喹诺酮类抗生素：膀胱癌膀胱内化疗的一种潜在辅助药物。

Quinolone antibiotics: a potential adjunct to intravesical chemotherapy for bladder cancer.

作者信息

Kamat A M, DeHaven J I, Lamm D L

机构信息

Department of Urology, West Virginia University, Morgantown 26506-9251, USA.

出版信息

Urology. 1999 Jul;54(1):56-61. doi: 10.1016/s0090-4295(99)00064-3.

DOI:10.1016/s0090-4295(99)00064-3

PMID:10414727

Abstract

OBJECTIVES

Despite complete transurethral resection of superficial bladder tumors, the recurrence rate averages 88% at 15 years. Intravesical chemotherapy decreases the recurrence rate, particularly if given immediately after tumor resection. Anticancer drugs such as doxorubicin target topoisomerase II as do the quinolone antibiotics. We evaluated two fluoroquinolones independently and in combination with doxorubicin for cytotoxic effects against bladder cancer cells in vitro.

METHODS

Three human transitional carcinoma cell lines, T24 (grade I), HTB9 (grade II), and TccSup (grade IV), were exposed to either ciprofloxacin or ofloxacin in concentrations ranging from 0 (control) to 1000 microg/mL for 24, 48, and 96 hours. In a separate experiment, a 30% cytotoxic dose (IC30) of doxorubicin was applied to the cell cultures for 1 hour and washed off, followed by exposure to ciprofloxacin or ofloxacin for 48 and 96 hours. Cytotoxicity was evaluated using the MTT colorimetric assay.

RESULTS

At 96 hours, significant cytotoxicity (P <0.05) for ciprofloxacin was seen starting at 12.5 microg/mL (HTB9, TccSup) and 50 microg/mL (T24) and for ofloxacin at 12.5 microg/mL (HTB9) and 50 microg/mL (TccSup, T24). Maximum cytotoxicity with ciprofloxacin was 95.4+/-0.4% (HTB9, 400 microg/mL) and with ofloxacin was 95.2+/-0.3% (HTB9, 800 microg/mL). Exposure to doxorubicin (IC30, 1 hour) resulted in cell kill rates of 30.9+/-5.2% (T24), 50.7+/-2.7% (HTB9), and 25.4+/-10.6% (TccSup). The addition of as little as 25 microg/mL of ciprofloxacin increased kill rates to 78.5+/-1.2% (T24), 61.2+/-1.6% (HTB9), and 74.2+/-2.4% (TccSup); P < 0.05 relative to doxorubicin alone. Similarly, 50 microg/mL of ofloxacin significantly increased kill rates to 81.8+/-1.6% (T24), 63.3+/-2.5% (HTB9), and 67.8+/-2.0% (TccSup). Both drugs showed even greater synergism at higher concentrations.

CONCLUSIONS

Ciprofloxacin and ofloxacin exhibit significant time- and dose-dependent cytotoxicity against transitional carcinoma cells and significantly enhance the cytotoxicity of doxorubicin. These effects occur at concentrations achievable in the urine of patients after oral administration. This suggests that quinolone antibiotics might be useful as an adjunct to intravesical chemotherapy and might reduce seeding of cancer cells after transurethral resection of bladder tumors.

摘要

目的

尽管对浅表性膀胱肿瘤进行了完全经尿道切除术，但15年的复发率平均为88%。膀胱内化疗可降低复发率，尤其是在肿瘤切除后立即进行化疗。阿霉素等抗癌药物与喹诺酮类抗生素一样靶向拓扑异构酶II。我们独立评估了两种氟喹诺酮类药物，并评估了它们与阿霉素联合使用对膀胱癌细胞的体外细胞毒性作用。

方法

将三种人移行癌细胞系T24（I级）、HTB9（II级）和TccSup（IV级）分别暴露于浓度范围为0（对照）至1000μg/mL的环丙沙星或氧氟沙星中24、48和96小时。在另一项实验中，将30%细胞毒性剂量（IC30）的阿霉素应用于细胞培养物1小时，然后冲洗掉，接着将细胞暴露于环丙沙星或氧氟沙星中48和96小时。使用MTT比色法评估细胞毒性。

结果

在96小时时，环丙沙星在12.5μg/mL（HTB9、TccSup）和50μg/mL（T24）开始显示出显著的细胞毒性（P<0.05），氧氟沙星在12.5μg/mL（HTB9）和50μg/mL（TccSup、T24）开始显示出显著的细胞毒性。环丙沙星的最大细胞毒性为95.4±0.4%（HTB9，400μg/mL），氧氟沙星的最大细胞毒性为95.2±0.3%（HTB9，800μg/mL）。暴露于阿霉素（IC30，1小时）导致细胞杀伤率分别为30.9±5.2%（T24）、50.7±2.7%（HTB9）和25.4±10.6%（TccSup）。加入低至25μg/mL的环丙沙星可将杀伤率提高至78.5±1.2%（T24）、61.2±1.6%（HTB9）和74.2±2.4%（TccSup）；相对于单独使用阿霉素，P<0.05。同样，50μg/mL的氧氟沙星可将杀伤率显著提高至81.8±1.6%（T24）、63.3±2.5%（HTB9）和67.8±2.0%（TccSup）。两种药物在更高浓度下显示出更强的协同作用。