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Application of Cyclin-dependent Kinase 4/6 Inhibitors in the Treatment of Malignancies and the Mechanism of Drug Resistance
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摘要: 增殖失控是恶性肿瘤的重要特征之一。细胞周期依赖性激酶4/6(cyclin-dependent kinase 4/6, CDK4/6)抑制剂能作用于各种原因导致的过度活化的CDK4/6，恢复正常细胞周期，并可通过增强免疫、改变肿瘤微环境等发挥抗肿瘤作用。目前，CDK4/6抑制剂在激素受体阳性乳腺癌治疗中取得了良好疗效，已被批准联合内分泌治疗作为此类肿瘤的一线治疗方案，在其他肿瘤中的应用亦逐渐开展，疗效有待验证。对CDK4/6抑制剂天然或获得性耐药是影响其疗效的重要因素，目前激素受体阳性(主要为雌激素受体阳性)能较为准确预测内分泌联合CDK4/6抑制剂治疗的反应性，其他标志物需进一步探索和验证。本文对CDK4/6抑制剂治疗恶性肿瘤的作用机制、应用现状及耐药机制进行梳理和总结，并对当前CDK4/6抑制剂治疗乳腺癌尚存争议的临床决策问题作简要讨论。
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关键词:
- 细胞周期依赖性激酶4/6抑制剂 /
- 细胞周期调控 /
- 乳腺癌 /
- 治疗 /
- 耐药机制
Abstract: Uncontrolled cell proliferation is one of the important hallmarks of malignancies. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors act on CDK4/6 that is over activated by various causes. CDK4/6 inhibitors play anti-tumor roles by restoring normal cell cycle, enhancing anti-tumor immunity, and reforming tumor microenvironment. Currently, CDK4/6 inhibitors have been confirmed to be effective in hormone-receptor-positive breast cancer and were approved as the first-line treatment for this breast cancer in combination with endocrine therapy. Furthermore, CDK4/6 inhibitors have been gradually applied to the treatment of other tumors, but the efficacy remains to be evaluated. Natural or acquired resistance to CDK4/6 inhibitors is a major factor affecting their efficacy. However, at present, only hormone receptor-positive (mainly estrogen receptor-positive) can relatively accurately predict the responsiveness of CDK4/6 inhibitors in combination with endo- crine treatment, and other markers need to be further explored and verified in clinical studies. The mechanism of action, the