Clinical Studies of Multidrug Resistance Reversal

我们部门的研究计划的重点是开发旨在克服癌症耐药性的治疗策略。我们的研究一直致力于将耐药逆转策略转化为临床应用。我们的临床试验设计得到了实验室的支持，使我们能够分析临床样本并解释临床试验结果。一项重要的临床试验与抑制P-糖蛋白有关，P-糖蛋白是一种ABC转运蛋白，通过向外转运抗癌药物来调节耐药性。这些研究是与蒂托·福霍博士合作进行的，并评估了PGP调节可能提高抗癌药物疗效的假设。在全球范围内进行的试验中，从使用效力不足的药物的失败的第一代试验开始，到以valspodar为中心的失败的第二代试验及其伴随的抗癌药物剂量减少的需求，这一领域一直存在许多令人失望的情况。甚至一项将新药替奎达尔与紫杉醇或长春瑞滨相结合的跨国随机试验也因毒性而提前关闭。必须指出的是，到目前为止还没有令人信服的证据表明这一策略最终将提供临床益处，耐药逆转范例仍然是一个假设。早期失败的策略并不否定支持PGP拮抗剂继续发展的强有力证据。然而，该项目可以被视为高风险，对多种肿瘤类型具有潜在的高收益，因此非常适合NCI的内部计划。目前的研究正在评估第三代抑制剂Tariquidar(XR9576)。在我们完成的与长春瑞滨和他奎达的I期相互作用研究中，观察到Pgp介导的药物外流在CD56+细胞中被完全抑制，并且在单次静脉注射他奎达后持续抑制48小时。99mTC-Sestamibi显像作为正常组织和肿瘤组织药物蓄积改变的替代物。超过一半的患者对99mTC-Sestamibi的肿瘤摄取可检测到增加。我们发起一项新的TARQUIDAR试验的目的是收集更多关于TARQUIDAR与化疗药物联合使用的安全性的数据，并确定一种可以作为单一药物使用的组合。多西紫杉醇被选为一种良好的PGP底物，其疗效已知，可通过增加肺癌、宫颈癌或卵巢癌中的药物积聚而受益。在计划多西紫杉醇与他奎达的相互作用试验中，我们选择了有效但保守的剂量-多西紫杉醇-75 mg/m2，疗程为q-3周。该试验同时进行了药代动力学和药效学分析。为了检查他奎达尔是否干扰多西紫杉醇的清除，将对使用和不使用他奎达尔的剂量的多西他赛进行仔细的药代动力学研究。为了限制患者在没有调节剂的情况下接受治疗的时间长度，研究的药代动力学部分以两个40 mg/m2的多西紫杉醇剂量进行，相隔一周。他奎达的给药顺序在第1天到第8天之间随机进行。患者开始接受75 mg/m2的q3周的治疗，并在第二周期中联合他奎达。除了药代动力学分析外，我们还对服用和不服用他奎达的每个登记患者进行了99mTC-Sestamibi研究，我们的实验室还进行了外周单核细胞中CD56+罗丹明的检测。这项试验是公开的，没有重大毒性，到目前为止有39名患者参加了试验。尽管99mTc-Sestamibi研究提供了很好的概念证据，表明在使用Tariquidar后放射性核素积累增加，但这些研究缺乏量化，因为它们是平面图像，而且背景往往盖过了差异。

The focus of our section's research program is to develop therapeutic strategies aimed at overcoming drug resistance in cancer. Our research has been dedicated to the translation of drug resistance reversal strategies to the clinic. The design of our clinical trials has been enhanced by laboratory support that has allowed us to analyze clinical samples and interpret the clinical trial findings. A significant clinical trial effort has related to the inhibition of P-glycoprotein, an ABC transporter mediating resistance through outward transport of anticancer agents. These studies have been carried out collaboratively with Dr. Tito Fojo and evaluate the hypothesis that Pgp modulation may increase anticancer drug efficacy. In trials carried out across the globe, beginning with the failed first-generation trials that employed agents without sufficient potency, and continuing with the failed second-generation trials centered on valspodar with its accompanying need for anticancer agent dose reduction, there has been much disappointment in this field. Even a multinational randomized trial combining the new agent tariquidar with paclitaxel or vinorelbine closed early for toxicity. It must be stated that there is no convincing proof to date that this strategy will eventually be shown to provide clinical benefit and the resistance reversal paradigm remains a hypothesis. The failed earlier strategies do not negate strong evidence supporting continued development of Pgp antagonists. However, the project can be viewed as high risk with potentially high gain for multiple tumor types and thus very appropriate for the NCI intramural program.Current studies are evaluating the third generation inhibitor tariquidar (XR9576). In our completed Phase I interaction study with vinorelbine and tariquidar, total inhibition of Pgp-mediated drug efflux was observed in CD56+ cells, with persistence of inhibition for 48 hours after a single intravenous dose of tariquidar. 99mTc-sestamibi imaging was employed as a surrogate for altered drug accumulation in normal and tumor tissues. More than half of the patients had detectable increases in tumor uptake of 99mTc-sestamibi. Our goal in launching a new tariquidar trial was to gather more data regarding the safety of tariquidar in combination with a chemotherapeutic agent and to identify a combination that could be used as a single agent. Docetaxel was chosen as an excellent Pgp substrate with known efficacy that could be benefited by increasing drug accumulation in lung, cervical, or ovarian cancer. In planning an interaction trial of docetaxel with tariquidar, we selected an effective but conservative dose of docetaxel - 75 mg/m2 on a q-3-week schedule. The trial is designed with both pharmacokinetic and pharmacodynamic assays. To examine whether tariquidar interferes with docetaxel clearance, careful pharmacokinetics will be performed on a dose of docetaxel administered with and without tariquidar. To limit the length of time that a patient is treated without the modulator, the pharmacokinetic portion of the study is carried out on two 40 mg/m2 docetaxel doses, one week apart. The order of administration of tariquidar is randomized between the day 1 and day 8 doses. Patients begin therapy with 75 mg/m2 q-3-weeks in combination with tariquidar in the second cycle. In addition to pharmacokinetic analysis, 99mTc-sestamibi studies are performed in each enrolled patient with and without tariquidar, and our laboratory carries out CD56+ rhodamine assays in peripheral mononuclear cells. The trial is open and accruing patients without major toxicity, with 39 patients enrolled to date.Although the 99mTc-sestamibi studies provide good proof-of-concept showing increased radionuclide accumulation following tariquidar, the studies are poorly quantitative because they are planar images and background often overwhelms differences.