Pharmacodynamics of Gemcitabine by MRS in Pancreatic CA

描述(申请人提供)：去年约有30,000名美国人患上了胰腺癌，其中29,900人(99.7%)死于胰腺癌。胰腺癌约占所有Gl肿瘤的25%，是迄今为止预后最差的一种。事实上，确诊后的平均预期寿命只有3个月，这种疾病代表了抗癌战争中最严峻的前线之一。目前只有一种FDA批准的药物用于治疗这种疾病，吉西他滨，一种核苷类抗代谢药物。不幸的是，在FDA批准的剂量和时间表下使用单一药物吉西他滨的多个III期试验显示，(I)稳定的应答率仅为10%；(Ii)中位生存期约为6个月；以及(Iii)一年存活率为20%。然而，最近的II期数据表明，吉西他滨的释放率可以对中位生存期产生有利影响。因此，我们的主要假设是，肿瘤中吉西他滨摄取和合成代谢的数量和速率将与特定患者的反应相关。验证这一假设是至关重要的，以便能够为每个患者定制剂量、给药率和方案。为了验证这一假设，我们建议在7特斯拉的超高磁场下应用局部荧光磁共振波谱(19F-MRS)，以无创、活体监测药物及其活性合成代谢产物二氟脱氧胞苷三磷酸(DFdCTP)。

DESCRIPTION (provided by applicant): Some 30,000 Americans contracted pancreatic cancer last year, and, 29,900 (99.7%) of them succumbed to their disease. Pancreatic cancer accounts for approximately 25% of all Gl neoplasms, and is by far the one with the worst prognosis. Indeed, with a mean life expectancy from diagnosis of only 3 months, this disease represents one of the grimmest fronts of the War on Cancer. Currently there is only one FDA approved drug for the treatment of this disease, Gemcitabine, a nucleoside antimetabolite. Unfortunately, multiple phase III trials using single agent Gemcitabine at the FDA approved dose and schedule have shown, (i) a consistent response rate of only <10%; (ii) median survival of approximately 6 months; and (iii) one year survival rates of <20%. Recent phase II data, however, have suggested that the rate of delivery of gemcitabine can have a favorable impact on the median survival. Consequently, our overarching hypothesis is that the amount and rate of Gemcytabine uptake and anababolism in the tumor will correlate with that particular individual patient response. Validating this assumption is crucial in order to be able to customize dose and administration rate and regimens to each individual patient. To test this hypothesis we propose to apply localized Fluorine Magnetic Resonance Spectroscopy (19F-MRS) at ultra high magnetic field of 7 Tesla, for non invasive, in vivo monitoring the drug and its active anabolic by product di-fluoro, de-oxycytadine tri-phosphate (dFdCTP).