上皮粘膜在放化療作用下發(fā)生炎癥反應(yīng)可導(dǎo)致粘膜炎，粘膜炎可影響胃腸道和口腔，導(dǎo)致患者疼痛、無法進(jìn)食、體重減輕甚至造成局部感染。此外，級別嚴(yán)重的粘膜炎可導(dǎo)致患者化療劑量降低或抗腫瘤治療延遲，最終影響患者的抗腫瘤療效和預(yù)后。大約30-40%接受化療的癌癥患者可發(fā)生粘膜炎，接受造血干細(xì)胞移植（Hematopoietic stem cell transplantation，HSCT）的患者這一比例上升到60-85%，接受放療聯(lián)合化療的頭頸部腫瘤（Head and neck cancer,HNC）患者粘膜炎的發(fā)生率上升到90%[1]。粘膜炎的程度不僅取決于抗腫瘤治療方案、劑量和給藥周期，還取決于患者自身因素。例如，女性患者在接受5-氟尿嘧啶（5-FU）治療時發(fā)生嚴(yán)重粘膜炎的風(fēng)險更大[2]，與5-氟尿嘧啶分解代謝的關(guān)鍵酶二氫嘧啶脫氫酶缺乏的患者類似[3]。然而，受異常上皮增生影響的患者，如銀屑病，粘膜炎發(fā)病率明顯降低。一般來說，老年、女性、超重、藥物清除率降低和遺傳易感性是粘膜炎發(fā)生的風(fēng)險因素。

粘膜炎的發(fā)生由一連串事件組成，這些事件可以分為五個階段，連續(xù)發(fā)生并在機(jī)制上相互關(guān)聯(lián)。粘膜損傷稱為粘膜炎起始期，由放療和/或化療引起，與化療或放療同時發(fā)生。全身化療和放療誘導(dǎo)組織損傷，導(dǎo)致活性氧（Reactive oxygen species，ROS）釋放以及DNA損傷，從而導(dǎo)致基底和基底上皮細(xì)胞死亡[4]。特別是，DNA鏈斷裂激活細(xì)胞凋亡[5]，壞死細(xì)胞釋放內(nèi)源性損傷相關(guān)的分子模式（DAMP），是粘膜炎發(fā)生的第二階段特征，損傷的粘膜細(xì)胞促進(jìn)參與粘膜炎過程的基因轉(zhuǎn)錄包括核因子-κB（NF-κB）和促炎細(xì)胞因子（TNF-α、 L-6、IL-1β）、細(xì)胞粘附分子等 [6-7]。促炎細(xì)胞因子也存在于粘膜內(nèi)，可誘導(dǎo)結(jié)締組織和內(nèi)皮的早期損傷，并抑制組織氧化和促進(jìn)上皮基底細(xì)胞死亡。在這一階段， c-JUN和c-JUN氨基末端激酶（JNK）被激活，進(jìn)而引起細(xì)胞膜結(jié)合分子的釋放導(dǎo)致參與該過程的其他轉(zhuǎn)錄因子的激活[8]。如核因子-紅系2相關(guān)因子2（NRF2），它是一種堿性亮氨酸拉鏈蛋白，可促進(jìn)損傷和炎癥過程中抗氧化蛋白的表達(dá)[9]。此外，化療或放療也會損傷成纖維細(xì)胞，從而導(dǎo)致蛋白-1（AP1）的激活和金屬蛋白酶（MMPs）的分泌，如MMP1和MMP3，它們可降解膠原上皮下基質(zhì)和分解上皮基底膜。上述過程中產(chǎn)生的損傷反應(yīng)信號可不斷放大，在激活其他通路的同時，通過正反饋機(jī)制放大了最初的損傷。如釋放的TNF-α啟動靶細(xì)胞上絲裂原活化蛋白激酶（MAPK）的激活，同時也可維持NF-κB的活性。在這一階段，幾次損傷會損害粘膜和粘膜下結(jié)構(gòu)。然而，患者在此階段表現(xiàn)出的癥狀很少。MAPK信號傳導(dǎo)通過JNK的激活介導(dǎo)胱天蛋白酶3的激活和細(xì)胞死亡，進(jìn)而微調(diào)AP1的轉(zhuǎn)錄活性。此外，高水平的TNF-α激活鞘磷脂酶，增加神經(jīng)酰胺途徑介導(dǎo)的促凋亡信號，并與IL-1β一起調(diào)節(jié)MMP1和MMP3的活性[10-11]。此外，受損的角蛋白細(xì)胞釋放轉(zhuǎn)化生長因子β1（TGF-β1），進(jìn)而抑制細(xì)胞周期，募集白細(xì)胞并維持NF-κB活性，從而改善損傷介導(dǎo)的信號傳導(dǎo)[12]。粘膜炎的臨床表現(xiàn)在炎癥過程的第四階段，即潰瘍期是很明顯的。在此階段，粘膜和粘膜下的完整性受到破壞，患者會自述疼痛，需要進(jìn)行臨床干預(yù)。粘膜下層損傷的存在可導(dǎo)致單核細(xì)胞浸潤介導(dǎo)的炎癥反應(yīng)，從而促進(jìn)新的促炎細(xì)胞因子的釋放，從而放大促凋亡介質(zhì)的表達(dá)并增加組織損傷[13-14]。同時化療或放療后出現(xiàn)的中性粒細(xì)胞減少癥，其持續(xù)時間長和嚴(yán)重程度，患者可能會出現(xiàn)菌血癥或敗血癥，主要由鏈球菌和葡萄球菌引起[15]。粘膜炎是一種急性反應(yīng)，大多數(shù)可隨著抗腫瘤治療的結(jié)束而消退。在這個階段，愈合過程被激活，在此過程中，來自粘膜下層細(xì)胞外基質(zhì)和間充質(zhì)的刺激促進(jìn)組織上皮化[16]。

