Immunohistochemical analysis of Ki-67, p21waf1/cip1 and apoptosis in marker lesions from patients with superficial bladder tumours treated with vinorelbine intravesical therapy in a preliminary phase I trial.
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.


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.


CONCLUSIONS
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.
Bonfil
R D
RD
Laboratory of Fundación de Investigación del Cáncer at CEFYBO, Buenos Aires, Argentina. fundic@velocom.com.ar
Gonzalez
A D
AD
Siguelboim
D
D
Cuello Carrion
F D
FD
Ciocca
D R
DR
Villaronga
A
A
Metz
L
L
Mosso
F
F
Fayad
E
E
Reale
M
M
Schmilovich
A J
AJ
D000283:Administration, Intravesical; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001706:Biopsy / Q000379:methods; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014747:Vinblastine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D000077235:Vinorelbine
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D014747:Vinblastine; D000077235:Vinorelbine