MUCOSITIS

Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of drug and radiation therapy for cancer The disorder is characterized by breakdown of the oral mucosa that results in the formation of ulcerative lesions. In granulocytopenic patients, these lesions are frequent portals of entry for indigenous oral bacteria often leading to sepsis or bacteremia Mucositis occurs to some degree in more than one third of patients receiving anti-neoplastic drug therapy. In occurs in almost all patients undergoing radiation therapy for cancer of the head and neck as well as a high percentage of patients undergoing bone marrow transplantation


There are 3 stages of Oral Mucositis

(1) Inflammation accompanied by painful mucosal erythema, which can respond to local anesthetics.

(2) Painful ulceration with pseudomembrane formation and, in the case of myelosuppressive treatment, potentially life-threatening sepsis, requiring antimicrobial therapy. Pain is often of such intensity as to require treatment with parenteral opiate analgesics.

(3) Spontaneous healing, occurring about 2 - 3 weeks after cessation of anti neoplastic therapy.

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CURRENT THERAPY FOR ORAL MUCOSITIS

Standard therapy for oral mucositis is predominantly palliative, including application of topical analgesics such as lidocaine and/or systemic administration of opiates and antibiotics.

There is no approved treatment for oral mucositis

THE PATHOBIOLOGY OF MUCOSITIS—5

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Biomodels has experience with numerous models, with exclusive rights to the robust hamster models for oral mucositis developed at Harvard’s Brigham and Women’s Hospital by Stephen T. Sonis, DMD, DMSc. In addition to rat and mouse models of oral mucositis.The hamster models involve analysis of changes in the buccal mucosa using a validated scoring scale at defined times after initiation of cancer therapy. The models are designed to emulate different cancer treatment modalities.

Acute Radiation Model
In this model animals are given radiation targeted to the buccal pouch mucosa. Ulcerative mucositis develops and reaches peak severity on day 16 and gradually resolves by day 28. This model is used to establish efficacy, dose and schedule of experimental compounds.

Chemotherapy Models
Chemotherapy regimens, chosen to model specific clinical protocols, are given according to established protocols. A reproducible pattern of mucositis is observed over the course of 30 days. The model recapitulates systemic chemotherapy regimens and permits the demonstration of efficacy in animals exhibiting both oral mucositis and concomitant neutropenia.Chemotherapy/Radiation Models Chemotherapy regimens, chosen to model specific clinical protocols, are combined with a single dose of radiation targeted to the buccal pouch to induce mucositis. These models permit demonstration of efficacy in a protocol that parallels clinical protocols for head and neck cancers.
Fractionated Radiation Models
In this model animals are given radiation targeted to the buccal pouch mucosa on 8 days over a 2-week period. Ulcerative mucositis develops and reaches peak severity on day 19 and gradually resolves by day 35. This model is sed to predict the efficacy of different dosing schedules in patients being treated with fractionated radiation protocols.

Mouse and Rat  Models
For mechanism of action studies hamsters present difficulties related to the availability of reagents to hamster markers, and lack of available gene sequences for the Syrian Golden Hamster precludes even gene based assays to a large extent.  For these situations, we have develop models of oral mucositis in rats and mice, which make the evaluation of mechanism of action more feasible.

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