The Standardized Herbal Formulation PHY906 Decreases the Toxicity of Abdominal Irradiation in Mice

Abstract

Because the delivery and efficacy of abdominal and pelvic radiation therapy is limited primarily by the inherent radiosensitivity of the small and large intestine, agents that protect the intestines from radiation injury could be of great value in the treatment of intra-abdominal malignancies. PHY906, a state-of-the-art adaptation of a traditional Chinese herbal medicine, is a standardized, well-characterized pharmaceutical product subjected to rigorous quality-control procedures that include chemical fingerprinting by LC/MS, individual target bioassays and genomic bioresponse profiling. PHY906 decreased intestinal injury from chemotherapy (CPT-11 and VP16) in prior preclinical studies and is being evaluated in Phase II clinical trials as an adjunct to chemotherapy. The goal of this project was to test the hypothesis that PHY906 would reduce the intestinal toxicity of irradiation in mice. EMT6 cells were used in vitro and as tumors in the same mouse strain (SPF BALB/cRw) used to study intestinal injury. PHY906 was administered by oral gavage at 500 mg/kg/fraction BID for 4 days. Mice were treated with whole-abdomen irradiation (2 Gy/day x 4 days) on the same days. Intestinal injury was assayed by physiological observations and histological studies. Effects on tumor growth and radiation response were assayed in tumor growth studies. PHY906 did not alter growth or radiosensitivity of cells in vitro. PHY906 decreased the toxic effects of fractionated abdominal irradiation. Mice receiving radiation alone had marked blunting and loss of villi, crypt loss, and crypt hyperplasia with irregular crypt morphology; these changes were reduced in mice receiving PHY906. Numbers of viable crypts per circumference were decreased in irradiated mice; crypt loss was reduced in mice receiving PHY906. Irradiation produced weight loss, with a nadir occurring 8 days after the 1st irradiation and an increase in weight occurring over the next 3 weeks. PHY906 did not alter the initial weight loss, but resulted in a more rapid recovery. PHY906 did not alter the growth, local invasion, or metastatic spread of EMT6 tumors and did not protect tumors from growth delays produced by single-dose and fractionated irradiation. In this mouse model PHY906 decreased the toxicity of abdominal irradiation, without protecting tumors, thereby increasing the therapeutic ratio. These findings suggest that further preclinical studies of PHY906 as an adjunct to radiation therapy regimens involving pelvic or large-field abdominal irradiation are warranted. These results also provide the basis for our proposed phase II clinical studies of PHY906 as an adjunct to pre-operative radiation therapy and Capecitabine for patients with locally advanced rectal cancer.