A conditional replication-competent adenoviral vector, Ad-OC-E1a, to cotarget prostate cancer and bone stroma in an experimental model of androgen-independent prostate cancer bone metastasis

Citation
S. Matsubara et al., A conditional replication-competent adenoviral vector, Ad-OC-E1a, to cotarget prostate cancer and bone stroma in an experimental model of androgen-independent prostate cancer bone metastasis, CANCER RES, 61(16), 2001, pp. 6012-6019
Citations number
73
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
61
Issue
16
Year of publication
2001
Pages
6012 - 6019
Database
ISI
SICI code
0008-5472(20010815)61:16<6012:ACRAVA>2.0.ZU;2-N
Abstract
Prostate cancer has a high propensity to metastasize to bone, which often r esists hormone, radiation, and chemotherapies. Because of the reciprocal na ture of the prostate cancer and bone stroma interaction, we designed a cota rgeting strategy using a conditional replication-competent adenovirus to ta rget the growth of tumor cells and their associated osteoblasts. The recomb inant Ad-OC-Ela was constructed using a noncollagenous bone matrix protein osteocalcin (OC) promoter to drive th, viral early Ela gene with restricted replication in cells that express OC transcriptional activity. Unlike Ad-P SE-Ela, Ad-OC-Ela was highly efficient in inhibiting the growth of PSA-prod ucing (LNCaP, C4-2, and ARCaP) and nonproducing (PC-3 and DU145) human pros tate cancer cell lines. This virus was also found to effectively inhibit th e growth of human osteoblasts and human prostate stromal cells in vitro. At hymic mice bearing s.c. androgen receptor-negative and PSA-negative PC-3 xe nografts responded to a single intratumoral administration of 2 x 10(9) pla que-forming unit(s) of Ad-OC-Ela. In SCID/bg mice, intraosseous growth of a ndrogen receptor-positive and PSA-producing C4-2 xenografts responded marke dly to Lv. administrations of a single dose of Ad-OC-E Ia. One hundred perc ent of the treated mice responded to this systemic Ad-OC-Ela therapy with a decline of serum PSA to an undetectable level, and 80% of the mice with PS A rebound responded to the second dose of systemic Ad-OC-Ela. Forty percent of the mice were found to be cured by systemic Ad-OC-Ela without subsequen t PSA rebound or tumor cells found in the skeleton. This cotargeting strate gy shows a broader spectrum and appears to be more effective than systemic Ad-PSE-Eta in preclinical models of human prostate cancer skeletal metastas is.