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

Abstract

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 F 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 modelof mucositis, a dose-dependent increase inprotection 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 radiationinduced 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.

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

“…⁎ p b 0.05, ⁎⁎ p b 0.001. and assumed that the binding would reduce the antitumor efficacy of the cisplatin. However Deegan et al (1994) clearly demonstrated that the cisplatin-methionine complex retains most of its cytotoxic activity against tumors which is consistent with the results of the testing in appropriate tumor models (Jones and Basinger, 1989;Cloven et al, 2000;Vuyyuri et al, 2008). Consequently, D-methionine appears to be an appropriate candidate for a clinical therapy to reduce the side effects of cisplatin therapy.…”

“…Further D-methionine does not interfere with the tumor kill of cisplatin in combination with radiation or radiation alone (Vuyyuri et al, 2008). These studies were appropriately designed and powered to determine if any statistically significant antitumor interference occurred and used tumor models for cancers commonly treated with cisplatin clinically including ovarian cancer (Cloven et al, 2000), carcinosarcoma (Jones and Basinger, 1989) and murine squamous cell carcinoma cells (Vuyyuri et al, 2008).…”

Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy with or without Cisplatinum for Head and Neck Cancer

“…Interest in D-met as a radioprotector was spurred by reports that, in animal models, it could effectively prevent the oxidative stress-induced ototoxicity and nephrotoxicity associated with the chemotherapeutic agent cisplatinum (21,22). A recent report also documented radiation protection with D-met of primary nontransformed human cells (fibroblasts, keratinocytes, and endothelial cells) with a protective factor of 1.2 to 1.6 in clonogenic assays in vitro, whereas radiation protection was not observed in a panel of transformed human tumor cell lines in vitro or in vivo (23). Further, irradiation of the snouts of mice daily for 5 days resulted in mucositis compared with control animals, with a peak mucositis score of 3.5 ± 0.25 on a scale from 0 to 7 that was elevated compared with control animals (peak value, 0.4 ± 0.2; P < 0.001).…”

Review of Preclinical Studies on Treatment of Mucositis and Associated Pain

“…D-Methionine treatment did not alter tumor control following cisplatin and radiation. Pharmacokinetics showed that liquid suspension of D-Methionine in rats had 68% bioavailability relative to IV administration (Vuyyuri et al, 2008). In a mouse model of radiation-induced mucositis, D-Methionine showed a dose-dependent increase in protection from mucositis.…”

“…In a mouse model of radiation-induced mucositis, D-Methionine showed a dose-dependent increase in protection from mucositis. Furthermore, D-Methionine did not compromise chemoradiationmediated tumor control (Vuyyuri et al, 2008). A phase I clinical trial was conducted to assess the pharmacokinetics of MRX-1024, the orally bioavailable formulation of D-Methionine, in healthy individuals and head and neck cancer patients undergoing radiation therapy and/or chemotherapy.…”