低剂量化疗作用机制的研究进展
2017-04-01梁语丝谭永刚综述邹华伟审校
梁语丝 谭永刚 综述 邹华伟 审校
低剂量化疗作用机制的研究进展
梁语丝 谭永刚 综述 邹华伟 审校
化疗是肿瘤综合治疗的主要方式之一,多年来在肿瘤治疗中发挥着重要作用。但近年来低剂量化疗(Low-dose chemotherapy)利用其化疗药物的作用点,采取合理的给药方式和计划,且相对于最大耐受剂量化疗具有毒副反应小、患者耐受性明显提高、疗效更佳等优势,已逐渐成为临床中常用的治疗策略。本文就低剂量化疗的作用机制的研究进展做一系统综述。
低剂量化疗;抗血管生成;细胞凋亡
化疗开始于19世纪40年代,随着研究结果的不断增多,在癌症患者中实施低剂量、间隔时间短的持续化疗,能得到与传统化疗相似甚至更好的疗效和生存期,且毒副作用减少,患者耐受性明显提高,生活质量显著改善,称之为低剂量化疗(Low-dose chemotherapy)。一项系统性回顾研究表明最常用的低剂量化疗药物是环磷酰胺(43%),低剂量化疗常与其他疗法结合,平均反应率(RR)为26.03%,中位无进展生存时间(PFS)为4.6个月,平均疾病控制率(DCR)为56.3%,发生3~4级不良事件少(贫血7.78%,疲劳13.4%)[1]。
目前对于低剂量化疗的研究大多数来自早期的II期研究,主要内容为低剂量化疗与传统化疗的预后比较以及给药方式、副作用的比较。少数进入III期临床试验,其中CAIRO3研究证实转移性结直肠癌在使用标准奥沙利铂、卡培他滨及贝伐单抗一线治疗后,采用每日口服低剂量卡培他滨联合贝伐单抗作为维持治疗的无进展生存率较单纯观察组有所提高[2]。低剂量化疗一般为传统剂量的1/3~1/2,采用静脉或口服给药方式,时间间隔短,疗效相当,不良反应少[3]。最近的一项Meta分析支持低剂量化疗与常规剂量化疗在抗肿瘤效果方面相似,但低剂量方案具有毒性低的优点[4],这在乳腺癌及其他许多实体肿瘤中已经得到证实[5-6],正在进行的SYSUCC-001试验和IBCSG 22-00试验明确了激素受体阴性乳腺癌患者在标准辅助治疗后应用环磷酰胺联合甲氨蝶呤低剂量维持治疗的价值[7]。最近的一项研究显示新型脂质体阿霉素与5-氟尿嘧啶(5-Fu)以最佳的协同比联合,可以在低剂量下实现肿瘤消失[8]。有报道口服型紫杉醇生物利用度良好,低剂量口服同样可以通过TOLL4受体发挥其抗肿瘤作用,且没有神经毒性[9]。即便在内脏转移疾病进展中,低剂量化疗也有很强的抗肿瘤效应[10]。明确低剂量化疗的作用机制可以为其临床应用提供理论依据,目前低剂量化疗的作用机制可以总结为以下几方面。
1 低剂量化疗作用机制
1.1 促进肿瘤细胞凋亡
低剂量化疗的作用体现在其促进肿瘤细胞凋亡的方面。在对HT-29结肠癌细胞的体外研究发现,低剂量伊立替康可以通过TNF增强Bax及Caspase-9表达,并且肿瘤坏死因子相关凋亡诱导配体(TRAIL)协同其作用,促进大肠癌细胞凋亡[11-12]。对宫颈黏液细胞癌的研究中发现,低剂量的SN-38协同紫杉醇可有效杀伤肿瘤细胞,其中Caspase-3及Caspase-7被激活,说明低剂量的SN-38协同紫杉醇通过Caspase-3及Caspase-7诱导细胞凋亡[13]。但也有研究显示高剂量化疗导致细胞凋亡,而低剂量化疗通过有丝分裂障碍导致细胞死亡[14-15],这一论点为进一步的实验验证提供了方向。
1.2 抗肿瘤血管生成