雖然目前臨床上有越來越多的新抗腫瘤藥物，但用于預(yù)防或治療粘膜炎的治療方案很少。值得注意的是，Palifermin是一種重組人角質(zhì)形成細(xì)胞生長因子1（Keratinocyte growth factor 1，KGF-1），是唯一一個獲得FDA和EMA批準(zhǔn)的藥物，用于預(yù)防HSCT前接受高劑量化療加全身放療的口腔粘膜炎[17]。Palifermin可刺激上皮細(xì)胞增殖和分化，從而促進(jìn)化療和/或放療誘導(dǎo)的損傷后更快的組織再生。此外，它還具有抗氧化和抗凋亡活性以及抗促炎作用。該藥物在預(yù)防口腔粘膜炎方面的療效也在頭頸癌患者中得到了驗(yàn)證。兩項(xiàng)不同的研究表明，用Palifermin治療的患者表現(xiàn)出高級別（≥3級）口腔粘膜炎的發(fā)生率較低[18-19]，然而，該藥物的高成本和對該藥物可能會促進(jìn)腫瘤生長使得其不適合用于HNC患者。此外下表中我們列舉了一些迄今為止在臨床前和臨床階段已經(jīng)證實(shí)可預(yù)防口腔粘膜炎的藥物，并根據(jù)其作用機(jī)制進(jìn)行分組。

表1根據(jù)作用機(jī)制對預(yù)防口腔粘膜炎的藥物進(jìn)行分組

抗腫瘤治療的發(fā)展顯著改善了患者的生存率。然而，盡管治療變得越來越有效，但抗腫瘤治療誘導(dǎo)的口腔粘膜炎治療或預(yù)防僅有很少的有效選擇，口腔粘膜炎通常會導(dǎo)致治療終止或需要調(diào)整治療方案，同時增加了住院率，從而增加了公共衛(wèi)生成本并降低了患者的生活質(zhì)量。通過從機(jī)制方面深入了解并匯總相關(guān)的治療方案，利于臨床醫(yī)為不同的患者設(shè)計(jì)個體化靶向治療，降低嚴(yán)重不良反應(yīng)的發(fā)生，延長抗腫瘤治療的治療時間，從來改善癌癥患者的生活質(zhì)量，從而降低其管理成本。

參考文獻(xiàn)

[1]Villa A, Sonis ST. Pharmacotherapy for the management of cancer regimen- related oral mucositis[J]. Expert Opin Pharmacother. 2016;17:1801–7.

