title: Recovery of urothelial mediator release but prolonged elevations in interleukin-8 and nitric oxide secretion following mitomycin C treatment.
abstract: Intravesical mitomycin C (MMC) is commonly used to treat bladder cancer but is associated with local adverse effects. Here, we investigate the effects of MMC on release of urothelial mediators and production of inflammatory cytokines. Recovery and the effects of repeat treatment were also investigated. Urothelial cells were treated with MMC for 2 h at 37 °C. Immediately, 24 h and 7 days following MMC treatment, effects were assessed in terms of changes in ATP, acetylcholine and PGE2 release, and the presence of inflammatory cytokines and nitric oxide in incubation medium. Endpoints were also assessed 7 days after repeat MMC treatment. Immediately following MMC treatment at the clinical concentration (2 mg/mL), stretch-induced ATP release was significantly decreased, basal acetylcholine release was enhanced, while basal PGE2 was depressed and response to stretch increased. Twenty-four hours after treatment, basal acetylcholine was significantly increased ([MMC] ≥0.0002 mg/mL) and basal PGE2 enhanced (0.02 mg/mL). A 326-fold increase in interleukin-8 secretion and significant increase in nitric oxide release were also detected at 24 h. One week after single and repeat MMC treatment, urothelial ATP, acetylcholine and PGE2 had recovered while the increase in nitric oxide and interleukin-8 was still evident. These results indicate that urothelial mediator release is affected by MMC treatment with full recovery by 1 week. However, a concurrent increase in secretion of the inflammatory cytokine interleukin-8 and nitric oxide was also detected 24 h following treatment, which were still evident after the recovery period. These changes may play a role in the local adverse effects associated with intravesical MMC treatment.
authors: Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, 4229, Australia.
authors: Sung Hyun
authors: SH
authors: Kang
authors: Russ
authors: R
authors: Chess-Williams
authors: Shailendra
authors: S
authors: Anoopkumar-Dukie
authors: Catherine
authors: C
authors: McDermott
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D016685:Mitomycin / Q000009:adverse effects / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D013997:Time Factors; D019459:Urothelium / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D018836:Inflammation Mediators; D016209:Interleukin-8; D009569:Nitric Oxide; D016685:Mitomycin
references: Invest Ophthalmol Vis Sci. 2007 May;48(5):2009-16
references: 17460254
references: Neurourol Urodyn. 2010;29(1):107-11
references: 20025014
references: Acta Urol Belg. 1996 Mar;64(1):47-53
references: 8659335
references: Neurourol Urodyn. 2010 Apr;29(4):598-602
references: 20432319
references: Cancer Res. 1991 Aug 15;51(16):4347-54
references: 1907883
references: Urology. 2000 Feb;55(2):161-8
references: 10688071
references: Urol Clin North Am. 1992 Aug;19(3):529-39
references: 1636237
references: Cancer Res. 1991 Oct 1;51(19):5144-52
references: 1913640
references: Am J Physiol. 1998 Aug;275(2 Pt 2):F226-9
references: 9691011
references: Nature. 2000 Oct 26;407(6807):1011-5
references: 11069181
references: Auton Neurosci. 2005 Oct 30;122(1-2):9-20
references: 16125470
references: BJU Int. 2012 Dec;110 Suppl 4:12-21
references: 23194118
references: Am J Physiol Renal Physiol. 2007 Mar;292(3):F1065-72
references: 17107944
references: Am J Physiol Renal Physiol. 2008 Apr;294(4):F971-81
references: 18272602
references: Life Sci. 1991;48(25):2429-36
references: 1675415
references: BJU Int. 2002 Jun;89(9):942-9
references: 12010245
references: Kidney Int. 2007 Nov;72(9):1057-64
references: 17667988
references: J Urol. 2006 Jun;175(6):2004-10
references: 16697786
references: Neurosci Lett. 2010 Jun 21;477(2):91-4
references: 20417249
references: Biomed Res. 2009 Dec;30(6):343-7
references: 20051643
references: Br J Pharmacol. 2008 Apr;153(7):1438-44
references: 18246091
references: Eur J Pharmacol. 2013 Jan 30;700(1-3):102-9
references: 23219793
references: PLoS One. 2011;6(6):e20792
references: 21674053
references: Cancer Res. 1993 Jul 15;53(14):3314-20
references: 8324743
references: Life Sci. 2007 May 30;80(24-25):2298-302
references: 17363007
references: Biomed Res Int. 2014;2014:359179
references: 24982868
references: J Urol. 2011 Jan;185(1):341-6
references: 21075387
references: Nature. 2000 Oct 26;407(6807):1015-7
references: 11069182
references: Neurourol Urodyn. 2010 Jun;29(5):771-6
references: 19816919
references: BJU Int. 2004 Apr;93(6):851-8
references: 15050004
references: Br J Cancer. 2003 Jul 21;89(2):357-62
references: 12865930
references: Urol Res. 1997;25(1):31-4
references: 9079743
references: Urology. 2002 May;59(5 Suppl 1):61-7
references: 12007524
references: J Urol. 2014 Nov;192(5):1564-8
references: 24813342
references: J Urol. 2007 Oct;178(4 Pt 1):1533-6
references: 17707056
references: Am J Physiol Regul Integr Comp Physiol. 2009 May;296(5):R1661-70
references: 19279288
references: BJU Int. 2011 Jan;107(2):192-204
references: 21208364
references: Eur J Pharmacol. 1988 Jan 12;145(2):105-12
references: 3162418
references: Urology. 1999 Aug;54(2):264-7
references: 10443722
references: Urol Clin North Am. 2000 Feb;27(1):125-35, x
references: 10696251
references: BJU Int. 2007 Aug;100(2):419-29
references: 17617145
references: J Urol. 2012 Mar;187(3):1087-93
references: 22266010
references: Eur Urol. 2012 Nov;62(5):797-802
references: 22633362
references: Biomed Res Int. 2014;2014:830374
references: 24829920
references: Nitric Oxide. 2012 Oct 15;27(3):185-91
references: 22819699
references: BJU Int. 2014 May;113(5b):E34-8
references: 24053461
references: Auton Neurosci. 2010 Feb 16;153(1-2):33-40
references: 19666243
references: Biomed Res Int. 2014;2014:182862
references: 24839598
references: Eur J Pharmacol. 2012 Jan 15;674(2-3):445-9
references: 22119378
references: Neurourol Urodyn. 2012 Jan;31(1):185-9
references: 21953769
references: Eur Urol. 2011 Feb;59(2):264-71
references: 21067861
references: Am J Physiol Renal Physiol. 2005 Sep;289(3):F489-95
references: 16093424
references: Urology. 1996 Nov;48(5):700-2
references: 8911512
references: Front Pharmacol. 2011 Jun 07;2:27
references: 21713125
references: J Urol. 2004 Mar;171(3):1148-50; discussion 50-1
references: 14767289
references: Int J Urol. 2003 Oct;10 Suppl:S49-55
references: 14641415
references: Eur Urol. 2010 Jun;57(6):1087-92
references: 20022422