Kortmansky Jeremy, Shah Manish A, Kaubisch Andreas, Weyerbacher Amanda, Yi Sandy, Tong William, Sowers Rebecca, Gonen Mithat, O'reilly Eileen, Kemeny Nancy, Ilson David I, Saltz Leonard B, Maki Robert G, Kelsen David P, Schwartz Gary K
Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
J Clin Oncol. 2005 Mar 20;23(9):1875-84. doi: 10.1200/JCO.2005.03.116. Epub 2005 Feb 7.
Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01.
FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m(2) over 72 hours in cycle 1 and 67.5 mg/m(2) over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction.
We escalated the weekly FU dose to 2,600 mg/m(2) in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 micromol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines.
The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m(2).
临床前研究表明，细胞周期蛋白依赖性激酶和蛋白激酶C抑制剂7-羟基星孢菌素（UCN-01）可增强氟尿嘧啶（FU）的细胞毒性作用。我们设计了一项FU联合UCN-01的I期临床试验。
FU采用每周24小时静脉输注给药。剂量根据改良的斐波那契设计在连续队列中逐步递增。UCN-01每4周给药一次，在停止输注FU后立即给药，第1周期剂量为135mg/m²，持续72小时，后续周期剂量为67.5mg/m²，持续36小时。对所有患者进行FU和UCN-01的药代动力学研究，并通过逆转录聚合酶链反应测定外周血单核细胞中的胸苷酸合成酶（TS）活性。
我们将每周FU剂量逐步递增至2600mg/m²，联合每月输注一次UCN-01。剂量限制性毒性包括心律失常和晕厥。其他毒性包括高血糖、头痛、恶心和呕吐。UCN-01的平均最大血浆浓度为33.5μmol/L。患者间存在显著差异，这与α-1酸性糖蛋白的血浆浓度相关。FU清除迅速，其剂量对UCN-01的曲线下面积无影响。给予UCN-01后，外周血单核细胞中可检测到TS表达的变化，但与毒性或活性无关。尽管有7例患者病情稳定，其中6例曾接受过氟嘧啶类药物治疗，但未观察到客观缓解。
每周输注FU与每月输注UCN-01的联合方案可安全给药，值得在II期试验中进一步研究。FU联合每月UCN-01的推荐II期剂量为2600mg/m²。
