Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimidine-2,4,6-trione derivative, an orally active and selective matrix metalloproteinases inhibitor.

Abstract

PURPOSE:

The implication of matrix metalloproteinases (MMPs) in the major stages of cancer progression has fueled interest in the design of synthetic MMP inhibitors (MMPIs) as a novel anticancer therapy. Thus far, drugs used in clinical trials are broad-spectrum MMPIs the therapeutic index of which proved disappointingly low. The development of selective MMPIs for tumor progression-associated MMPs is, thus, likely to offer improved therapeutic possibilities.

EXPERIMENTAL DESIGN:

The anti-invasive capacity of a series of pyrimidine-trione derivatives was tested in vitro in a chemoinvasion assay, and the most potent compound was further evaluated in vivo in different human tumor xenograft models. The activity of this novel selective MMPI was compared with BB-94, a broad-spectrum inhibitor.

RESULTS:

Ro-28-2653, an inhibitor with high selectivity for MMP-2, MMP-9, and membrane type 1 (MT1)-MMP, showed the highest anti-invasive activity in vitro. In vivo, Ro-28-2653 reduced the growth of tumors induced by the inoculation of different cell lines producing MMPs and inhibited the tumor-promoting effect of fibroblasts on breast adenocarcinoma cells. Furthermore, Ro-28-2653 reduced tumor vascularization and blocked angiogenesis in a rat aortic ring assay. In contrast, BB-94 up-regulated MMP-9 expression in tumor cells and promoted angiogenesis in the aortic ring assay.

CONCLUSION:

Ro-28-2653, a selective and orally bioavailable MMPI with inhibitory activity against MMPs expressed by tumor and/or stromal cells, is a potent antitumor and antiangiogenic agent. In contrast to broad-spectrum inhibitors, the administration of Ro-28-2653 was not associated with the occurrence of adverse side effects that might hamper the therapeutic potential of these drugs.

• Authors: Erik Maquoi, Nor Eddine Sounni, Laetitia Devy, Fabrice Olivier, Francis Frankenne, Hans-Willi Krell, Frank Grams, Jean-Michel Foidart, Agnès Noël
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 12 Pt 1 Pg. 4038-47 (Jun 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15217936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA, Complementary
• Enzyme Inhibitors
• Matrix Metalloproteinase Inhibitors
• Piperazines
• Protease Inhibitors
• Pyrimidines
• Ro 28-2653
• Thiophenes
• Phenylalanine
• batimastat
• Matrix Metalloproteinase 2

Topics

• Adenocarcinoma (drug therapy)
• Administration, Oral
• Animals
• Antineoplastic Agents (pharmacology)
• Aorta (pathology)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• DNA, Complementary (metabolism)
• Disease Progression
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (metabolism)
• Humans
• Inhibitory Concentration 50
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase Inhibitors
• Microscopy, Fluorescence
• Models, Chemical
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Phenylalanine (analogs & derivatives, pharmacology)
• Piperazines (pharmacology)
• Protease Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Thiophenes (pharmacology)
• Time Factors
• Up-Regulation