Traditional Chinese Medicine Treatment May Enhance Chemotherapy
Center for Cancer ResearchAn herbal mixture used in traditional Chinese medicine for over 1,700 years for gastrointestinal problems including diarrhea, nausea, and vomiting has been reformulated in the U.S. This reformulation –PHY 906 – interested U.S. researchers looking for new and better ways to treat the often severe gastrointestinal side effects that can result from chemotherapy.
Yung-Chi Cheng, Ph.D., Henry Bronson Professor of Pharmacology at the Yale University School of Medicine, first looked at the ability of PHY 906 to lessen the gastrointestinal side effects of chemotherapy nine years ago. In an early small clinical study, the compound was successful in reducing the side effects in colon cancer patients receiving the drugs irinotecan and 5-FU.
In animal studies, Dr. Cheng and his colleagues observed a synergistic anti-cancer effect of the compound when given in combination with irinotecan. Although PHY 906 had no effect on animal tumors when given alone, irinotecan plus PHY 906 had greater anti-tumor activity than irinotecan alone. “Initially, we didn’t expect antitumor activity. We were testing PHY 906 purely for relieving side effects,” said Dr. Cheng.
PHY 906 is being tested for potential anti-cancer activity in combination with chemotherapy drugs in three different clinical trials: irinotecan for advanced colon cancer resistant to first-line treatment; capecitabine in liver cancer; and capecitabine in pancreatic cancer resistant to first-line gemcitabine. In the pancreatic study, the hope is that reducing the side effects with PHY 906 will allow greater doses of the drug to be given.
So far, preliminary results from all three studies have been promising. In the study with liver cancer patients, the combination appeared to provide a significant survival advantage (compared to historical controls) in Asian patients but not Caucasian patients, although the number of participants was too small to draw definitive conclusions. In the pancreatic cancer study, the addition of PHY 906 allowed for a 50% dose escalation of capecitabine without an increase in side-effects.
One concern with any natural product preparation is consistency, as the levels of active compounds in herbs or other plants can vary from batch to batch and year to year. Dr. Cheng and his colleagues have been able to show that a consistent preparation of PHY 906 can be achieved* by using the tools of mass spectrometry and RNA fingerprinting, which allow different herbal mixtures’ effects on RNA expression to be compared.
“The next question was, how exactly does PHY 906 enhance the anti-cancer activity of chemotherapy drugs?” noted Dr. Cheng. In 2008, his laboratory collaborated with Francesco Marincola, M.D., chief of the Infectious Disease and Immunogenetics Section at the NIH Clinical Center**. Dr. Marincola’s laboratory has extensive experience using RNA technology to look at the tumor microenvironment under different treatment conditions.
Dr. Marincola is now using whole mouse genome arrays to look at global RNA expression after PHY 906 and chemotherapy drug administration. “We were initially looking for immune altering effects of PHY 906,” he explained. “That was our hypothesis of how it worked.”
His lab analyzed tumor samples, comparing untreated animals with those treated with chemotherapy only, PHY 906 alone, or the combination. The analysis demonstrated that the herbal formula, when used alone, has potent anti-inflammatory activity that lessens the chronic inflammatory process caused by cancer cells. The combination of PHY 906 and chemotherapy causes a potent inflammatory response similar to that observed during rejection of allografts or of cancer cells during immunotherapy, Dr. Marincola added. “These findings suggest that the PHY 906 may enhance the effects of chemotherapy by adding an anti-cancer immune response.”
Future work will look at whether the combination of the herbs and chemotherapy impacts tissues other than those affected by cancer, and if so, what the effects might be.
*Ye M, Liu SH, Jiang Z, Lee Y, Tilton R, Cheng YC. Liquid chromatography/mass spectrometry analysis of PHY906, a Chinese medicine formulation for cancer therapy. Rapid Communications in Mass Spectrometry, 2007; 21(22):3593-607.
**Project Number: 5R01CA063477-13