Bond Urology Group, Faculty of Health Sciences and Medicine, Bond University, QLD, Australia.
Eur J Pharmacol. 2013 Jan 30;700(1-3):102-9. doi: 10.1016/j.ejphar.2012.11.053. Epub 2012 Dec 5.
Intravesical treatment with cytotoxic drugs such as doxorubicin is associated with local adverse effects in bladder cancer patients. Here we investigate the effects of doxorubicin on urothelial release of ATP, acetylcholine and prostaglandin E(2), and production of inflammatory cytokines. Urothelial cells were treated with doxorubicin for 1h at 37 °C. Immediately or 24 h following treatment the level of ATP, acetylcholine and prostaglandin E(2) released under basal and stimulated conditions was measured and compared to release from vehicle treated control cultures. The presence of inflammatory cytokines, in culture medium was also assessed 24 h after doxorubicin pre-treatment. Immediately following treatment, stimulated ATP release was inhibited at doxorubicin concentrations ≥1 μg/ml and showed partial recovery at 24 h. Immediately following treatment, basal acetylcholine release was increased by doxorubicin at its clinical concentration (1 mg/ml), while a concentration-dependent decrease in stimulated acetylcholine release was observed. Twenty four hour after treatment, basal acetylcholine release was increased in culture treated with 0.01 mg/ml doxorubicin while stimulated acetylcholine release remained depressed. A significant increase in prostaglandin E(2) release was observed in cells immediately and 24 h after treatment with doxorubicin. A 5.5- and 2-fold increase in interleukin -8 and -1β secretion, respectively was detected 24 h following doxorubicin treatment. These findings indicate that inflammatory cytokines interleukin-8 and -1β are induced and urothelial mediator release is affected by treatment with doxorubicin at clinically relevant concentrations and durations of treatment. These changes may play a role in the adverse effects associated with intravesical doxorubicin treatment.
膀胱内给予多柔比星等细胞毒性药物治疗与膀胱癌患者的局部不良反应有关。在这里，我们研究了多柔比星对尿路上皮细胞释放 ATP、乙酰胆碱和前列腺素 E2 以及炎症细胞因子产生的影响。将尿路上皮细胞在 37°C 下用多柔比星处理 1 小时。在处理后立即或 24 小时，测量并比较基础和刺激条件下释放的 ATP、乙酰胆碱和前列腺素 E2 的水平，以及药物处理对照培养物释放的水平。还在多柔比星预处理 24 小时后评估培养基中炎症细胞因子的存在。处理后立即，刺激的 ATP 释放被浓度≥1μg/ml 的多柔比星抑制，并在 24 小时后部分恢复。处理后立即，基础乙酰胆碱释放被多柔比星在其临床浓度（1mg/ml）增加，而观察到刺激的乙酰胆碱释放浓度依赖性降低。治疗 24 小时后，在接受 0.01mg/ml 多柔比星治疗的培养物中，基础乙酰胆碱释放增加，而刺激的乙酰胆碱释放仍然受到抑制。在处理后立即和 24 小时观察到前列腺素 E2 释放显著增加。处理 24 小时后，检测到白细胞介素-8 和-1β 的分泌分别增加了 5.5 倍和 2 倍。这些发现表明，炎症细胞因子白细胞介素-8 和-1β 被诱导，并且在临床相关浓度和治疗持续时间下用多柔比星治疗会影响尿路上皮介质的释放。这些变化可能在与膀胱内多柔比星治疗相关的不良反应中发挥作用。
