摘要
目的：
铂类药物广泛应用于临床抗多种类型肿瘤的化学治疗。其中,卡铂属于第二代铂类药物,以其低毒性且与顺铂具有几乎相同效能谱的优势,成为目前临床化疗中最为常用的抗肿瘤药物之一。以铂药为基础的联合化疗是非小细胞肺癌及膀胱移行细胞癌的标准疗法。然而,化学耐药性的存在使部分患者的病情难以从化疗中得到改善；同时,在化疗前对药物化学耐药性的鉴定未能达到医疗需要。DNA是铂药抗肿瘤作用的主要靶点,DNA损伤即Pt-DNA加合物形成,是肿瘤细胞对铂药化疗产生反应的关键环节。假设铂类药物诱导低水平DNA损伤可预测化学耐药性,即肿瘤细胞基因组DNA未形成或形成低水平的DNA损伤预示其对铂类药物具有潜在的治疗抵抗。加速质谱测定法(AMS)是检测碳-14超灵敏方法,当14C标记的卡铂诱导Pt-DNA单加合物形成时,带有14C的卡铂会与DNA共价结合。通过AMS检测基因组DNA上14C含量,可量化卡铂-DNA加合物水平。此外,检测某些相关参数,如药物摄取/排出、细胞内药物失活及DNA修复,可揭示化学耐药性的机制。超灵敏AMS可在患者或肿瘤细胞接受亚毒性微小剂量14C标记的卡铂时完成上述研究,以期建立亚毒性微小剂量方法对卡铂耐药的鉴定及预测。预测肿瘤对特定化疗方案的反应性实用性强,使个体化治疗达到最佳疗效,最小化毒副作用的危险率,避免有效治疗期的延误。本研究检测人肿瘤细胞系及肿瘤患者卡铂-DNA加合物形成及修复,以鉴定化学耐药性及探讨耐药性的潜在机制,为患者接受化学治疗前制定具有高度针对性的个体化治疗方案。
方法及结果：
本研究开展六种肺癌细胞系及五种膀胱癌细胞系的体外实验,采用AMS对放射性14C标记的卡铂亚毒性微小剂量与临床治疗剂量在不同时间点诱导的DNA单加合物水平及DNA修复水平进行检测,以及对二者相关性进行分析。结果显示,14C标记的卡铂微小剂量在放射性强度为50,000 dpm/ml、治疗剂量的1%用量时可诱导DNA损伤(治疗剂量卡铂的生理学靶标),且两个剂量下诱导的DNA单加合物形成水平呈高度相关(r2=0.95,p<0.0001肺癌与膀胱癌)。MTT法检测肿瘤细胞对卡铂的耐药水平,并通过计算半数抑制浓度IC50加以反映；同时,通过比较每种细胞DNA单加合物形成水平与IC50的相关性,揭示DNA损伤程度与肿瘤细胞对卡铂耐药之间的相互关系。结果显示,经卡铂微小剂量与临床治疗剂量分别诱导的DNA单加合物水平(r2=0.77,p=0.022微小剂量;r2=0.83,p=0.011治疗剂量)及AUC(r2=0.77,p=0.022微小剂量；r2=0.83,p=0.011治疗剂量)与六种NSCLC细胞系IC50值呈直线相关,提示微小剂量卡铂诱导的DNA单加合物水平可潜在性鉴定及预测卡铂耐药性。经两个剂量分别诱导的DNA单加合物修复率与五种膀胱癌细胞系IC50值呈直线相关(r2=0.80,p=0.04微小剂量；r2=0.82,p=0.03治疗剂量),提示DNA单加合物水平可潜在性鉴定膀胱癌细胞对卡铂耐药的部分机制。此外,采用电感耦合等离子体质谱测定法(ICP-MS),检测五种膀胱癌细胞系经治疗剂量卡铂诱导DNA加合物中的总铂含量及其修复率,结果显示,ICP-MS检测结果与AMS检测单加合物水平呈直线相关(r2=0.85,p<0.0001),提示卡铂诱导单加合物水平亦可替代DNA总加合物水平对膀胱癌卡铂耐药进行鉴定及预测。此外,采用实时定量PCR检测六种肺癌细胞系及五种膀胱癌细胞系中以铂药为基础的化疗效果指示剂ERCC1及RRM1 mRNA表达,结果表明,采用AMS检测微小剂量或治疗剂量诱导的Pt-DNA单加合物水平及其修复率明显优于ERCC1及RRM1 mRNA表达水平与卡铂耐药性之间的相关性。
在分子水平探讨影响DNA损伤及铂药耐药的潜在机制。检测药物摄取/排出及细胞内药物失活深入探讨耐药机制。与铂药敏感细胞系H23比较,耐药细胞系A549的DNA损伤水平低、IC50高(p<0.001),液体闪烁计数法(LSC)检测两种细胞系具有相同的药物吸收水平,而H23细胞表现出较强的药物外排能力,说明此机制不是两种细胞系耐药差异的影响因素。此外,细胞内谷胱甘肽(GSH)水平参与铂药在A549细胞内的失活作用。结果显示,A549细胞总GSH水平较H23高(p<0.001),使用γ-谷氨酰半胱氨酸合成酶抑制剂BSO抑制GSH的生物合成,明显增强A549细胞对卡铂的敏感性,即IC50降低(p<0.01),单加合物水平升高(p<0.05)。研究中通过卡铂长期诱导获得膀胱癌5637耐药细胞,检测耐药细胞较亲代敏感细胞GSH水平增高(p<0.05)。
探讨DNA修复机制是否参与铂药化学耐药性的形成。检测DNA修复方式核苷酸切除修复(NER)体系中的关键蛋白ERCC1。应用siRNA下调耐药细胞A549中该基因的表达,可明显升高DNA单加合物水平(p<0.01)及增强A549对卡铂的敏感性,即IC50降低(p<0.001)。此外,采用PCR阵列及Western blot检测5637亲代细胞及耐药细胞之间DNA修复基因的表达差异,耐药细胞MGMT mRNA及蛋白表达水平均明显升高(p<0.05)。提示多种潜在机制共同参与卡铂化学耐药性。
为验证微小剂量方法在临床应用的可行性,本研究开展了在体实验。经小鼠及荷瘤裸鼠尾静脉注射微小剂量或治疗剂量卡铂(2或200mg/m2,其中14C标记的卡铂50,000dpm/g),LSC检测血液样本14C含量,以计算药代动力学参数；AMS检测PBMC与荷瘤组织DNA单加合物水平。结果显示,卡铂微小剂量与治疗剂量的药代动力学相同,二者DNA单加合物水平呈直线相关(r2=0.94,p<0.001),荷瘤组织DNA单加合物水平对卡铂耐药性的鉴定与体外实验结果一致,提示在体内亚毒性微小剂量卡铂亦是其治疗剂量理想的替代方式。基于上述结果,本研究首次开展了微小剂量临床0期试验。试验初期结果显示,四位肿瘤患者接受一亚毒性微小剂量卡铂(14C标记的卡铂为10×106dpm/kg,14C非标记的卡铂为临床治疗剂量1%用量),半衰期为1.5-2h,与治疗剂量一致。PBMC中代表卡铂-DNA单加合物水平的14C信号较AMS检测的本底辐射数值高10～100倍,达到AMS有效检测范围。此微小剂量对患者无毒性作用,同时14C射线照射量低于一次腹部CT的0.2%,适合应用于后续的临床试验。
