Zhijun Liu, Eugene A. Woltering and Peiying Yang
After initial treatments of cancer through surgery, chemotherapy or radiation therapy, the next task is to prevent the cancers, especially recurrence-prone cancers, from recurring. This is because remnant cancer cells that survived the initial treatment or metastasized tend to grow, first by initiating new blood vessel formation when the environment is favorable.
Because preventing cancer recurrence requires long-term management, a safe regimen with no or minimal adverse effects would provide an optimal profile for managing the disease. Current therapeutics directed toward the prevention or treatment of cancer are often highly toxic at effective doses. Targeted therapies such as agents that inhibit angiogenesis – the process by which new blood vessels initiate and grow – offer great hope in cancer management.
Avastin, a U.S. Food and Drug Administration-approved antibody prescription drug targeted at the angiogenic growth factor VEGF, is administered by injection, but has limited efficacy and serious adverse effects. This plus its high cost make it an impractical cancer-management agent.
While the pharmaceutical industry searches for single-entity drugs that target angiogenesis, many efforts have also been made to search for anti-angiogenic agents from botanical sources based on their medicinal-use records. LSU AgCenter researchers have identified a number of such botanical agents. One that has shown great promise is Chinese sweet leaf tea. Sweet leaf tea water extract at a dose of 0.45 grams per pound of body weight completely and totally blocked blood-vessel initiation and growth in a human tissue-based angiogenesis test.
The sweet leaf tea plant, native to the Guangxi-Guizhou regions of southwestern China, has been consumed as a beverage tea for years, mainly for its naturally sweet taste (said to be 300 times sweeter than cane sugar). This humanuse history, plus the scientific discovery of its anti-angiogenic property, prompted a multiinstitutional investigation led by the LSU AgCenter and supported by the National Center for Complementary and Alternative Medicine of the National Institutes of Health. The ongoing twoyear project focuses on pre-clinical evaluation of the sweet leaf tea extract, with the goal of spinning it off into human clinical investigations as a cancer-preventative agent.
Although the enormous advantages of using safe botanical extracts as cancerpreventative agents are yet to unfold, the greatest challenge is to standardize the extract so that the batch-to-batch variations are assessed and controlled. This is especially challenging given the natural variations of botanical materials and the nature of mixed compounds in a singleleaf extract compared to single-entity drugs, such as aspirin.
The lack of quality control of botanical extracts often results in the lack of reproducible results of clinical efficacy. This investigation placed great emphasis on achieving standardization using multiple chemical markers that have proven combined anti-angiogenic activity. A chemical fingerprinting analysis method has been developed to assess the similarity of overall chemical constituents among different batches against a “standard extract” with a defined efficacy. Any batch that falls outside 90 percent similarity to this standard extract is disqualified.
The standardized sweet leaf tea extract was tested against numerous and diverse tumor specimens harvested from patients, and it was found that the extract repeatedly and consistently inhibits the initiation and growth of new blood vessels regardless of each tumor’s angiogenic potential (Figure 1). This is very encouraging because it shows efficacy against solid tumors of various types in which growth or recurrence depends on new blood vessel formation.
A positive anti-tumor efficacy result using appropriate animal models is a “gold standard” for beginning human clinical trials. In a preliminary study with mice that are highly susceptible to infection, two groups 25-39 days old were injected with human breast cancer cells to develop a tumor. Immediately after the injection, one group of mice received the standardized sweet leaf tea extract via tubes to the stomach (a process called oral gavage) on days zero, 4, 8, 10 and 14. The control group received only water, which is the vehicle used to prepare the sweet leaf tea extract.
The result of this study shows that tumor volume continued to increase in the nontreated control group, whereas tumor volume in the treated group remained constant starting at day 4 after the initial onset of the tumor growth (Figure 2). This encouraging finding is a proof of concept that the sweet leaf tea extract is orally active in stopping tumor growth, possibly by inhibiting angiogenesis that deprives the implanted cancer cells from accessing blood vessel networks to feed their growth.
Ongoing animal studies are determining the minimal effective dose in a multiple-dose study and variations in a different cancer type (pancreatic). A toxicity and safety study of the standardized sweet leaf tea also is being planned to define safe dose range. However, all indications are that it is safe for short-term use and predicted safe in longer-term use as a cancer-preventative agent.
To gain insight on the mechanisms of action, a number of studies were conducted using endothelial cells – the cells that become angiogenic to produce new blood vessels – from human umbilical veins. It was found that the sweet leaf tea extract markedly inhibited the expression of a basic growth factor that stimulates and promotes angiogenesis, and the suppression depended on the concentration of the extract. In contrast, it did not affect other vascular growth factors, including VEGF – the one targeted by the drug Avastin.
The extract did suppress the VEGF receptor on the cells regardless of the presence or absence of VEGF. These results suggest that the observed anti-angiogenic property of sweet leaf tea works by inhibiting receptors on the cell rather than the growth factors themselves. Moreover, the sweet leaf tea extract has the ability to slow the growth of endothelial cells and disrupt blood vessel formation. Additional investigations are ongoing to determine if and how the multiple constituents of the sweet leaf tea extract combine and work together to produce the anti-angiogenic effect.
LSU AgCenter researchers hope to develop the sweet leaf tea extract as an effective and safe cancer preventativeagent that will allow cancer patients to manage cancer and keep any residual cancer cells in remission indefinitely. Zhijun Liu, Professor, School of Renewable Natural Resources, LSU AgCenter, Baton Rouge, La.; Eugene A. Woltering, James D. Rives Professor of Surgery and Neurosciences, Department of Surgery, LSU Health Sciences Center, New Orleans, La.; Peiying Yang, Assistant Professor, Section of Integrative Medicine, Department of General Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas(This article was published in the summer 2009 issue of Louisiana Agriculture.)