[2] Chansky K, Benedetti J, Macdonald JS. Differences in toxicity between men and women treated with 5-fluorouracil therapy for colorectal carcinoma[J]. Cancer. 2005;103:1165–71.

[3] Sloan JA, Goldberg RM, Sargent DJ, Vargas-Chanes D, Nair S, Cha SS, et al. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer[J]. J Clin Oncol. 2002;20:1491-8.

[4] Sonis ST. The pathobiology of mucositis[J]. Nat Rev Cancer. 2004;4:277-84.

[5] Manakova S, Puttonen KA, Raasmaja A,et al. Ara-C induces

apoptosis in monkey fibroblast cells[J]. Toxicol In Vitro. 2003;17:367–73.

[6] Logan RM, Stringer AM, Bowen JM,et al. Serum levels of NF-kappaB and pro-inflammatory cytokines following administration of mucotoxic drugs[J]. Cancer Biol Ther. 2008;7:1139–45.

[7] Logan RM, Stringer AM, Bowen JM, et al. The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs[J]. Cancer Treat Rev. 2007;33:448-60.

[8] Davis RJ. Signal transduction by the JNK group of MAP kinases[J]. Cell. 2000; 103:239–52.

[9] Braun S, Hanselmann C, Gassmann MG, et al. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound[J]. Mol Cell Biol. 2002;22:5492–505.

[10] Bamba S, Andoh A, Yasui H,et al. Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17[J]. J Gastroenterol. 2003;38:548-54.

[11] Sasaki M, Kashima M, Ito T, et al. Differential regulation of metalloproteinase production, proliferation and chemotaxis of human lung fibroblasts by PDGF, interleukin-1beta and TNF- alpha. Mediators Inflamm. 2000;9:155-60.

[12] Bian L, Han G, Zhao CW,et al. The role of Smad7 in oral mucositis[J]. Protein Cell. 2015;6:160–9.

[13] Alikhani M, Alikhani Z, He H,et al. Lipopolysaccharides indirectly stimulate apoptosis and global induction of apoptotic genes in fibroblasts[J]. J Biol Chem. 2003;278:52901-8.

[14] Engels-Deutsch M, Pini A, Yamashita Y, et al. Insertional inactivation of pac and rmlB genes reduces the release of tumor necrosis factor alpha, interleukin-6, and interleukin-8 induced by Streptococcus mutans in monocytic, dental pulp, and periodontal ligament cells[J]. Infect Immun. 2003;71:5169-77.

[15] Mougeot JC, Stevens CB, Morton DS,et al;. Oral Microbiome and Cancer The rapy-Induced Oral Mucositis[J]. J Natl Cancer Inst Monogr. 2019;53:lgz002.

[16] Sonis ST. Pathobiology of mucositis[J]. Semin Oncol Nurs. 2004;20:11-5.

[17] Spielberger R, Stiff P, Bensinger W, Gentile T, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers[J]. N Engl J Med. 2004;351:2590-8.

[18] Henke M, Alfonsi M, Foa P, et al. Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo- controlled trial[J]. J Clin Oncol. 2011;29:2815–20.

[19] Le QT, Kim HE, Schneider CJ, et al. Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study[J]. J Clin Oncol. 2011;29:2808-14.

[20] Koukourakis MI. Amifostine in clinical oncology: current use and future applications. Anticancer Drugs. 2002;13:181-209.

[21] Mell LK, Movsas B. Pharmacologic normal tissue protection in clinical radiation oncology: focus on amifostine. Expert Opin Drug Metab Toxicol. 2008;4:1341-50.