结论：
1.亚毒性微小剂量与临床治疗剂量卡铂的药代动力学相同。
2.亚毒性微小剂量卡铂可诱导体外培养的肿瘤细胞、体内移植物肿瘤,以及小鼠及患者PBMC基因组DNA损伤。
3.微小剂量与治疗剂量卡铂分别诱导的肿瘤细胞、荷瘤组织中DNA单加合物水平呈直线相关,可潜在鉴定及预测治疗剂量下DNA的损伤程度。
4.卡铂诱导低水平的单加合物和(或)高DNA修复率与卡铂耐药性(IC50值)呈正相关,可潜在鉴定及预测其化学耐药性。
5.DNA单加合物水平与总铂含量(即总加合物水平)的变化趋势呈直线相关,可反映总加合物对DNA的损伤程度。
6.药物代谢、细胞内药物失活及DNA修复途径可不同程度影响Pt-DNA单加合物形成水平,进而影响卡铂耐药性。
■
Objectives:
Platinum (Pt)-based drugs are widely used in the treatment of a variety of cancers. Carboplatin, the second generation of Pt drug, is among the most commomly used anticancer chemotherapeutic drugs because of approximately the same spectrum of activity as cisplatin but reduced toxicity. Pt-based combination chemotherapy is the standard regimen for the treatment of non-small cell lung cancer (NSCLC) or bladder transitional cell carcinoma (TCC). However, most patients will not benefit from chemotherapy because of chemoresistance. The ability to characterize tumors for drug resistance prior to toxic chemotherapy is an unmet medical need. DNA is considered as the major target of Pt drugs. DNA damage or Pt-DNA adduct formation, is the critical step in cancer cell response to Pt chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance, that is, cancer cells with no or low DNA damage will survive and be resistant to Pt chemotherapy. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring carbon-14. When 14C-labeled carboplatin induces carboplatin-DNA monoadducts, carboplatin, together with 14C, is covalently linked to DNA. By measuring the amount of 14C on genomic DNA with AMS, we are able to determine the level of carboplatin-DNA adducts. Furthermore, some relevant parameters, such as drug uptake/ efflux, intracellular drug inactivation, and DNA repair, can also be measured that helps determine the mechanisms of chemoresistance. Because of the supersensitivity of AMS, all these studies can be performed after patients or cancer cells are treated with non-toxic midcrodose of 14C-labeled carboplatin. It is desirable to establish the microdosing approach to identify and predict the chemoresistance to Pt-based drugs. Predictive tests of how a tumor would react to a particular chemotherapeutic regimen would be extremely useful, since this would permit personalized chemotherapy to maximize the therapeutic effects while minimizing the risk of serious side effects and not delaying effective treatment of the disease. This proposal focuses on measurement of carboplatin-DNA adduct formation and repair in human cell lines and human cancer patients with the ultimate goal of identifying chemoresistance and determining the underlying chemoresistant mechanisms for designing of personalized therapy before patients receive toxic chemotherapy.
