Prolonged survival of mice with multiple liver metastases of human colon cancer by intravenous administration of replicable E1B-55K-deleted adenovirus with E1A expressed by CEA promoter.
Liver is the most preferential site for metastasis of colon cancer. We, in the present study, constructed a self-replicable adenovirus in which E1A is driven by a CEA promoter and E1B-55K is deleted from the E1B region (AdCEAp/Rep) and examined its effects on multiple metastases of a human colon cancer cell in a mouse xenograft model. We first showed effective replication of the virus in various CEA-producing human colon cancer cells (M7609, HT-29) and subsequent lysis of the infected cells in vitro. We then demonstrated that a single intratumoral injection of the virus (1 x 10(8) PFU/100 microl) induced a complete regression of subcutaneous tumors (M7609) inoculated into nude mice. Further, we demonstrated that systemic administration of the virus (1 x 10(8) PFU/100 microl) through the tail vein to nude mice, which 1 week prior had been inoculated with tumor cells (colon carcinoma cell line HT-29) via the spleen and showed apparent multiple metastases in the liver, effectively suppressed the metastasis formation. The mean survival time of the treated mice was significantly longer than that of the controls. Thus, the systemic administration of AdCEAp/Rep was considered to be effective on multiple liver metastases of CEA-positive colon cancer in a xenograft model.
Sagawa
Tamotsu
T
Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
Takahashi
Minoru
M
Sato
Tsutomu
T
Sato
Yasushi
Y
Lu
Yue
Y
Sumiyoshi
Tetsuya
T
Yamada
Yasuyuki
Y
Iyama
Satoshi
S
Fukaura
Junki
J
Sasaki
Katsunori
K
Hamada
Hirofumi
H
Miyanishi
Koji
K
Takayama
Tetsuji
T
Kato
Junji
J
Niitsu
Yoshiro
Y
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D017501:Adenovirus E1B Proteins / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D015316:Genetic Therapy; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D051379:Mice; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary / Q000628:therapy; D015996:Survival Rate; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D002272:Carcinoembryonic Antigen