Induction of apoptosis by mitomycin-C in an ex vivo model of bladder cancer.
OBJECTIVE
To examine mitomycin-C (MMC)-induced apoptosis in an ex vivo model of superficial TCC, and relate it to the in vivo response to chemotherapy. Materials and methods Dose- and time-response curves were constructed to determine the optimal conditions for the induction of apoptosis by MMC in an ex vivo model of superficial bladder cancer. Subsequently, 41 individual tumours were exposed to MMC in the model and the effects assessed by measuring of apoptosis before and after chemotherapy. The relationships between tumour grade and stage and the intrinsic and induced apoptotic counts were determined. In tandem, in a clinical study, the relationship between in vivo response of a marker tumour to MMC and the ex vivo induction of apoptosis was determined.


RESULTS
In the ex vivo model, apoptosis was induced at a MMC concentration of 0.5 mg/mL after an incubation time of 8 h. In 41 tumours the intrinsic apoptotic index (AI) was higher with increased grade and stage of tumour (P = 0.048). There was no correlation between the intrinsic AI and the AI after treatment with MMC (induced AI). In 21 tumours (51%) the induced AI did not increase above a predetermined response threshold and these tumours were considered resistant to MMC. Resistance to MMC was related to tumour grade (P = 0.037) with a trend for G3 pT1 tumours to be resistant to the therapy. There was a significant association between ex vivo sensitivity and in vivo marker tumour response (P = 0.02).


CONCLUSIONS
Apoptosis is differentially induced in an ex vivo incubation model of superficial TCC by MMC and evidence suggests that this response matches that seen in vivo. The measurement of apoptosis before therapy does not predict the apoptotic response of a tumour to chemotherapy. The ability to undergo apoptosis correlates with clinical outcome.
Kelly
J D
JD
Department of Urology, Belfast City Hospital, Belfast, N. Ireland, UK. jdk2002@mail.med.cornell.edu
Williamson
K E
KE
Weir
H P
HP
McManus
D T
DT
Hamilton
P W
PW
Keane
P F
PF
Johnston
S R
SR
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016685:Mitomycin / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology
D000903:Antibiotics, Antineoplastic; D016685:Mitomycin