低剂量化疗不仅对肿瘤细胞起作用,而且对微环境也有影响,低剂量化疗药物损害内皮细胞的修复过程,从而导致抗血管生成作用[5]。血管内皮生长因子(VEGF)是血管生成不可缺少的条件,低剂量化疗可以使VEGF表达有不同程度的下降[16],通过VEGF途径抑制了肿瘤组织中的血管生成,进而抑制肿瘤生长。Zhou等在体外对H22肝癌细胞的研究发现,低剂量顺铂通过抑制VEGF抑制血管内皮细胞生长[17]。在小鼠模型中,低剂量多西他赛抑制VEGF表达进而抑制微血管生成,并且没有表现出巨大的毒副作用[18]。在非小细胞肺癌(NSCLC)的临床研究中同样发现,低剂量口服长春瑞滨可能通过抑制血管生成达到临床疗效[19]。低剂量化疗在抑制血管生成方面表现出许多优势,如在HT-29结肠癌模型小白鼠中使用紫杉醇和西妥昔单抗的低剂量联合方案,其抑制肿瘤细胞血管生成的活性比最大耐受剂量强[20],且低剂量化疗可以选择性抑制肿瘤组织中的血管形成,而对全身血管没有抑制[21]。
低剂量化疗药物不仅通过VEGF发挥作用,在小鼠移植瘤模型的体内研究发现维拉帕米联合低剂量紫杉醇增强了其抗血管效应,说明抑制P糖蛋白(P-gp)也可能是低剂量化疗抗血管生成的机制之一[22]。
1.3 增强免疫系统功能
除了抗血管生成作用外,低剂量化疗还可以通过恢复免疫系统的抗肿瘤作用和诱导肿瘤休眠而起到免疫作用。因此,低剂量化疗与靶向治疗及免疫治疗结合可提高其疗效[5]。在老年急性白血病患者中的研究发现,低剂量化疗配合免疫治疗,患者体内树突细胞(DC)活性增强并且细胞因子表达增加[23],大部分化疗药物均可使DC细胞成熟,诱导产生CD8细胞,并且促进其发挥生物学功能。临床中许多药物如紫杉醇、环磷酰胺等在低浓度时表现出这方面的优势:高浓度的紫杉醇抑制DC成熟,而低浓度的紫杉醇不但不会对DC细胞产生抑制作用,反而能够阻止肿瘤细胞对DC细胞成熟表达的抑制[24]。骨髓源性的抑制细胞(MDSC)抑制NK细胞的活性,使肿瘤细胞逃脱免疫监视,低剂量紫杉醇使肿瘤小鼠体内MDSC水平下降,抑制肿瘤的生长[25-26]。低剂量环磷酰胺抑制成熟结肠癌细胞生长,实时PCR分析表明,IFN-γ、TNF-α的mRNA表达增加,Foxp3和TGF-β表达下降,使调节T细胞发挥功能[27]。在小鼠乳腺癌转移模型中低剂量环磷酰胺可增强TOLL受体激动剂活性及CD4、CD8、CD11的肿瘤细胞滤过效应,增强小鼠的免疫系统抗肿瘤能力[28]。低剂量环磷酰胺联合吉西他滨在CT-26结肠癌小鼠模型中能够增强抗肿瘤T细胞的免疫活性,抑制由MDSC介导的免疫抑制[29]。在黑色素瘤小鼠模型中,低剂量吉西他滨可增强小鼠的免疫系统抗肿瘤作用,且增强巨噬细胞及DC活性[30],更多低剂量化疗药物在免疫调节方面的优势有待进一步发掘。
低剂量化疗联合免疫治疗也是未来肿瘤治疗的趋势。Nars总结得出低剂量化疗可以增强免疫细胞活性,且配合免疫调节治疗可以大幅度发挥免疫系统的功能[31]。最新的一项研究通过高通量系统方法分析得出低剂量化疗相比最大耐受剂量化疗的优势可能与免疫宿主效应有关[32]。总之,低剂量化疗可能通过对肿瘤组织中的血管、肿瘤细胞及免疫系统的作用,达到了抗肿瘤的效果,但低剂量化疗的抗肿瘤作用机制庞大,仍需大量研究来阐明。
1.4 抗肿瘤转移
