In vivo evaluation of intravesical paclitaxel and combined bcl-xL antisense oligodeoxynucleotide treatment for orthotopic urothelial carcinoma

Abstract

Purpose: To evaluate intravesical paclitaxel monotherapy and combined treatment with antiapoptotic bcl-xL antisense oligodeoxynucleotides (AS-ODNs) on urothelial carcinoma (UC).

Methods: Forty-eight FoxN(rnu) athymic nude rats with orthotopic human bladder UC were randomized to four treatment groups [1, paclitaxel; 2, paclitaxel/bcl-xL AS-ODNs; 3, bcl-xL AS-ODNs (control); 4, medium (control)]. Three consecutive instillations were applied and weekly endoscopic tumor size measurements were performed.

Results: Significant tumor size reduction was achieved in groups 1 and 2 (each P < 0.0001), whereas continuous UC growth was observed in control animals (groups 3 and 4; P < 0.0001 and P < 0.0020). Complete tumor eradication was achieved in four treated animals (groups 1 and 2). No significant difference in chemoresection effects was found between groups 1 and 2 (P = 0.2251).

Conclusions: We present an in vivo evaluation of intravesical treatment with paclitaxel and combined bcl-xL AS-ODNs. Despite efficient tumor size reduction, no gain was observed when adding bcl-xL AS-ODNs in this experimental setting.

Fig. 1

a Semirigid mini-endoscope (Karl Storz, Tuttlingen, Germany, outer diameter 0.89 mm) with introduced flexible scaled wire (a–c; outer diameter 0.25 mm) via the working/irrigation channel for tumor size measurements in vivo

Fig. 2

a Bcl-xL expression (hematoxylin counterstaining, reduced from ×1,000), b transfected UMUC-3 cells after incubation with FITC-labelled oligodeoxynucleotides (reduced from ×400), c hematoxylin–eosin stained section of orthotopic human bladder with intact detrusor muscle layer (arrow) and intraluminal urothelial carcinoma with suburothelial tumor growth pattern (arrowhead, reduced from ×100), d urothelial carcinoma penetration of FITC-labelled oligodeoxynucleotides in peripheral cell layers of orthotopic human urothelial carcinoma (reduced from ×200)

Fig. 3

Body weight (grams) of experimental animals at different time points in the 4 treatment groups

Fig. 4

Results from urine strip analyses in the different intravesical treatment groups at different time points [a = group 1, paclitaxel; b = group 2, paclitaxel/bcl-xL AS-ODNs; c = group 3, bcl-xL AS-ODNs (control); d = group 4, essential medium (control)]

Fig. 5

Tumor size (cm) at different time points in the 4 treatment groups. Note the tumor size decrease in groups 1 and 2, whereas net tumor growth was observed in groups 3 and 4

Fig. 6

a Bladder and sectioned kidney (b) from a treated animal in group 2 in which complete tumor eradication was achieved after 2 instillations. Tumor-bearing bladder (c) from an untreated animal in group 4 with renal pelvis tumor (d) on necropsy