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

被引:140
作者
Maquoi, E
Sounni, NE
Devy, L
Olivier, F
Frankenne, F
Krell, HW
Grams, F
Foidart, JM
Noël, A
机构
[1] Univ Liege, Ctr Hosp Unit, Lab Tumor & Dev Biol, B-4000 Liege, Belgium
[2] Roche Diagnost GmbH, Div Pharma, Penzberg, Germany
[3] Hoffmann La Roche Ag, CH-4002 Basel, Switzerland
关键词
D O I
10.1158/1078-0432.CCR-04-0125
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页码:4038 / 4047
页数:10
相关论文
共 54 条
  • [1] Arlt M, 2002, CANCER RES, V62, P5543
  • [2] Loss of collagenase-2 confers increased skin tumor susceptibility to male mice
    Balbín, M
    Fueyo, A
    Tester, AM
    Pendás, AM
    Pitiot, AS
    Astudillo, A
    Overall, CM
    Shapiro, SD
    López-Otín, C
    [J]. NATURE GENETICS, 2003, 35 (03) : 252 - 257
  • [3] A NOVEL METALLOPROTEINASE GENE SPECIFICALLY EXPRESSED IN STROMAL CELLS OF BREAST CARCINOMAS
    BASSET, P
    BELLOCQ, JP
    WOLF, C
    STOLL, I
    HUTIN, P
    LIMACHER, JM
    PODHAJCER, OL
    CHENARD, MP
    RIO, MC
    CHAMBON, P
    [J]. NATURE, 1990, 348 (6303) : 699 - 704
  • [4] Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis
    Bergers, G
    Brekken, R
    McMahon, G
    Vu, TH
    Itoh, T
    Tamaki, K
    Tanzawa, K
    Thorpe, P
    Itohara, S
    Werb, Z
    Hanahan, D
    [J]. NATURE CELL BIOLOGY, 2000, 2 (10) : 737 - 744
  • [5] Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells
    Bisson, C
    Blacher, S
    Polette, M
    Blanc, JF
    Kebers, F
    Desreux, J
    Tetu, B
    Rosenbaum, J
    Foidart, JM
    Birembaut, P
    Noel, A
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2003, 105 (01) : 7 - 13
  • [6] Improved quantification of angiogenesis in the rat aortic ring assay
    Blacher S.
    Devy L.
    Burbridge M.F.
    Roland G.
    Tucker G.
    Noël A.
    Foidart J.-M.
    [J]. Angiogenesis, 2001, 4 (2) : 133 - 142
  • [7] CAMPION C, Patent No. 9005719
  • [8] Cancer therapy - Matrix metalloproteinase inhibitors and cancer: Trials and tribulations
    Coussens, LM
    Fingleton, B
    Matrisian, LM
    [J]. SCIENCE, 2002, 295 (5564) : 2387 - 2392
  • [9] Della Porta P, 1999, ANTICANCER RES, V19, P3809
  • [10] Deryugina EI, 2002, CANCER RES, V62, P580