status of application, and mechanisms of drug-resistance of CDK4/6 inhibitors in the treatment of malignancies were reviewed and summarized in this paper, and the controversy over clinical decision-making on the treatment of breast cancer with CDK4/6 inhibitors was briefly discussed. -
计算机辅助的角膜地形图的广泛应用，使临床医师能够系统、精确、全面地了解角膜表面性状，并为定量分析角膜表面各分布和形状的研究提供客观依据。本研究通过测量角膜前表面角膜地形图参数数值，对儿童与成人近视眼角膜前表面形态的发展变化趋势进行分析和探讨。
对象和方法
对象
2008年8月至2010年8月在北京协和医院验光配镜的儿童和拟接受准分子激光手术的成人近视患者，同时排除有眼部急慢性炎症、干眼症、眼部外伤史、手术史、角膜病变、眼表结构异常和隐形眼镜配戴史的患者。研究对象分为2组:儿童组100例200眼，其中男45例，女55例; 年龄8 ~ 15岁，平均(11. 54 ± 3. 54)岁，球镜屈光度－ 1. 00 D ~ － 5. 75 D，平均(－ 2. 68 ± 0. 87) D，柱镜屈光度0 D ~ － 3. 00 D，平均(－ 0. 37 ± 0. 53) D; 成人组100例200眼，其中男45例，女55例; 年龄19 ~ 45岁，平均(29. 03 ± 6. 31)岁，球镜屈光度－ 1. 00 D ~ － 5. 50 D，平均(－ 2. 88 ± 0. 80) D，柱镜屈光度0 D ~ － 3. 00 D，平均(－ 0. 52 ± 0. 61) D。
检查方法
角膜地形图检查:采用TMS-4型角膜地形图仪分析系统(日本TOMEY公司)，均由同一熟练技师操作完成，除外泪液和眼睑的干扰，选择图像显示X、Y、Z轴的误差值(offset)在允许范围内(显示绿色)，角膜相间环线均无扭曲、断开、缺失现象，摄取质量最佳的图像结果进行分析，并分别记录陡峭子午线角膜屈光力(K1)、平坦子午线角膜屈光力(K2)、最小角膜屈光力子午线(minK)的轴向和数值、角膜表面规则指数(surface regularity index，SRI)、角膜表面非对称指数(surface asymmetry index，SAI)，以及角膜地形图的中央图形形态和角膜最大散光轴位。
验光检查:对所有患者均进行散瞳验光和主观验光，分别记录近视球镜、柱镜、轴位和最佳矫正视力等。
统计学处理
所有数据分析采用SPSS 18. 0软件，屈光度、角膜地形图参数进行差异性比较，样本分析采用t检验，P＜0. 05表示差异有统计学意义，同时其相关性使用Pearson相关系数进行分析。
结果
儿童组与成人组各参数的比较
成人组近视度数平均值略高于儿童组，角膜地形图的参数中K2、SRI、SAI值较儿童组增大，且差异均具有统计学意义(P＜0. 05);而参数K1、minK在两组间的差异无统计学意义(P＞0. 05) (表 1)。
表 1 儿童组和成人组间各参数的比较(x±s)组别 屈光度(D) K1 (D) K2 (D) minK (D) SRI SAI 儿童组 － 2. 68 ± 0. 87 43. 89 ± 1. 22 42. 76 ± 1. 25 42. 72 ± 1. 25 0. 12 ± 0. 13 0. 26 ± 0. 09 成人组 － 2. 88 ± 0. 80* 43. 99 ± 1. 28 43. 06 ± 1. 17* 42. 95 ± 1. 23 0. 17 ± 0. 18* 0. 29 ± 0. 13* P 0. 016 0. 451 0. 012 0. 062 0. 002 0. 012 K1 :陡峭子午线角膜屈光力; K2 :平坦子午线角膜屈光力; minK:最小角膜屈光力子午线; SRI:角膜表面规则指数; SAI:角膜表面非对称指数; 与儿童组比较，* P＜0. 05 不同性别间各参数的比较
