重组人角质细胞生长因子对放射性和放疗性口腔黏膜炎的防治作用

摘要

OBJECTIVE To evaluate preventive and therapeutic effects of recombinant human keratinocyte growth factor (rhKGF) on oral mucositis (OM) and to anticipate clinical utility of rhKGF in OM. METHODS Effect of rhKGF in vitro on 32D-KGFR cell proliferation was evalu-ated by MTT assay. Radiotherapy-induced OM model was induced by 15. 3 Gy 60Co radiotherapy, and rhKGF 0.75, 1.5 and 3 mg-kg~ and palifermin 1.5 mg·kg-1 was iv given, once daily, for 3 d before radiotherapy as preventive treatment, and added rhKGF 1.5 mg·kg-1 on the 2nd and 4th days after radiotherapy as rhKGF preventive + therapeutic treatment. Chemotherapy-induced OM mice were iv given 5 -fluorouracil 50 mg·kg-1 continuously for 4 d, the treatment schedule was simi-lar with the former, however rhKGF 1. 25, 2. 5 and 5 mg·kg-1 and palifermin 2. 5 mg·kg-1 , re-spectively. Clinical observations, food consumption, body mass loss, mortality, OM incidence and severity were monitored. RESULTS rhKGF 6. 25 - 100μg·L-1 could stimulate proliferation of 32D-KGFR cells. In radiotherapy-induced OM model, normal control, model, rhKGF 0. 75 , 1.5 and 3 mg·kg-1 prevention, prevention + therapy and palifermin prevention groups occurred OM with incidence of 0/12, 12/12, 8/12, 6/12, 5/12, 5/12 and 5/12, respectively, of which the last 4 groups significantly increased appetite compared with model group (P <0. 05) on the 6th day after radiotherapy, and on the 6th and 12th days, the body mass in all treatment groups was significantly higher than that in model group (P <0. 05). In addition, the treatment group could decrease OM symptom scores, delay the onset, and shorten the duration. In chemother apy-induced OM model, each group occurred OM with incidence of 0/16, 16/16, 10/16, 8/16, 5/16, 10/16 and 6/16, re-spectively all treatment groups significantly alleviated food consumption loss caused by chemotherapy on the 3rd and 6th day; Compared with model group, rhKGF and palifermin prevention groups obvi-ously increased gut thickness of bowel mucosa, enlarged size of Goblet cells, and boty crypt and vil-lus, while rhKGF prevention + therapy group showed lower potency than prevention of the rhKGF equal dose. CONCLUSION rhKGF is effective on experimental OM and can be used as a prophy-lactic application for OM caused by radiotherapy or chemotherapy for cancer patients.%目的 评价重组人角质细胞生长因子(rhKGF)对口腔黏膜炎(OM)的预防和治疗作用.方法 以MTT法检测rhKGF对32D-KGFR细胞体外增殖的促进作用.大鼠头部经15.3 Gy 60Co辐射制备放射性OM模型,预防组在照射前3 div给予rhKGF 0.75,1.5和3 mg·kg-1或帕利非明1.5 mg·kg-1,每天1次,共3次；预防+治疗组在照射前3d及照射后第2天和第4天iv给予rhKGF 1.5 mg·kg-1,共5次.小鼠iv给予5-氟尿嘧啶50 mg· kg-1,每天1次,连续4d,制备化疗性OM模型,预防组在化疗开始前3 div给予rhKGF1.25,2.5,5 mg·kg-1或帕利非明2.5 mg·kg-1,每天1次,共3次；预防+治疗组在化疗开始前3d及末次化疗后第2天和第4天iv给予rhKGF 2.5 mg· kg-1,共5次.通过观察临床症状、进食量、体质量变化、死亡率和OM发生率以及组织形态变化评价对OM的预防和治疗作用.结果 rhKGF 6.25 ～ 100 μg·L-1可促进32D-KGFR细胞增殖反应.在放射性OM模型中,正常对照组、模型组、rhKGF 0.75,1.5和3 mg· kg-1预防组、预防+治疗组及帕利非明预防组大鼠OM发生率分别为0/12,12/12,8/12,6/12,5/12,5/12和5/12,rhKGF 1.5和3.0 mg·kg-1预防组、预防+治疗组和帕利非明预防组在放疗后第6天大鼠进食量显著高于模型组(P＜0.05),第6和12天时各给药组体质量均显著高于模型组(P＜0.05)；另外,各给药组OM症状积分均降低,出现时间延迟,病程缩短.在化疗模型中,正常对照组、模型组、rhKGF预防1.25,2.5,5 mg· kg-1组、预防+治疗组及帕利非明预防组小鼠OM发生率分别为0/16,16/16,10/16,8/16,5/16,10/16和6/16,各给药组在末次化疗后第3和6天能显著缓解化疗引起的进食量减少；与模型组比较,rhKGF和帕利非明预防组小鼠肠黏膜厚度增加,绒毛膜上皮细胞增加,杯状细胞饱满粗大,小肠隐窝深度可见,绒毛形态正常,尤以rhKGF 2.5 mg· kg-1预防组作用最明显；rhKGF预防+治疗组的作用不及同剂量rhKGF预防组.结论 rhKGF可预防放射性或化疗所致OM.