Intravesical Ad-IFNalpha causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-alpha protein.
We have produced prolonged, high local concentrations of interferon in vivo by intravesical instillation of adenoviruses encoding interferon-alpha (Ad-IFNalpha) together with the gene transfer-enhancing agent Syn3. We found sustained interferon protein levels for days, both in normal mouse urothelium and in human bladder cancer cells growing as superficial bladder tumors in nude mice using an orthotopic bladder model developed by us. Tumor burden in the bladder was determined utilizing cancer cells containing the green fluorescent protein. Marked tumor regression was observed following two 1-h exposures of Ad-IFNalpha/Syn3 and little or no cytotoxicity was detected in normal cells. Similar intravesical instillation of clinically relevant concentrations of IFN protein alone or Ad-IFNalpha without Syn3 was ineffective. Surprisingly, in vitro, Ad-IFNalpha also caused caspase-dependent death of bladder cancer cell lines that were resistant to high concentrations of IFN-alpha protein, including the cell line used in vivo. These findings demonstrate that Ad-IFNalpha can overcome resistance to IFN-alpha protein both in vitro and in vivo and support evaluation of intravesical Ad-IFNalpha/Syn3 for the treatment of superficial bladder cancer.
Benedict
William F
WF
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. wbenedic@mdanderson.org
Tao
Ziming
Z
Kim
Chang-Soo
CS
Zhang
Xinqiao
X
Zhou
Jain-Hua
JH
Adam
Liana
L
McConkey
David J
DJ
Papageorgiou
Angela
A
Munsell
Mark
M
Philopena
Jennifer
J
Engler
Heidrun
H
Demers
William
W
Maneval
Daniel C
DC
Dinney
Colin P N
CP
Connor
Robert J
RJ
D000256:Adenoviridae / Q000235:genetics*; D000283:Administration, Intravesical; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D004351:Drug Resistance; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007120:Immunochemistry; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000235:genetics* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009757:Nylons / Q000494:pharmacology; D011994:Recombinant Proteins; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009757:Nylons; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D020169:Caspases