Immunohistochemical analysis of Ki-67, p21Waf1/Cip1 and apoptosis in marker lesions from patients with superficial bladder tumors treated with vinorelbine intravesical therapy in preliminary phase I trial

BONFIL R. D.; GONZALEZ A. D.; SIGUELBOIM D.; CUELLO CARRIÓN F. D.; CIOCCA D. R.; VILLARONGA A.; METZ L.; MOSSO F.; FAYAD E.; REALE M.; SCHMILOVICH A. J.

BRITISH JOURNAL OF UROLOGY

JOHN WILEY & SONS, INC.

Lugar: New Jersey; Año: 2001 vol. 88 p. 425 - 431

0007-1331

Objective: To investigate Ki-67 and p21Waf1/Cip1 expression and apoptosis, before and after treatment, in tumour biopsies obtained from patients with superficial bladder cancer who underwent vinorelbine intravesical therapy. Patients and methods: Twenty patients with high-risk superficial bladder cancer (including one or more of the following parameters: tumour diameter >3 cm, histological grade 3, or multicentric tumours) were treated 1 ± 6 times (weekly) with intravesical vinorelbine (50 mg/mL) instillations. Transurethral tumour marker biopsies were obtained one week before the first instillation of the drug and one week after the last. The biopsies were immunostained for Ki-67 and p21Waf1/Cip1 with monoclonal antibodies, on tissue sections derived from paraffin-embedded samples obtained before and after vinorelbine treatments. In addition, apoptosis was determined using a terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labelling (TUNEL) technique. Results: There were no significant differences in the cell proliferation marker Ki-67 in biopsies taken before or after treatment. However, p21Waf1/Cip1 showed significantly higher expression in biopsies obtained after vinorelbine treatment, with median (range) values of 40 (20 ± 90)% before and 70 (50 ± 80)% after (P<0.001, paired nonparametric Wilcoxon test). The apoptotic index was significantly higher after vinorelbine therapy, with median (range) values of 0.89 (0.06 ± 3.8)% before and 2.25 (0.17 ± 18.7)% after treatment (P<0.001, paired nonparametric Wilcoxon test). Despite the brief treatment and few patients there was a clinical response in nine patients, together with low toxicity in all. Conclusion: The intravesical treatment of tumours with vinorelbine affects p21Waf1/Cip1 expression without blocking cell proliferation, although increasing apoptosis. The preliminary results suggest that vinorelbine may be useful for treating superficial bladder tumours, and thus a phase II study is warranted.