儿童组和成人组中，女性角膜地形图参数K1、K2和minK均高于男性，差异均具有统计学意义(P＜0. 05);而参数SRI、SAI在不同性别间差异均无统计学意义(P＞0. 05) (表 2，3)。
表 2 儿童组不同性别间各参数的比较(x±s)组别 屈光度(D) K1 (D) K2 (D) minK (D) SRI SAI 男性 － 2. 65 ± 0. 77 43. 66 ± 1. 10 42. 47 ± 1. 14 42. 44 ± 1. 13 0. 13 ± 0. 14 0. 26 ± 0. 08 女性 － 2. 71 ± 0. 97 44. 05 ± 1. 23* 42. 89 ± 1. 25* 42. 88 ± 1. 26* 0. 11 ± 0. 12 0. 26 ± 0. 10 P 0. 678 0. 024 0. 018 0. 015 0. 465 0. 540 K1、K2、minK、SRI、SAI:同表 1; 与男性比较，* P＜0. 05 表 3 成人组不同性别间各参数的比较(x±s)组别 屈光度(D) K1 (D) K2 (D) minK (D) SRI SAI 男性 － 2. 76 ± 0. 90 43. 87 ± 1. 29 42. 94 ± 1. 18 42. 85 ± 1. 29 0. 19 ± 0. 18 0. 29 ± 0. 14 女性 － 3. 09 ± 0. 80 44. 30 ± 1. 18* 43. 39 ± 1. 17* 43. 26 ± 1. 28* 0. 16 ± 0. 18 0. 29 ± 0. 15 P 0. 015 0. 034 0. 021 0. 035 0. 259 0. 866 K1、K2、minK、SRI、SAI:同表 1; 与男性比较，* P＜0. 05 儿童组与成人组角膜中央图形形态的比较
两组角膜中央图形形态的构成比分别为:儿童组圆形14%、椭圆形17%、对称蝴蝶结形29. 5%、非对称性蝴蝶结形32. 5%、不规则形7%;成人组圆形12. 5%、椭圆形15%、对称蝴蝶结形27. 5%、非对称性蝴蝶结形36%、不规则形9%。两组角膜中央图形形态均多见于蝴蝶结形，其次为椭圆形和圆形，而不规则形少见。
儿童组与成人组角膜散光轴位的比较
两组角膜散光轴位所占的比例分别为:儿童组循规性散光91%，逆规性散光2%，斜轴性散光7%;成人组循规性散光70. 3%，逆规性散光13. 7%，斜轴性散光16%。两组中角膜散光均以循规性散光为主，但成人组的斜轴性散光和逆规性散光多于儿童组。
SRI、SAI与年龄和屈光度的相关性分析
相关性分析结果显示，成人组SRI、SAI值与年龄有明显相关性(SRI: r = 0. 20，P = 0. 004; SAI:r = 0. 19，P = 0. 007)，而与屈光度不具有相关性(SRI: r = － 0. 08，P = 0. 285; SAI: r = － 0. 05，P = 0. 498);儿童组SRI、SAI值与年龄(SRI: r = 0. 03，P = 0. 805; SAI: r = － 0. 08，P = 0. 410)和屈光度(SRI: r = 0. 05，P = 0. 488; SAI: r = 0. 03，P = 0. 657)均无显著相关性。
讨论
角膜是眼屈光介质的重要组成部分，角膜的屈光力占眼总屈光力的3 /4，而角膜前表面又是产生屈光作用的主要部分，其细微的变化均可使眼的光学特性发生改变。因而角膜前表面的形态在维持视功能中起着非常重要的作用。计算机辅助的角膜地形图能够精确地反映整个角膜前表面形态和屈光分布的变化情况。因此，准确测定和了解角膜形态对于临床诊断和手术设计以及效果的评估是十分重要的[1]。
计算机辅助角膜地形图分析系统原理是利用Placido盘投射系统将25 ~ 31个同心圆环从中心到周边均匀地投射到角膜表面上，每个环有256个点，因此整个角膜就有6400 ~ 8000个数据点进入分析系统，中心环直径可小至0. 4 mm，圆环几乎可覆盖整个角膜，使整个角膜均处于投射分析范围之内，投射角膜表面的环形图像通过计算机监测、调整和处理后再将分析结果以不同颜色的彩色图像以及数字化的结果显示出来，系统性和精确性地定量表达角膜形态、屈光分布等情况[2]。
