Puri Rajiv, Palit Victor, Loadman Paul M, Flannigan Michael, Shah Tariq, Choudry Guzanfar A, Basu Saurajyoti, Double John A, Lenaz Gino, Chawla Shanta, Beer Mario, Van Kalken Coen, de Boer Richard, Beijnen Jos H, Twelves Christopher J, Phillips Roger M
Department of Urology, Bradford Royal Infirmary, Bradford, United Kingdom.
J Urol. 2006 Oct;176(4 Pt 1):1344-8. doi: 10.1016/j.juro.2006.06.047.
The quinone based bioreductive drug apaziquone (EO9) failed to demonstrate efficacy in previous phase II studies following intravenous administration. We determined the dose of apaziquone that can be safely administered intravesically and explored its activity for superficial bladder transitional cell carcinoma.
Six patients with multifocal, Ta/T1 and G1/G2 transitional cell carcinoma of the bladder received escalating doses of apaziquone formulated as EOquintrade mark (0.5 mg/40 ml up to 16 mg/40 ml) weekly for 6 weeks. A further 6 patients received weekly apaziquone at the highest nontoxic dose established. Pharmacokinetic parameters were determined in urine and blood, and the pharmacodynamic markers NQO1 (reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase-1) and glucose transporter 1 were also characterized. Efficacy was determined against a marker lesion.
Local toxicity (grades 2 and 3 dysuria, and hematuria) was observed at doses of 8 mg/40 ml and above but 4 mg/40 ml was well tolerated with no systemic or local side effects. Apaziquone in urine increased linearly with the dose but no apaziquone was detected in plasma. In 8 of 12 patients complete macroscopic and histological disappearance of the marker lesion occurred. A correlation between response and NQO1 and/or glucose transporter 1 expression could not be established.
Intravesical administration of 4 mg/40 ml apaziquone was well tolerated and had ablative activity against superficial bladder cancer marker lesions.
基于醌的生物还原药物阿帕齐醌（EO9）在先前的静脉给药II期研究中未能显示出疗效。我们确定了可安全膀胱内给药的阿帕齐醌剂量，并探讨了其对浅表性膀胱移行细胞癌的活性。
6例患有多灶性Ta/T1期和G1/G2级膀胱移行细胞癌的患者每周接受递增剂量的阿帕齐醌（商品名EOquintrade mark，剂量从0.5mg/40ml至16mg/40ml），共6周。另外6例患者接受已确定的最高无毒剂量的阿帕齐醌每周给药。测定尿液和血液中的药代动力学参数，并对药效学标志物NQO1（还原型烟酰胺腺嘌呤二核苷酸磷酸：醌氧化还原酶-1）和葡萄糖转运蛋白1进行表征。根据一个标记性病变确定疗效。
在8mg/40ml及以上剂量时观察到局部毒性（2级和3级排尿困难和血尿），但4mg/40ml耐受性良好，无全身或局部副作用。尿液中的阿帕齐醌随剂量呈线性增加，但血浆中未检测到阿帕齐醌。12例患者中有8例标记性病变出现完全的肉眼和组织学消失。未发现反应与NQO1和/或葡萄糖转运蛋白1表达之间存在相关性。
膀胱内给予4mg/40ml阿帕齐醌耐受性良好，对浅表性膀胱癌标记性病变具有消融活性。