传统化疗杀死了一部分肿瘤细胞,但它也激活了基质,促进残留肿瘤细胞的生长和存活,从而促进肿瘤的复发和转移。近期的一项研究表明,干细胞样肿瘤起始细胞(TICs)的扩增导致了肿瘤的转移及对治疗的抵抗,最大耐受剂量化疗诱导STAT-1和NF-κB活性,导致ELR阳性趋化因子的表达和分泌,通过CXCR-2使肿瘤细胞表型转化为TICs,促进肿瘤细胞的侵袭性。相反,低剂量化疗方案在很大程度上预防治疗诱导的基质ELR阳性趋化因子的旁分泌信号,从而提高治疗反应并延长带瘤小鼠的生存[33]。说明了基质在癌症治疗中的重要性,以及如何通过改变全身化疗的剂量计划来减轻其对治疗耐药性的影响。另一项研究在小鼠模型的术后辅助治疗中证实抑制Tie2的配体Ang2能够有效地阻止肿瘤转移,Ang2抗体联合低剂量化疗有效而联合最大耐受剂量无效。Ang2阻滞可能与转移灶的炎症终止及内皮细胞(ECs)血管生成反应相关,降低内皮细胞黏附分子和趋化因子的表达能够抑制转移相关巨噬细胞的补充[34]。
1.5 降低肿瘤干细胞性
血管内皮细胞被确定为神经干细胞微环境的重要组成部分,肿瘤干细胞样细胞(TSLC)与附近肿瘤血管的信号相互作用使其保持干细胞状态,TSLC对化疗疗效有重要影响。有实验研究脑胶质瘤中TSLC所占的比例对抗血管治疗的影响,结果表明在大鼠移植胶质瘤细胞系模型中采用单纯抗血管治疗或传统最大耐受剂量环磷酰胺化疗并不能降低肿瘤球形成单位(SFU),而抗血管治疗联合低剂量化疗则引起SFU显著减少[35]。说明低剂量化疗可能通过降低肿瘤干细胞性靶向肿瘤微环境,从而实现抗肿瘤效应。
2 小结与展望
低剂量化疗已逐渐成为肿瘤治疗学方面研究的热点,传统的化疗方案副作用大,患者耐受性较差,相比较低剂量化疗显现出优势,其作用机制是研究的重点,除上述机制外,低剂量化疗的作用机制还与克隆形成和抗氧化等相关[36,37],更多的机制有待进一步的试验去发现。根据现有的研究结果我们大致可以确定低剂量化疗的四个主要临床适应症:难治性疾病、虚弱/晚期疾病、早期疾病及诱导化疗后的维持治疗。但低剂量化疗目前缺乏大规模的临床试验,没有规范化的应用指南,其巨大的应用潜能没有被挖掘,如针对不同的个体,我们所采用的低剂量化疗如何确定给药剂量、方式和间隔;传统化疗方案耐受较好的患者使用低剂量化疗是否也能有较好的治疗效果;采用低剂量化疗对患者总生存是否有影响;低剂量化疗与靶向治疗及免疫疗法的联合策略等,这些都有待进一步研究。因此,研究低剂量化疗的机制并将其应用于临床,根据大量临床经验制定低剂量化疗的标准方案是未来的研究方向。
1 Lien K,Georgsdottir S,Emmenegger L,et al.Low-dose metronomic chemotherapy:A systematic literature analysis[J].Eur J Cancer,2013,49:3387-3395.
2 Simkens LH,van Tinteren H,May A,et al.Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer(CAIRO3):a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group[J].Lancet,2015,385(9980):1843-1852.
3 Pasquier E,Kavallaris M,Andre N,et al.Metronomic chemotherapy:new rationale for new directions[J].Nat Rev Clin Oncol,2010,7(8):455-465.
