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Evaluation of D-Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis

Authors' Affiliations: Departments of ¹ Radiation Oncology, ² Radiology, and ³ Biological Chemistry, and ⁴ Center for Molecular Imaging, University of Michigan Medical Center; ⁵ Molecular Therapeutics, Inc., Ann Arbor, Michigan; and ⁶ Department of Surgery, Southern Illinois University School of Medicine, Springfield, Illinois

Requests for reprints: Daniel A. Hamstra, Department of Radiation Oncology, University of Michigan Medical Center, 109 Zina Pitcher Place, Biomedical Sciences Research Building A504, Ann Arbor, MI 48109-2200. E-mail: dhamm{at}umich.edu.

Purpose: Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. D-Methionine (D-Met), the dextro-isomer of the common amino acid L-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults.

Experimental Design: We evaluated if D-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice.

Results: Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with D-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P < 0.05) whereas it did not confer a similar protection on transformed tumor cells. D-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6 ± 0.15). D-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by D-Met treatment. Pharmacokinetics following administration of a liquid suspension of D-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral D-Met doses between 200 and 500 mg/kg (P < 0.0003).

Conclusions: D-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of D-Met to protect from oral mucositis are warranted.