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.

Abstract

PURPOSE:

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.

• Authors: Kotaro Miyake, Mitsuo Shimada, Masanori Nishioka, Koji Sugimoto, Erdenebulgan Batmunkh, Yoshihiro Uto, Hideko Nagasawa, Hitoshi Hori
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 64 Issue 5 Pg. 885-92 (Oct 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19214512 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-nitroimidazole acetamide
• Nitroimidazoles
• Radiation-Sensitizing Agents
• Urokinase-Type Plasminogen Activator
• Matrix Metalloproteinase 7
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Female
• Humans
• Hypoxia
• Lymphatic Metastasis
• Matrix Metalloproteinase 2 (biosynthesis)
• Matrix Metalloproteinase 7 (biosynthesis)
• Matrix Metalloproteinase 9 (biosynthesis, genetics)
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Nitroimidazoles (therapeutic use)
• Radiation-Sensitizing Agents (therapeutic use)
• Rats
• Rectal Neoplasms (pathology, radiotherapy)
• Reverse Transcriptase Polymerase Chain Reaction
• Urokinase-Type Plasminogen Activator (biosynthesis, genetics)
• X-Rays
• Xenograft Model Antitumor Assays