Murphy Christopher K, Fey Edward G, Watkins Brynmor A, Wong Vivien, Rothstein David, Sonis Stephen T
ActivBiotics, Inc., Lexington, Massachusetts, USA.
Clin Cancer Res. 2008 Jul 1;14(13):4292-7. doi: 10.1158/1078-0432.CCR-07-4669.
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.
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.
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.
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.
M40403是一种小分子超氧化物歧化酶模拟物，在超氧阴离子被认为起关键作用的动物模型疾病状态中已显示出疗效。癌症的放射治疗和化疗会产生游离氧自由基，据推测这些自由基会在健康组织中引发不良副作用。对于一些接受这些抗肿瘤治疗的患者，最常见的副作用之一是口腔黏膜炎，这是一种疼痛的、通常会限制剂量的病症。对这种病症的临床前和临床研究表明，用能减少游离氧自由基的化合物进行治疗具有积极效果。本研究在急性辐射诱导的口腔黏膜炎的临床相关仓鼠模型中研究了M40403的疗效。
通过照射颊囊在仓鼠中诱导口腔黏膜炎。在以不同剂量和给药方案治疗后，评估腹腔注射M40403降低口腔黏膜炎持续时间和严重程度的能力。使用世界卫生组织分级量表对口腔黏膜炎进行评分。
与接受安慰剂治疗的动物相比，在第0天接受照射并每天两次用30mg/kg M40403治疗的动物，在一系列治疗方案中，包括从第-1天至第3天、第0天至第3天以及仅第0天，其黏膜炎的严重程度明显较低且持续时间较短。在第-1天至第3天每天两次给予10mg/kg和3mg/kg的剂量时也取得了类似的疗效。
这些结果表明游离氧自由基与口腔黏膜炎的发生有关，也为进一步开发M40403以预防高危癌症患者的这种病症提供了依据。
