Polyamine depletion by ODC-AdoMetDC antisense adenovirus impairs human colorectal cancer growth and invasion in vitro and in vivo.
BACKGROUND
Polyamine biosynthesis is controlled primarily by ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC). Polyamine concentrations are elevated in colorectal cancer. Depletion of polyamine content in colorectal cancer by chemotherapy is related to tumor regression and impaired tumorigenicity. The current study evaluates the therapeutic effects of antisense ODC and AdoMetDC sequences on colorectal cancer in vitro and in vivo.


METHODS
Antisense ODC and AdoMetDC sequences were cloned into an adenoviral vector (Ad-ODC-AdoMetDCas). The human colon cancer cell lines, HT-29 and Caco-2, were infected with Ad-ODC-AdoMetDCas as well as with control vector. Viable cell counting, determination of polyamine concentrations, cell cycle analysis, and Matrigel invasion assays were performed in order to assess properties of tumor growth and invasiveness. Furthermore, the antitumor effects of Ad-ODC-AdoMetDCas were also evaluated in vivo in a nude mouse tumor model.


RESULTS
Our study demonstrated that adenovirus-mediated ODC and AdoMetDC antisense expression inhibits tumor cell growth through a blockade of the polyamine synthesis pathway. This inhibitory effect cannot be reversed by the administration of putrescine. Tumor cells were arrested at the G1 phase of the cell cycle after gene transfer and had reduced invasiveness. The adenovirus also induced tumor regression in established tumors in nude mice.


CONCLUSIONS
Our study suggests that Ad-ODC-AdoMetDCas has antitumor activity and therapeutic potential for the treatment of colorectal cancer.
Zhang
Bing
B
Institute of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan 250012, China.
Liu
Xian-xi
XX
Zhang
Yan
Y
Jiang
Chun-ying
CY
Hu
Hai-yan
HY
Gong
Lei
L
Liu
Min
M
Teng
Qing-shan
QS
D012437:Adenosylmethionine Decarboxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003587:Cytomegalovirus / Q000235:genetics; D000229:Dependovirus / Q000145:classification / Q000235:genetics; D005069:Evaluation Studies as Topic; D005164:Factor IX / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008156:Luciferases / Q000235:genetics; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D009955:Ornithine Decarboxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism; D012703:Serotyping; D012737:Sex Factors; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes; D001616:beta-Galactosidase / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D011073:Polyamines; D005164:Factor IX; D008156:Luciferases; D001616:beta-Galactosidase; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase