Efficacy of superoxide dismutase mimetic M40403 in attenuating radiation-induced oral mucositis in hamsters.
OBJECTIVE
M40403 is a small-molecule superoxide dismutase mimetic that has shown efficacy in animal model disease states in which superoxide anions are thought to play a key role. Radiation treatment and chemotherapy for cancer generate free oxygen radicals that are hypothesized to trigger unwanted side effects in healthy tissue. For some patients undergoing these antineoplastic treatments, one of the most prevalent side effects is oral mucositis, which is a painful, often dose-limiting condition. Preclinical and clinical studies of this condition have shown the positive effect of treatment with compounds that decrease free oxygen radicals. This study investigated the efficacy M40403 in a clinically relevant hamster model of acute, radiation-induced oral mucositis.


METHODS
Oral mucositis was induced in hamsters by irradiation of the cheek pouch. The ability of i.p. administered M40403 to decrease the duration and severity of oral mucositis was assessed after treatment at different doses and dosing schedules. Oral mucositis was scored using the WHO grading scale.


RESULTS
Compared with placebo-treated animals, those irradiated on day 0 and treated twice daily with 30 mg/kg M40403 had significantly less severe and shorter duration mucositis over a range of treatment schedules, including from days -1 to 3, day 0 to 3, and day 0 alone. Similar efficacy was achieved at doses of 10 and 3 mg/kg twice daily on days -1 to 3.


CONCLUSIONS
These results implicate free oxygen radicals in the onset of oral mucositis and also provide the basis for further development of M40403 in the prevention of this condition in at-risk cancer patients.
Murphy
Christopher K
CK
ActivBiotics, Inc., Lexington, Massachusetts, USA. chriskmurphy@hotmail.com
Fey
Edward G
EG
Watkins
Brynmor A
BA
Wong
Vivien
V
Rothstein
David
D
Sonis
Stephen T
ST
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D006224:Cricetinae; D018450:Disease Progression; D005609:Free Radicals; D008297:Male; D008345:Manganese; D008647:Mesocricetus; D008956:Models, Chemical; D009369:Neoplasms / Q000532:radiotherapy*; D009942:Organometallic Compounds / Q000494:pharmacology*; D010100:Oxygen / Q000737:chemistry; D011832:Radiation Injuries; D011878:Radiotherapy / Q000009:adverse effects*; D013280:Stomatitis / Q000188:drug therapy*; D013482:Superoxide Dismutase / Q000378:metabolism*
D000975:Antioxidants; D005609:Free Radicals; D009942:Organometallic Compounds; C121876:imisopasem manganese; D008345:Manganese; D013482:Superoxide Dismutase; D010100:Oxygen