Downregulation of matrix metalloprotease-9 and urokinase plasminogen activator by TX-1877 results in decreased tumor growth and metastasis on xenograft model of rectal cancer.
OBJECTIVE
It is well known that hypoxic milieu is the primary cancer environment. Therefore, tumor hypoxia is considered to be a potential therapeutic target. In the present study, we investigated the antitumor and antimetastatic effect of hypoxic cell radiosensitizer, TX-1877 on xenograft model of rectal cancer.


METHODS
Nude mice bearing subcutaneously or orthotopically implanted human colon cancer cell lines HCT-116 and HT-29 were treated with TX-1877, irradiation or TX-1877 with irradiation. Tumor volume, survival, expression of matrix metalloproteinase (MMP)-2, MMP-7, MMP-9 and urokinase-type plasminogen activator (uPA) and incidence of lymph node metastasis were evaluated in treatment versus control group.


RESULTS
In subcutaneous model, tumor treated with TX-1877 and irradiation showed significant reductions in volume (P < 0.05 vs. control, TX-1877 or irradiation group). Quantitative real-time reverse transcription-PCR and immunohistochemical analysis revealed that TX-1877 significantly inhibited expression of the MMP-9 and uPA. These treatments also inhibited the para-aortic lymph node metastasis, however, did not prolong the survival in orthotopic model.


CONCLUSIONS
These data show that the treatment of TX-1877 with irradiation decreased growth of human rectal cancer and, furthermore, suppressed lymph node metastasis.
Miyake
Kotaro
K
Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. kota166@clin.med.tokushima-u.ac.jp
Shimada
Mitsuo
M
Nishioka
Masanori
M
Sugimoto
Koji
K
Batmunkh
Erdenebulgan
E
Uto
Yoshihiro
Y
Nagasawa
Hideko
H
Hori
Hitoshi
H
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D000860:Hypoxia; D008207:Lymphatic Metastasis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D051381:Rats; D012004:Rectal Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
C115855:2-nitroimidazole acetamide; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D014568:Urokinase-Type Plasminogen Activator; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9