Methods and results:
Six NSCLC cell lines and five bladder TCC cell lines were studied in vitro. The levels of DNA monoadduct formation induced by subtoxic microdosing and therapeutic 14C-labeled carboplatin and its repair rate were detected by AMS at different time points, and the linear regression analysis was calculated. The data showed that microdosing 14C-labeled carboplatin at 50,000 dpm/ml and 1% of therapeutic dose could induce DNA damage, the physiological target of therapeutic carboplatin. The DNA damage induced by microdoses is linearly correlated to that of therapeutic carboplatin (r2=0.95,P<0.0001 for both lung and bladder cancer). Cellular resistance to carboplatin (IC50 value) was determined by the MTT assay. The data showed that DNA monoadduct levels at 4h time point (r2=0.77, p=0.022 for microdose; r2=0.83,p=0.011 for therapeutic dose) and AUC (r2=0.70,p=0.038 for microdose; r2=0.75,p=0.026 for therapeutic dose) induced by both microdosing and therapeutic carboplatin were linearly correlated to the IC50 values of NSCLC cell lines, suggesting the levels of DNA monoadduct induced by microdosing carboplatin can potentially identify and predict the cellular resistance to carboplatin. In addition, DNA repair rate induced by microdosing or therapeutic carboplatin was linearly correlated to the IC50 value of bladder cancer cell lines (r2=0.80, p=0.04 for microdose; r2=0.82, p=0.03 for therapeutic dose). The level of total Pt induced by therapeutic carboplatin and its repair rate in five bladder cancer cell lines were confirmed in parallel by inductively coupled plasma mass spectrometry (ICP-MS) at different time points. The data showed that the kinetics of total Pt level is consistent to that of DNA monoadduct level measured by AMS (r2=0.85,p＜0.0001), suggesting the DNA monoadduct level can substitute total adduct level to potentially identify and predict cellular resistance to carboplatin in bladder cancer cell lines. Quantitative real time PCR was performed to determine the mRNA expression levels of ERCC1 and RRM1 in six lung cancer cell lines and five bladder cancer cell lines. These two genes have been used to predict resistance to chemotherapy in NSCLC patients. The carboplatin-DNA monoadduct levels induced by both microdosing and therapeutic carboplatin treatment were superior in predicting chemoresistance, when compared to the ERCC1 and RRM1 expression levels in these 11 cell lines.
