Inhibition of tumor growth and metastasis with antisense oligonucleotides (Cantide) targeting hTERT in an in situ human hepatocellular carcinoma model.
OBJECTIVE
To evaluate the in vivo antitumor effects of Cantide and the combined effect with 5-fluorouracil.


METHODS
An in situ human hepatocellular carcinoma model was established in mice livers orthotopically. Drugs were administered intravenously and tumor sizes were monitored with calipers. Plasma alpha-fetoprotein(AFP) were detected by radiation immunoassay. Morphology of tumors was evaluated by hematoxylin-eosin (H and E) staining of histological sections. Human telomerase reverse transcriptase (hTERT) protein levels were detected by Western blotting.


RESULTS
Cantide significantly inhibit in situ human hepatocellular carcinoma growth in mice with a 75 and 50 mg.kg(-1).d(-1) administration of Cantide compared to the saline group in a dose-dependent manner, which included injecting Cantide 25 mg.kg(-1).d(-1) by iv for 20 d after surgically removing the tumor in liver. Cantide was also found to prevent tumor recurrence in the liver and metastasis in the lung, showing a dose-dependent response. When Cantide was administered by iv combined with 5-fluorouracil, it resulted in a significant reduction in tumor growth compared to either agent alone treatment group. After the treatment with Cantide alone or combined with 5-fluorouracil, plasma AFP concentration decreased in a dose-dependent manner.


CONCLUSIONS
These results demonstrated that Cantide was an effective antitumor antisense oligonucleotide in vivo and has the potential to be developed into a clinical anti-cancer drug.
Lin
Ru-xian
RX
Beijing Institute of Radiation Medicine, Beijing 100850, China, 3Department of Pathology, PLA 202 Hospital, Shenyang 110001, China.
Tuo
Chao-wei
CW
Lü
Qiu-jun
QJ
Zhang
Wei
W
Wang
Sheng-qi
SQ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000097:blood / Q000473:pathology*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D009368:Neoplasm Transplantation; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D054735:Phosphorothioate Oligonucleotides; D019098:Telomerase / Q000235:genetics*; D000509:alpha-Fetoproteins / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020320:Oligoribonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D000509:alpha-Fetoproteins; C478563:cantide; D019098:Telomerase; D005472:Fluorouracil