SBC-014

Oral mucositis can be a significant problem for cancer patients and is frequently seen in the patient population receiving high-dose head and neck radiation therapy (85%-100%), stem cell transplantation (75%-100%), and myelosuppressive chemotherapy for solid tumors (5%-40%). Current guidelines published through the joint efforts of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology recommend strategies for the prevention and treatment of mucositis in the setting of radiation therapy, chemotherapy, and combined chemoradiation therapy. An improved understanding of its pathologic basis has led to the development of targeted agents to combat mucositis. One of these drugs, palifermin, is a keratinocyte growth factor agent approved for patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. Another agent is AES-14, an uptake-enhanced L-glutamine suspension that has shown efficacy in phase III trials in reducing the risk of developing oral mucositis in breast cancer patients receiving chemotherapy. As the understanding of the pathobiology of mucositis improves, clinicians should be able to customize future therapies based on each patients risk for developing the condition.

The mechanism by which oral glutamine (GLN) prevents 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer is unknown. While GLN triples the negative extraction of gut glutathione (GSH) in rats, DMBA significantly disrupts it. Actual gut GSH flux has not been reported. We hypothesized that the gut is a producer of GSH; DMBA blocks gut GSH production and supplemental oral GLN antagonizes this effect.

Eighty Sprague-Dawley rats were randomized to four groups (n = 20/group): DMBA + GLN, DMBA + FA, OIL + GLN, OIL + FA. Rats (age 50 days) were gavaged with a one-time dose of 100 mg/kg DMBA or oil. Rats were gavaged with AES-14 as GLN (1 gm/kg/day) or an isonitrogenous amount of Freamine (FA) from 1 week before till sacrifice at 1 week after DMBA (greatest effect on gut GSH extraction). Arterial and portal blood was taken for GLN and GSH levels, and blood flow was measured using (14)C-PAH. Gut GLN and GSH fluxes (uptake or production) were calculated.

DMBA abrogated the normal GSH production (negative flux) in OIL + FA while not affecting GLN metabolism. GLN maintained GSH production in DMBA + GLN.

Oral GLN restores to normal GSH production in DMBA-treated animals suggesting one of the mechanism(s) by which GLN prevents breast cancer in this model. Unchanged uptake of GLN in the DMBA-treated animals may indicate a block in GSH transport rather than actual intracellular production.