Treatment of prostate cancer with Ad5/3Delta24hCG allows non-invasive detection of the magnitude and persistence of virus replication in vivo.
Hormone refractory metastatic prostate cancer is a deadly disease that currently lacks curative treatments. Conditionally replicating adenoviruses (CRAds) are promising new agents against cancer due to their innate capability to cause oncolysis of tumor cells. Their antitumor effect is determined in part by their capacity for infecting cancer cells. However, the respective primary receptor, the coxsackie-adenovirus receptor (CAR), is variably expressed in many cancer types. We created Ad5/3Delta24hCG, a novel CRAd retargeted to the adenovirus serotype 3 receptor, which has been reported to be highly expressed in tumors. Furthermore, we added a transgene for the beta-chain of human chorionic gonadotropin (hCGbeta), whose expression was tightly coupled to virus replication. Ad5/3Delta24hCG was found effective in killing prostate cancer cells, and oncolysis was seen in concordance with hCGbeta production. In a s.c. in vivo model of hormone refractory prostate cancer, Ad5/3Delta24hCG treatment resulted in statistically significant tumor growth inhibition. Moreover, i.v. injection of Ad5/3Delta24hCG prolonged the survival of mice with hormone refractory prostate cancer metastatic to the lung. Detection of hCGbeta in serum samples confirmed viral replication in vivo. Infection of human clinical samples of cancerous and normal prostatic tissue resulted in effective hCGbeta production in cancer tissue, whereas it remained low in nonmalignant tissue, suggesting cancer-specific replication. These results suggest that Ad5/3Delta24hCG is a potent virus for the treatment of hormone refractory prostate cancer in vitro and in vivo. These preclinical data set the stage for translation into clinical studies.
Rajecki
Maria
M
Molecular Cancer Biology Program, Department of Oncology, University of Helsinki, P.O. Box 63, (Haartmaninkatu 8), Helsinki 00014, Finland.
Kanerva
Anna
A
Stenman
Ulf-Håkan
UH
Tenhunen
Mikko
M
Kangasniemi
Lotta
L
Särkioja
Merja
M
Ala-Opas
Martti Y
MY
Alfthan
Henrik
H
Sankila
Anna
A
Rintala
Erkki
E
Desmond
Renee A
RA
Hakkarainen
Tanja
T
Hemminki
Akseli
A
D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000235:genetics / Q000494:pharmacology*; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004279:DNA, Viral / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000821:virology; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy* / Q000821:virology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000378:metabolism; D050130:Oncolytic Virotherapy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D011991:Receptors, Virus / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D006063:Chorionic Gonadotropin; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004279:DNA, Viral; D009842:Oligopeptides; D011991:Receptors, Virus; C047981:arginyl-glycyl-aspartic acid