4 Xie X,Wu Y,Luo S,et al.Efficacy and toxicity of low-dose versus conventional-dose chemotherapy for malignant tumors:a meta-analysis of 6 randomized controlled trials[J].Asian Pac J Cancer Prev,2017,18(2):479-484.
5 Montagna E,Cancello G,Dellapasqua S,et al.Metronomic therapy and breast cancer:a systematic review[J].Cancer Treat Rev,2014,40(8):942-950.
6 Kobayashi N,Nakayama H,Osaka Y,et al.Tumor response after low-dose preoperative radiotherapy combined with chemotherapy for squamous cell esophageal carcinoma[J].Anticancer Res,2013,33(3):1157-1161.
7 Munzone E,Colleoni M.Clinical overview of metronomic chemotherapy in breast cancer[J].Nat Rev Clin Oncol,2015,12(11):631-644.
8 Camacho KM,Menegatti S,Vogus DR,et al.DAFODIL:A novel liposome-encapsulated synergistic combination of doxorubicin and 5FU for low dose chemotherapy[J].J Control Release,2016,229:154-162.
9 Moesa J,Koolena S,Huitema A,et al.Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel[J].Eur J Pharm Biopharm,2013,83(1):87-94.
10 Jedeszko C,Paez-Ribes M,Di Desidero T,et al.Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib[J].Sci Transl Med,2015,7(282):282ra50.
11 Zhu H,Zhao F,Yu S,et al.The synergistic effects of low-dose irinotecan and TRAIL on TRAIL-resistant HT-29 colon carcinoma in vitro and in vivo[J].Int J Mol Med,2012,30(5):1087-1094.
12 Lee SC,Cheong HJ,Kim SJ,et al.Low-dose combinations of LBH589 and TRAIL can overcome TRAIL-resistance in colon cancer cell lines[J].Anticancer Res,2011,31(10):3385-3394.
13 Teramoto M,Suzuki T,Satohisa S,et al.Low-dose SN-38 with paclitaxel induces lethality in human uterine cervical adenocarcinoma cells by increasing caspase activity[J].Med Mol Morphol,2014,47(1):31-37.
14 Eom YW,Kim MA,Park SS,et al.Two distinct modes of cell death induced by doxorubicin:apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype[J].Oncogene,2005,24(30):4765-4777.
15 Park SS,Kim MA,Eom YW,et al.Bcl-xL blocks high dose doxorubicin-induced apoptosis but not low dose doxorubicin-induced cell death through mitotic catastrophe[J].Biochem Bioph Res Co,2007,363(4):1044-1049.
16 Stoelting S,Trefzer T,Kisro J,et al.Low-dose oral metronomic chemotherapy prevents mobilization of endothelial progenitor cells into the blood of cancer patients[J].In vivo,2008,22(22):831-836.
17 Zhou F,Hu J,Shao JH,et al.Metronomic chemotherapy in combination with antiangiogenic treatment induces mosaic vascular reduction and tumor growth inhibition in hepatocellular carcinoma xenografts[J].J Cancer Res Clin Oncol,2012,138(11):1879-1890.
18 Wu H,Xin Y,Xiao Y,et al.Low-dose docetaxel combined with(-)-epigallocatechin-3-gallate inhibits angiogenesis and tumor growth in nude mice with gastric cancer xenografts[J].Cancer Biother Radiopharm,2012,27(3):204-209.
19 Kontopodis E,Hatzidaki D,Varthalitis I,et al.A phase II study of metronomic oral vinorelbine administered in the second line and beyond in non-small cell lung cancer(NSCLC):a phase II study of the Hellenic Oncology Research Group[J].J Chemother,2013,25(1):49-55.
20 Albertsson P,Lennernäs B,Norrby K.Low-dosage metronomic chemotherapy and angiogenesis:topoisomerase inhibitors irinotecan and mitoxantrone stimulate VEGF-A-mediated angiogenesis[J].APMIS,2012,120(2):147-156.