[22] Blijlevens NM, Donnelly JP, Naber AH, Schattenberg AV, DePauw BE. A randomised, double-blinded, placebo-controlled, pilot study of parenteral glutamine for allogeneic stem cell transplant patients. Support Care Cancer. 2005;13:790-6.

[23] Cerchietti LC, Navigante AH, Lutteral MA, Castro MA, Kirchuk R, Bonomi M, et al. Double-blinded, placebo-controlled trial on intravenous L-alanyl-L-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2006;65: 1330-7.

[24] Peterson DE. New strategies for management of oral mucositis in cancer patients. J Support Oncol. 2006;4:9-13.

[25] Vidal-Casariego A, Calleja-Fernandez A, Ballesteros-Pomar MD,et al. Efficacy of glutamine in the prevention of oral mucositis and acute radiation-induced esophagitis: a retrospective study[J]. Nutr Cancer. 2013;65:424-9.

[26] Ward E, Smith M, Henderson M, et al. The effect of high-dose enteral glutamine on the incidence and severity of mucositis in paediatric oncology patients[J]. Eur J Clin Nutr. 2009;63:134–40.

[27] Rao S, Dinkar C, Vaishnav LK, et al. The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study. Integr Cancer Ther. 2014;13:201-10.

[28] Epstein JB, Silverman S Jr, Paggiarino DA, et al. Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double-blind, placebo- controlled clinical trial[J]. Cancer. 2001;92:875-85.

[29] Kazemian A, Kamian S, Aghili M,et al. Benzydamine for prophylaxis of radiation-induced oral mucositis in head and neck cancers: a double-blind placebo-controlled randomized clinical trial[J]. Eur J Cancer Care (Engl). 2009;18:174-8.

[30] Kudrimoti M, Curtis A, Azawi S, et al. Dusquetide: A novel innate defense regulator demonstrating a significant and consistent reduction in the duration of oral mucositis in preclinical data and a randomized, placebo-controlled phase 2a clinical study[J]. J Biotechnol. 2016;239:115-25.

[31] Biswal BM, Zakaria A, Ahmad NM. Topical application of honey in the management of radiation mucositis: a preliminary study[J]. Support Care Cancer. 2003;11:242-8.

[32] Khanal B, Baliga M, Uppal N. Effect of topical honey on limitation of radiation-induced oral mucositis: an intervention study[J]. Int J Oral Maxillofac Surg. 2010;39:1181-5.

[33] You WC, Hsieh CC, Huang JT. Effect of extracts from indigowood root (Isatis indigotica Fort.) on immune responses in radiation-induced mucositis[J]. J Altern Complement Med. 2009;15:771-8.

[34] Loo WT, Jin LJ, Chow LW, et al. Rhodiola algida improves chemotherapy-induced oral mucositis in breast cancer patients. Expert Opin Investig Drugs. 2010;19(Suppl 1):91-100.

[35] Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: a study of 98 patients[J]. J Prosthet Dent. 1991;66: 361-9.

[36] Fidler P, Loprinzi CL, O’Fallon JR, et al. Prospective evaluation of a chamomile mouthwash for prevention of 5-FU- induced oral mucositis[J]. Cancer. 1996;77:522-5.

[37] Eilers J, Harris D, Henry K.Evidence-based interventions for cancer treatment-related mucositis: putting evidence into practice[J]. Clin J Oncol Nurs. 2014;18 Suppl:80-96.

[38] Chaveli-Lopez B, Bagan-Sebastian JV. Treatment of oral mucositis due to chemotherapy[J]. J Clin Exp Dent. 2016;8:e201-9.

[39] Peterson DE, Boers-Doets CB, Bensadoun RJ,et al. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up[J]. Ann Oncol. 2015;26(Suppl 5):v139-151.

[40] Mego M, Chovanec J, Vochyanova-Andrezalova I, et al. Prevention of irinotecan induced diarrhea by probiotics: A randomized double blind, placebo controlled pilot study[J]. Complement Ther Med. 2015;23:356-62.

[41] Prisciandaro LD, Geier MS, Butler RN,et al. Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats[J]. Cancer Biol Ther. 2011;11:671-7.