Other major steps, like drug metabolism, cell uptake and efflux, and repair of DNA damage, can affect DNA damage and, therefore, cellular sensitivity to Pt chemotherapy. Measuring drug uptake/efflux and intracellular inactivation allows insights into resistance
chanisms. Pt-resistant A549 cells had lower DNA damage and higher IC50 when compared to sensitive H23 cells (p<0.001). The uptake/efflux did not contribute significantly to the resistance differences between these two specific cell lines. Intracellular glutathione (GSH) is involved in intracellular inactivation of Pt in A549. Depletion of GSH with buthionine sulphoximine (BSO) increased the carboplatin-DNA monoadduct levels (p<0.05) and sensitized A549 to carboplatin (p<0.01). We also developed a Pt-resistant 5637 sub-cell line by culturing 5637 cells with carboplatin for a long term. Compared with the parental chemosensitive cells, total GSH level increased in the 5637 resistant cells (p<0.05).
To determine if DNA repair is involved in chemoresistance, we used siRNA to knock down the expression of ERCC1 in the chemoresistant A549 cells. ERCC1 is one of the key proteins in the multi-subunit nucleotide excision repair complex. Downregulation of ERCC1 expression increased the DNA monoadduct levels (p<0.01), and sensitized A549 cells to carboplatin (p＜0.001). Compared with chemosensitive 5637 parental cells, the levels of MGMT mRNA and protein expression increased in 5637 resistant cells by PCR array and Western blot (p<0.05), indicating that multiple underlying mechanisms contribute to the chemoresistance.
We also performed in vivo studies to determine if the microdosing approach could be translated into clinical applications. We titrated and determined the dose of 14C-labeled carboplatin needed for the in vivo studies in mice. Balb/c mice and nude mice carrying tumor xenografts were treated, through intravenous injection, with one microdose (2 mg/m2) or one therapeutic dose (200 mg/m2) of carboplatin, each containing 50,000 dpm per gram of body weight of 14C-labeled carboplatin. Blood samples were taken up after 14C-labeled carboplatin injection. Liquid scintillation counter (LSC) was used to determine the drug metabolism (pharmacokinetics) of 14C-carboplatin in plasma. Peripheral blood mononuclear cells (PBMC) were isolated for DNA extraction. Tumor xenografts were excised. The kinetics of Pt-DNA monoadduct formation in PBMC and tumor xenografts treated with microdosing or therapeutic carboplatin was linear (r2=0.94, p<0.001), with the essentially identical pharmacokinetics. This suggests that the levels of DNA monoadducts induced by microdose can potentially predict the levels of monoadducts induced by therapeutic carboplatin, and microdoses are reasonable surrogates for therapeutic doses. Based on the above results, we have opened a Phase 0 microdosing trial in clinical cancer patients. In this clinical trial, four patients received one subtoxic microdose of 14C-labeled carboplatin at 10×106 dpm/kg and the total unlabeled carboplatin of 1% the therapeutic dose. The half lives of microdosing carboplatin were 1.5 to 2 hours, identical to that of therapeutic dose. The 14C signals in PBMC, representing carboplatin-DNA monoadduct levels, were 10～100 times the background levels, the desired level for AMS analysis. This data suggests that this dose of 14C-carboplatin (10×106 dpm/kg) and total carboplatin dose (1% of therapeutic dose) is the recommended dose for future clinical trials. We did not observe any toxicity in these four patients. The radiation exposure from 14C is less than 0.2% of that from an abdominal CT scan.
Conclusions:
1. The identical pharmacokinetics was observed for the subtoxic microdosing and therapeutic carboplatin.
2. The subtoxic microdosing carboplatin can induce genomic DNA damage in cancer cell lines in vitro, tumor xenografts in vivo, and PBMC from mice or human patients.
3. The level of carboplatin-DNA monoadducts in cancer cell lines and tumor xenografts in nude mice induced by microdosing carboplatin is linearly proportional to those induced by therapeutic doses. The subtoxic microdosing approach can potentially be used to identify and predict DNA monoadduct levels induced by therapeutic carboplatin.
4. The low level of DNA monoadducts induced by subtoxic microdosing carboplatin correlates with the cellular resistance to carboplatin. The subtoxic microdosing approach can potentially be used to identify and predict cellular chemoresistance to carboplatin.
5. DNA monoadduct levels measured by AMS is linearly correlated to the total Pt level induced by therapeutic carboplatin measured by ICP-MS.
6. The underlying mechanism, like drug metabolism, intracellular drug inactivation and DNA repair pathways can affect DNA monoadduct formation and, therefore, cellular sensitivity to Pt chemotherapy.
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