Harnessing the Biological Activity of Natural Products
At the same time, cancer researchers have been intrigued by the potent and beneficial biological activity shown by some natural products and are testing ways to incorporate them into standard and experimental treatment regimens, both to enhance the anticancer effects of therapy and reduce the side effects.
A Treatment More than 1,700 Years in the Making
Dr. Yung-Chi Cheng, Henry Bronson Professor of Pharmacology at the Yale University School of Medicine, is interested in herbal compounds that are used in traditional Chinese medicine (TCM). Among other projects, his laboratory has reformulated a Chinese herbal mixture that has been used in TCM for more than 1,700 years to treat gastrointestinal problems, including diarrhea, nausea, and vomiting.
This reformulation, called PHY906, was originally tested to lessen the gastrointestinal side effects of chemotherapy, and, in a small, early clinical study, the compound successfully reduced side effects in patients with colon cancer who received the drugs irinotecan and 5-fluorouracil.
Dr. Cheng and his colleagues also observed a synergistic anticancer effect when the compound was given in combination with irinotecan in animal studies—a result that was surprising, said Dr. Cheng.
PHY906 alone had no effect on these tumors, but irinotecan plus PHY906 had greater antitumor activity than irinotecan alone. Now PHY906 is being tested for potential anticancer activity in combination with traditional chemotherapy drugs in three clinical trials. (The trial for colorectal cancer is still accruing patients.)
In tandem, to understand the molecular mechanisms behind the combination’s effects, Dr. Cheng and colleagues are collaborating with Dr. Francesco Marincola, chief of the Infectious Disease and Immunogenetics Section at the NIH Clinical Center, who is using mouse models to measure changes in gene expression after PHY906 and chemotherapy drug administration.
Their preliminary results indicate that “when PHY906 is combined with chemotherapy, this causes a potent inflammatory response, similar to that observed during the rejection of cancer cells during immunotherapy,” said Dr. Marincola. “PHY906 may enhance the effects of chemotherapy by adding an anticancer immune response.”
From Supermarket to Clinic
Herbal medicines with a long history of use are one type of product being examined for potential uses in modern medicine. But some food products consumed in a normal diet can also affect the workings of the body at the molecular level. One of these foods—grapefruit juice—is now being studied for novel applications in cancer treatment.
Though widely consumed for its high levels of vitamin C and potassium, grapefruit juice is far from an innocuous drink in the eyes of doctors. It contains a class of compounds called furanocoumarins, which block an enzyme found in the digestive system and liver called CYP3A4.
As a result, certain drugs that are normally metabolized by the enzyme stay in the body longer and at higher concentrations if they are taken with grapefruit juice. This can lead to overdoses of some blood-pressure medications, antidepressants, and antiretroviral drugs for HIV, for example.
Grapefruit juice’s ability to slow the metabolism of certain drugs, however, caught the eye of researchers at the University of Chicago, who were interested in testing the immunosuppressant drug rapamycin as an anticancer agent.
Rapamycin has extremely poor bioavailability—when taken orally, less than 15 percent of the drug is absorbed into the body. As a result, “We had to use high doses of rapamycin to achieve the blood levels that we wanted,” explained Dr. Ezra Cohen from the University of Chicago Medical Center, and the high doses led to unwanted toxicities, such as severe diarrhea caused by surplus rapamycin leaving the intestines.
Looking for a way to give rapamycin more time to reach the bloodstream, Dr. Cohen and his colleagues hit on the idea of administering the drug with grapefruit juice.
In a promising phase I trial presented at the 2009 American Association for Cancer Research annual meeting, the combination was given to 28 patients with advanced, incurable solid tumors, 7 of who experienced stable disease and one who had a partial response to treatment that has lasted for more than a year.
An added benefit was that co-administration of grapefruit juice allowed for once-weekly doses of rapamycin instead of the traditional once-daily doses, greatly reducing the cost of the therapy.
“There are a lot of [anticancer] drugs that I think would be amenable to this type of approach, because they have poor oral bioavailability, have side effects related to that poor absorption, and are expensive,” said Dr. Cohen. He strongly cautioned that patients should not mix grapefruit juice and chemotherapy outside of clinical trials, as the safety of the combination is still being explored.