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Chemical Compound Review:

AG-E-80397 (2S)-3,3-dimethyl-2- methylamino-N-[(2S)-4...

Synonyms: AC1L3WNB, CID148203, CTK4F6732, DCL000003, BMS 275291, ...

Leighl, N.B. et al., Naglich, J.G. et al., Rizvi, N.A. et al., Douillard, J.Y. et al., Lara, P.N. et al., et al.

Miller, Saphner, Waterhouse, Chen, Rush-Taylor, Sparano, Wolff, Cobleigh, Galbraith, Sledge, Lara, Stadler, Longmate, Quinn, Wexler, Van Loan, Twardowski, Gumerlock, Vogelzang, Vokes, Lenz, Doroshow, Gandara, Rizvi, Humphrey, Ness, Johnson, Gupta, Williams, Daly, Sonnichsen, Conway, Marshall, Hurwitz,

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Disease relevance of D 2163

In early phase studies, BMS- 275291 was not associated with dose-limiting joint toxicity seen with other MMPIs [1].
Taken together, these data demonstrate that BMS-275291 inhibits MMP activities that contribute to tumor metastasis and angiogenesis [2].
PURPOSE: To determine whether BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor (MMPI), added to systemic chemotherapy improved survival in advanced non-small-cell lung cancer (NSCLC) [1].
All patients received paclitaxel 200 mg/m2 plus carboplatin (area under the curve, 6 mg/mL-min) intravenously every 21 days for up to 8 cycles, and were randomly assigned to receive BMS-275291, 1,200 mg orally daily, or placebo until disease progression [1].
Toxicity was significantly higher in the BMS-275291 arm, including flu-like symptoms, rash, hypersensitivity reactions (8.6% v 2.4%), and febrile neutropenia (9.7% v 5.5%) [1].

High impact information on D 2163

CONCLUSION: BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC [1].
BMS-275291 inhibits tumor growth in a B16BL6 model of experimental metastasis, and in this model, BMS-275291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls [2].
BMS-275291 also inhibits angiogenesis in a murine angiogenesis model, where once daily treatment with BMS-275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs [2].
A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases [3].
The mean plasma concentration of parent BMS-275291 at trough exceeded the calculated in vitro IC(80) value for MMP-2 and IC(90) value for MMP-9 at the recommended phase II dose of 1200 mg/day [4].

Biological context of D 2163

This trial was conducted to establish the recommended phase II dose; determine safety, toxicity, and pharmacokinetics of BMS-275291; and to assess potential markers of sheddase activity [tumor necrosis factor-alpha (TNFalpha) release and TNFalpha-RII shedding] [4].

Anatomical context of D 2163

Two patients receiving BMS-275291 developed palpable nodules along tendons [5].

Gene context of D 2163

Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291 [2].

Analytical, diagnostic and therapeutic context of D 2163

As planned, patient accrual continued to further investigate the effect of BMS-275291 on overall and progression-free survival in a phase III setting [6].

References

Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18. Leighl, N.B., Paz-Ares, L., Douillard, J.Y., Peschel, C., Arnold, A., Depierre, A., Santoro, A., Betticher, D.C., Gatzemeier, U., Jassem, J., Crawford, J., Tu, D., Bezjak, A., Humphrey, J.S., Voi, M., Galbraith, S., Hann, K., Seymour, L., Shepherd, F.A. J. Clin. Oncol. (2005) [Pubmed]
Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. Naglich, J.G., Jure-Kunkel, M., Gupta, E., Fargnoli, J., Henderson, A.J., Lewin, A.C., Talbott, R., Baxter, A., Bird, J., Savopoulos, R., Wills, R., Kramer, R.A., Trail, P.A. Cancer Res. (2001) [Pubmed]
A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases. Lara, P.N., Stadler, W.M., Longmate, J., Quinn, D.I., Wexler, J., Van Loan, M., Twardowski, P., Gumerlock, P.H., Vogelzang, N.J., Vokes, E.E., Lenz, H.J., Doroshow, J.H., Gandara, D.R. Clin. Cancer Res. (2006) [Pubmed]
A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Rizvi, N.A., Humphrey, J.S., Ness, E.A., Johnson, M.D., Gupta, E., Williams, K., Daly, D.J., Sonnichsen, D., Conway, D., Marshall, J., Hurwitz, H. Clin. Cancer Res. (2004) [Pubmed]
A randomized phase II feasibility trial of BMS-275291 in patients with early stage breast cancer. Miller, K.D., Saphner, T.J., Waterhouse, D.M., Chen, T.T., Rush-Taylor, A., Sparano, J.A., Wolff, A.C., Cobleigh, M.A., Galbraith, S., Sledge, G.W. Clin. Cancer Res. (2004) [Pubmed]
Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-275291 with paclitaxel plus carboplatin in advanced non-small cell lung cancer. Douillard, J.Y., Peschel, C., Shepherd, F., Paz-Ares, L., Arnold, A., Davis, M., Tonato, M., Smylie, M., Tu, D., Voi, M., Humphrey, J., Ottaway, J., Young, K., Vreckem, A.V., Seymour, L. Lung Cancer (2004) [Pubmed]

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