Abstract
Intravesical instillation of chemotherapeutic agents is a well-established treatment strategy to decrease recurrence following transurethral resection in non-muscle invasive bladder cancer. Gemcitabine is a recently developed treatment option. However, the curative effects of gemcitabine are far from satisfactory due to de novo or acquired drug resistance. In a previous study, we reported that intravesical administration of the c-Myc inhibitor KSI-3716 suppresses tumor growth in an orthotopic bladder cancer model. Here, we explored whether KSI-3716 inhibits gemcitabine-resistant bladder cancer cell proliferation. As expected from the in vitro cytotoxicity of gemcitabine in several bladder cancer cell lines, gemcitabine effectively suppressed the growth of KU19-19 xenografts in nude mice, although all mice relapsed later. Long-term in vitro exposure to gemcitabine induced gemcitabine-specific resistance. Gemcitabine-resistant cells, termed KU19-19/GEM, formed xenograft tumors even in the presence of 2 mg/kg gemcitabine. Interestingly, KU19-19/GEM cells up-regulated c-Myc expression in the presence of the gemcitabine and resisted to the gemcitabine, however was suppressed by the KSI-3716. The sequential addition of gemcitabine and KSI-3716 inhibited gemcitabine-resistant cell proliferation to a great extent than each drug alone. These results suggest that sequential treatment with gemcitabine and KSI-3716 may be beneficial to bladder cancer patients.
Highlights
Bladder cancer is the sixth most commonly diagnosed cancer in the United States [1]
As gemcitabine is known to block DNA synthesis, flow cytometer analysis showed that a large proportion of cells in both the KU19-19 (40.19%) and T24 (28.56%) cell lines were in an apoptotic state
The proportion of cells undergoing apoptosis in the 253J and MBT-2 mouse bladder cancer cell line was relatively small (5.29% and 4.93%, respectively), a large fraction of cells were arrested in the G2/M phase (Figure 1)
Summary
80% of patients with bladder cancer present with nonmuscle invasive bladder cancer (NMIBC) initially [2, 3]. Patients are treated with a complete transurethral resection of the tumor followed by intravesical instillation of antitumor agents. Bacillus Calmette-Guerin (BCG) is the most effective adjuvant agent for treating NMIBC [4]. Approximately 30–40% of NMIBC patients do not respond to BCG treatment; of the initial responders, 35% relapse within 5 years [5]. Intravesical instillation of gemcitabine is effective against BCG-refractory NMIBC as well as advanced bladder cancer [5,6,7,8]. Several randomized trials of intravesical gemcitabine therapy demonstrate that tumor recurrence is 25–53.1% in BCGrefractory NMIBC [9]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call