21 Francia G,Shaked Y,Hashimoto K,et al.Low-dose metronomic oral dosing of a prodrug of gemcitabine(LY2334737)causes antitumor effects in the absence of inhibition of systemic vasculogenesis[J].Mol Cancer Ther,2012,11(3):680-689.
22 Akiyama K,Maishi N,Ohga N,et al.Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic Paclitaxel[J].Am J Pathol,2015,185(2):572-580.
23 Dong M,Liang D,Li Y,et al.Autologous dendritic cells combined with cytokine-induced killer cells synergize low-dose chemotherapy in elderly patients with acute myeloid leukaemia[J].J Int Med Res,2012,40(4):1265-1274.
24 He Q,Li J,Yin W,et al.Low-dose paclitaxel enhances the anti-tumor efficacy of GM-CSF surface-modified whole-tumor-cell vaccine in mouse model of prostate cancer[J].Cancer Immunol Immunother,2011,60(5):715-730.
25 Michels T,Shurin GV,Naiditch H,et al.Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cells in vitro in a TLR4-independent manner[J].J Immunotoxicol,2012,9(3):292-300.
26 Lee JM,Seo JH,Kim YJ,et al.The restoration of myeloid-derived suppressor cells as functional antigen-presenting cells by NKT cell help and all-trans-retinoic acid treatment[J].Int J Cancer,2012,131(3):741-751.
27 Radojcic V,Bezak KB,Skarica M,et al.Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination[J].Cancer Immunol Immunother,2010,59(1):137-148.
28 Dewan MZ,Vanpouillebox C,Kawashima N,et al.Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer[J].Clin Cancer Res,2012,18(24):6668-6678.
29 Tongu M,Harashima N,Monma H,et al.Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo[J].Cancer Immunol Immunother,2013,62(2):383-391.
30 Triozzi PL,Aldrich W,Achberger S,et al.Differential effects of low-dose decitabine on immune effector and suppressor responses in melanoma-bearing mice[J].Cancer Immunol Immunother,2012,61(9):1441-1450.
31 Nars MS,Kaneno R.Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy[R].Int J Cancer,2013,132(11):2471-2478.
32 Shaked Y,Pham E,Hariharan S,et al.Evidence implicating immunological host effects in the efficacy of metronomic low-dose chemotherapy[J].Cancer Res,2016,76(20):5983-5993.
33 Chan TS,Hsu CC,Pai VC,et al.Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells[J].J Exp Med,2016,213(13):2967-2988.
34 Srivastava K,Hu J,Korn C,et al.Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth[J].Cancer Cell,2014,26(6):880-895.
35 Folkins C,Man S,Xu P,et al.Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors[J].Cancer Res,2007,67(8):3560-3564.
36 Hashimoto K,Man S,Xu P,et al.Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer[J].Mol Cancer Ther,2010,9(4):996-1006.
37 Akladios FN,Andrew SD,Parkinson CJ.Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis[J].Bioorg Med Chem,2015,23(13):3097-3104.
Researchprogressonmechanismoflow-dosechemotherapy
LIANGYusi,TANYonggang,ZOUHuawei
Department of Oncology,Shengjing Hospital of China Medical University,Shenyang 110022,China
Chemotherapy is one of the main ways for comprehensive treatment of tumors,and has played an important role in tumor treatment for many years.However,in recent years,low-dose chemotherapy(Low-dose chemotherapy) has gradually become a clinical treatment strategy commonly used to taken a reasonable mode of administration and planning,relative to the maximum tolerated dose of chemotherapy with small side effects,patient tolerance significantly improved,better efficacy and other.In this paper,the mechanism of low-dose chemotherapy on the progress is reviewed systematicly.
Low-dose chemotherapy;Anti-angiogenesis;Cell apoptosis
国家自然科学基金资助项目(81472806)
中国医科大学附属盛京医院肿瘤科(沈阳 110022)
梁语丝,女,(1989-),硕士,住院医师,从事恶性肿瘤耐药机制及逆转耐药策略的研究。
邹华伟,E-mail:zouhw@sj-hospital.org
R730.53
A
10.11904/j.issn.1002-3070.2017.06.011
(收稿:2017-06-11)