In vivo biological purging for lymph node metastasis of human colorectal cancer by telomerase-specific oncolytic virotherapy.
OBJECTIVE
The aim of this study was to develop a less invasive way of targeting lymph node metastasis for the treatment of human gastrointestinal cancer. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with malignancies.


METHODS
Human telomerase reverse transcription (hTERT) is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. OBP-301 (Telomelysin) is an attenuated adenovirus with oncolytic potency that contains the hTERT promoter element to regulate viral replication. We examined whether OBP-301 injected into the primary tumor might be useful for purging micrometastasis from regional lymph nodes in an orthotopic colorectal cancer model.


RESULTS
OBP-301 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice. By using a highly sensitive quantitative PCR analysis that targets the human-specific Alu sequence, we showed that OBP-301 caused viral spread into the regional lymphatic area and selectively replicated in neoplastic lesions, resulting in tumor-cell-specific death in metastatic lymph nodes. Moreover, although the surgical removal of primary tumors increased the tendency of lymph node metastasis, preoperative intratumoral injection of virus significantly reduced lymph node metastasis.


CONCLUSIONS
Our results indicate that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human cancer, especially gastrointestinal malignancies.
Kojima
Toru
T
Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Watanabe
Yuichi
Y
Hashimoto
Yuuri
Y
Kuroda
Shinji
S
Yamasaki
Yasumoto
Y
Yano
Shuya
S
Ouchi
Masaaki
M
Tazawa
Hiroshi
H
Uno
Futoshi
F
Kagawa
Shunsuke
S
Kyo
Satoru
S
Mizuguchi
Hiroyuki
H
Urata
Yasuo
Y
Tanaka
Noriaki
N
Fujiwara
Toshiyoshi
T
D020087:Alu Elements / Q000235:genetics; D000818:Animals; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy*; D019073:HT29 Cells; D006801:Humans; D015552:Injections, Intralesional; D008198:Lymph Nodes / Q000821:virology; D008207:Lymphatic Metastasis / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses; D016133:Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics*
C509186:TERT protein, human; D019098:Telomerase