -- known as cyclin E -- were a strong indication of a worse prognosis for patients with non-serous ovarian cancer. Non-serous ovarian cancer accounts for 40 percent of ovarian cancer cases in the United States.

The finding might lead to drug therapies for both forms of ovarian cancer that could target PKCi directly, to prevent ovarian cancer development and improve treatment results, the researchers said.

More information

For more on cancer treatment options, visit the American Cancer Society.

SOURCES: Tamara Minko, Ph.D., associate professor, department of pharmaceutics, School of Pharmacy, Rutgers, the State University of New Jersey; David C. Ward, Ph.D., deputy director, Nevada Cancer Institute, Las Vegas; Aug. 22-26, 2005, Proceedings of the National Academy of Sciences

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