Phytoestrogens and Antioxidants -- Bits of Experimental Evidence

Highlights of the Society for Integrative Oncology 1st International Conference; November 17-19, 2004; New York, NY

Sara M. Mariani, MD, PhD

Disclosures
In This Article

Dietary Antioxidants and Radiation Therapy

An issue that is raising quite a bit of controversy and, at times, polarization of opinions among patients, physicians, and other healthcare professionals is the use of antioxidants for the prevention of cancer, of further dissemination of tumors, and for the overall improvement of the general well-being of patients. As cancer is known to be associated with oxidative damage to intracellular structures, exogenous replacement with antioxidant agents is thought by some to achieve replenishment of the depleted endogenous stores and, thus, be of benefit for cancer patients.[6,7] Although some practitioners view this use in a favorable light, in many instances, antioxidants are being taken by cancer patients on their own, with or without the knowledge or consent of their physicians.

Although the general controversy[8,9] on the benefits and risks deriving from the use of antioxidants is far from being resolved (owing to very limited clinical evidence available to make informed decisions), a specific issue that may affect how radiation therapy is being given and received was discussed at the conference by Brian Lawenda,[10] of the Naval Medical Center, San Diego, California.

Although antioxidants are believed to protect from the damage inflicted by radiation therapy in normal tissues, little is known about how they can affect the sensitivity of cancer cells to treatment. What if exogenous antioxidants also protect the tumor? Should physicians, and in particular radiotherapists, advise against their use for patients undergoing radiation treatments? Or should they, instead, recommend them to prevent damage to normal tissues associated with treatment?

Radiation therapy efficacy is linked to its ability to induce DNA damage and cell death by free-radical injury. To assess the influence of 2 antioxidants, vitamin E and green tea extract (GTE), on radiation treatment, C3H mice were grafted with human Mca-4 breast cancer cells and given high doses of vitamin E (10-fold the daily dose) and 650 mcg/g of GTE for 120 days. Tumors of 1 mm on day 4 were allowed to grow up to 8 mm. The mice received increasing doses of radiation therapy up to 85 Gy and were observed for 3 months. The study was powered to 80% and able to resolve a difference of 15%.[10]

No significant difference was seen in the amount of radiation required for tumor control between mice receiving antioxidants in their diet and control animals. There was, however, a trend toward a slightly higher dose needed for tumor eradication in antioxidant-treated mice. On the other hand, there was a significant difference in the damages induced by radiation treatment in the 2 groups: Vitamin E and GTE-treated mice showed partial protection of normal tissues from radiation injury (59% of GTE-treated mice presented severe tissue damage vs 70% of controls).[10]

Entry of antioxidant compounds was shown to occur in tumor and normal tissues with preferential accumulation of vitamin E in the muscle beneath the tumor. Accumulation of vitamin E was associated with an increase in apoptosis and a decrease in tumor cell proliferation. Similar results were obtained with GTE. Both antioxidants inhibited growth of tumor cells in vitro as determined by an MTT proliferation assay. Endothelial cell proliferation was not significantly affected by either antioxidant. There was, however, a trend toward an increase in pericyte proliferation and toward a decrease in cell migration at lower concentrations of antioxidant.

Microarray analysis of expression patterns of angiogenesis-related genes confirmed the in vivo antiangiogenic effect attributed to GTE that may underlie its effect on inducing slower tumor cell growth. Conversely, GTE-treated host stromal cells present in homogenized tissues showed increased expression of the proangiogenic vascular endothelial growth factor. Both GTE and vitamin E showed an antiangiogenic effect in vitro (related to tumor cells) and a proangiogenic effect in vivo (related to host stromal cells) that may explain the protective effect seen in vivo in normal tissues.[10]

Thus, Lawenda concluded, vitamin E and GTE appear to exert a protective effect on normal tissues without inducing a significant decrease in radiation efficacy. However, as noted by a conference attendee, because very high doses of radiation were used in this study, it is unclear whether the use of a lower dose of radiation would have unmasked a more substantial interference of the antioxidants with radiation treatment. It also still remains to be determined whether there is a synergistic effect on either process by vitamin E and GTE that is often taken concomitantly by cancer patients.

At the final question -- "what, then, should we say to our patients?" -- Lawenda[10] answered that because the available experimental evidence is still far from conclusive, caution is advised, and antioxidants should not be taken during radiation treatment.

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