模拟角膜曲率读数(simulated keratometry reading，SimK)是计算机对所有子午线上的第6个到第8个圆环上各位点的角膜屈光力进行平滑处理和分析，显示两个互为正交的角膜曲率值读数及其所在的子午线，即陡峭子午线角膜屈光力(K1)和平坦子午线角膜屈光力(K2)。而minK是SimK计算得出的最小角膜屈光力的子午线及其数值。K1轴位为最大角膜散光轴位。
一般情况下，角膜形态相对比较稳定，以维持正常的功能视力。随着眼睑的压力、时间、泪液张力、激素水平等机体生理功能周期性变化也会呈现细微周期性的波动。Dubbelman等[3]认为角膜前表面形态会随着年龄的增长而发生变化。人类从出生到眼球发育成熟，眼轴的增长和角膜的变化是紧密相关的; 新生儿的角膜弯曲度较大，随着人眼的发育、眼轴的逐渐增长，角膜逐渐变扁平[4]; 同时，角膜弯曲度因受到眼附属器等因素的影响也会发生改变。
本研究在两组不同性别各参数的统计中，成人组女性K1、K2和minK均高于男性，可能与所抽取的研究对象中，女性平均屈光度略高于男性有关，但儿童组男女屈光度很接近，也出现了相同的结果，因此，这种性别之间差异的原因有待进一步研究和探讨。同时提示在临床诊断和筛选圆锥角膜时，男性患者更应关注角膜曲率的变化。
SRI和SAI是角膜地形图研究的重要指标，分别反映角膜中央区表面的规则性及对称性。SRI不仅反映瞳孔区的规则性，也反映了角膜光学区的光学质量。而SAI既反映角膜表面规则程度也反映角膜屈光力的对称性分布。正常国人SRI和SAI平均值分别为0. 20 ± 0. 20和0. 30 ± 0. 10;而在病变时，二者则会升高[5]。本研究结果显示成人组SRI和SAI平均值分别为0. 17 ± 0. 18和0. 29 ± 0. 13，儿童组分别为0. 12 ± 0. 13和0. 26 ± 0. 09。成人组SRI和SAI明显高于儿童组，差异均具有统计学意义，而且SRI和SAI值与年龄呈正相关，原因可能为随着年龄增长，上下眼睑对角膜长期逐渐积累的机械压迫，使角膜表面的规则性下降[6]。儿童组SRI和SAI与年龄差异无显著相关性，因儿童组研究对象的年龄跨度小。两组的SRI和SAI与屈光度差异均无显著相关性，考虑与两组研究对象屈光度均为中、低度近视有关。另外，在两组中男、女之间SRI和SAI比较差异无统计学意义。
正常情况下，人的角膜并非理想的球面，角膜的形态由中央到周边曲率半径逐渐加大，是一个中央较陡峭、周边较平坦的非球面[7]，因此，角膜前表面屈光力分布呈现中央高而周边低的对称性分布特点。Bogan等[8]将正常角膜地形图的中央图形分为五大类:圆形、椭圆形、对称性蝴蝶结形、非对称性蝴蝶结形和不规则形。两组角膜地形图中央图形均显示蝴蝶结形占多数，圆形和椭圆形次之，而不规则形较少。这与文献报道相一致[9]。
在角膜地形图图像上，每个轴位均可发现角膜散光，角膜散光是指角膜互相垂直的两个轴向的曲率半径或屈光度不等，而角膜地形图最大散光所在的轴位即为角膜散光轴位。正常人的角膜多数表现为循规性散光[10]。本研究结果也显示不论儿童组还是成人组角膜散光轴位大多均表现为循规性散光，但成人组中斜轴性散光及逆规性散光多于儿童组。正常的角膜形态可受内外多种因素的影响。婴幼儿时期，角膜形态接近于球形，随着年龄的增长，循规性散光表现明显，到了中青年角膜形态又近似球形，同时由于眼睑对角膜的压迫、泪膜及激素水平等因素的影响，使角膜形态出现逆规性和斜轴性散光多于儿童组。另外，成人组K2高于儿童组，而K1无明显变化。这可能也是一种生理性的改变。
综上所述，角膜形态具有动态变化的过程，随着年龄增长，角膜形态会发生某种程度的改变，提示医生在对患者作出临床诊断及相应处理之前，应结合角膜形态的变化规律，对患者眼部进行全面检查，客观地了解和分析角膜表面形态和屈光性状，建立各种矫正方法的角膜形态系数，选择合理的矫正方案。光学眼前节测量分析系统的出现，扩展了角膜真实曲率的观察及屈光力数据的选择范围，同时该系统还具有获取角膜前、后表面形态的独特功能，随着其应用范围的逐渐扩大，相信会有更广阔的临床前景。
作者贡献:唐辉负责文献检索、数据分析、示意图绘制、论文撰写；应红艳参与文献检索、数据分析、论文修改；白春梅提供修改建议并帮助修改论文。利益冲突 无 -
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