Effect of Matrix Metalloproteinase Inhibitor Batimastat on Breast Cancer Regrowth and Metastasis in Athymic Mice

Sledge, George W.; Qulali, Mona; Goulet, Robert J.; Bone, Elisabeth A.; Fife, Rose S.

doi:10.1093/jnci/87.20.1546

Cited by 180 publications

(67 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This study is the first published demonstration of anti-cancer activity for marimastat, and confirms the belief, substantiated by many studies with the related MMP inhibitor batimastat (Davies et al, 1993;Chirivi et al, 1994;Sledge et al, 1995;Taraboletti et al, 1995;Watson et al, 1995), a non-orally bioavailable drug, that MMPIs have promise as anti-cancer therapies.…”

Section: Discussionsupporting

confidence: 83%

Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA

et al. 1999

View full text Add to dashboard Cite

Summary Inhibition of matrix metalloproteinases (MMPs) is an attractive approach to adjuvant therapy in the treatment of cancer. Marimastat is the first orally administered, synthetic MMP inhibitor to be evaluated, in this capacity, in the clinic. Measurement of the rate of change of circulating tumour antigens was used for evaluating biological activity and defining optimum dosage in the early clinical trials of marimastat. Although tumour antigen levels have been used in the clinical management of cancer for many years, they have not been validated as markers of disease progression. In order to investigate the relationship between the effects of marimastat on tumour growth and circulating tumour antigen levels, mice bearing the human gastric tumour, MGLVA1, were treated with marimastat. The MMP inhibitor exerted a significant therapeutic effect, reducing tumour growth rate by 48% (P = 0.0005), and increasing median survival from 19 to 30 days (P = 0.0001). In addition, carcinoembryonic antigen (CEA) levels were measured in serum samples from animals sacrificed at regular intervals, and correlated with excised tumour weight. It was shown that the natural log of the CEA concentration was linearly related to the natural log of the tumour weight and that treatment was not a significant factor in this relationship (P = 0.7). In conclusion, circulating CEA levels were not directly affected by marimastat, but did reflect tumour size. These results support the use of cancer antigens as markers of biological activity in early phase trials of non-cytotoxic anticancer agents.

show abstract

Section: Discussionsupporting

confidence: 83%

Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA

et al. 1999

View full text Add to dashboard Cite

show abstract

“…Treatment of mice bearing human ovarian cancer xenografts with the broad spectrum MMP inhibitor BB94 (Batimastat) reduced tumour burden and increased survival (Davies et al, 1993b). In a more recent study, BB94 reduced the incidence of local tumour recurrence and formation of lung metastases when administered to nude mice after resection of MDA-MB-435 primary tumours (Sledge et al, 1995). This effect was not associated with changes in the tumour expression of MMPs or TIMP-2.…”

Section: Discussionmentioning

confidence: 90%

Proteinase inhibitors reduce basement membrane degradation by human breast cancer cell lines

Stonelake

Jones²,

Neoptolemos³

et al. 1997

Br J Cancer

View full text Add to dashboard Cite

SummaryThe relative importance of different proteinases, and their inhibition, in the breakdown of human endothelial basement membrane (BM) by MDA-MB-231 and MCF7ADR human breast cancer cell lines has been studied using 35S-labelled (Fidler, 1990). Basement membrane degradation (BMD) is brought about by extracellular proteinases, and there is currently interest in inhibitors of these enzymes as potential therapeutic agents. Possible candidates for the proteinases involved in breast cancer invasion are found in each of the four major classes of proteinases, i.e. aspartic, cysteine, serine and matrix metalloproteinases (MMPs).The aspartic proteinase cathepsin D, a lysosomal enzyme, is oversecreted by breast cancer cells in vitro and may be a major proteinase involved in BMD (Briozzo et al, 1988). This view is supported by in vivo experiments in which transfection of cathepsin D cDNA resulted in a higher frequency of metastases in mice (Garcia et al, 1990). Nevertheless, some workers have questioned whether this lysosomal enzyme, which is only active at acid pH, has a role in invasion under physiological conditions (Johnson et al, 1993).The cysteine proteinases, cathepsins B, L and H, are also lysosomal enzymes that are overexpressed in breast cancer (Vasishta et al, 1988;Gabrijelcic et al, 1992). Cathepsin B from normal human liver and from human breast carcinomas has been shown to degrade components of BM at neutral pH as well as at acid pH (Buck et al,

show abstract

“…Beside the Plg system, a number of serine, metallo, aspartic and cysteine proteases have been implicated in tumor invasion and metastasis (Danù et al, 1985;Duy 1992;Stetler-Stevenson et al, 1993;Crawford and Matrisian, 1995;Kohn and Liotta, 1995;Schwartz, 1995;Liotta and Steeg, 1991). The recent development of speci®c and ecient synthetic inhibitors of matrixdegrading proteases, as well as several transgenic mouse lines de®cient in matrix-degrading proteases or overexpressing protease inhibitors, has provided powerful tools to directly dissect the individual roles of matrix-degrading proteases in cancer invasion and metastasis in vivo (Bugge et al, 1995;Ploplis et al, 1995;Anderson et al, 1996;Carmeliet et al, 1994;Saftig et al, 1995;Wilson et al, 1997;Conway et al, 1996;Sledge et al, 1995;Shipley et al, 1996;Martin et al, 1996). Studies of the eect of the combined elimination of several tumor-associated matrix-degrading enzymes using available inhibitors and genede®cient mice will be critical for evaluating the potential for the development of ecient cancer treatments based on the inhibition of matrix-degrading proteases.…”

Section: Discussionmentioning

confidence: 99%

Reduced metastasis of Polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice

Lund²,

et al. 1998

View full text Add to dashboard Cite

To investigate the role of plasmin(ogen) in mammary tumor development and progression, plasminogende®cient mice were crossed with transgenic mice expressing Polyoma middle T antigen under the control of the mouse mammary tumor virus long terminal repeat. Virgin females carrying the Polyoma middle T antigen uniformly developed multiple, bilateral mammary tumors, regardless of the presence or absence of circulating plasminogen. Both the age at which these tumors became palpable and subsequent tumor growth were indistinguishable between plasminogen-de®cient mice and plasminogen-expressing littermates. However, plasminogen was found to greatly modify the metastatic potential in this model system; lung metastasis in plasminogende®cient mice was signi®cantly reduced as compared to littermate controls with respect to frequency of occurrence, total number of metastases, and total metastatic tumor burden. Plasminogen activators, as well as other key factors that govern the conversion of plasminogen to plasmin, were expressed within the mammary tumors, suggesting that the plasminogen/plasmin system may promote metastasis by contributing to tumor-associated extracellular proteolysis. The data provide direct evidence that plasmin(ogen) is a tumor progression factor in PymT-induced mammary cancer, and support the hypothesis that hemostatic factors play an important role in tumor biology.

show abstract

Effect of Matrix Metalloproteinase Inhibitor Batimastat on Breast Cancer Regrowth and Metastasis in Athymic Mice

Abstract: Batimastat inhibits human breast cancer regrowth and metastasis in a nude mouse xenograft model. Potential mechanisms for batimastat's inhibitory activity do not include direct cell toxicity or alteration of MMP or TIMP mRNA levels.

Cited by 180 publications

References 0 publications

Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA

Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA

Proteinase inhibitors reduce basement membrane degradation by human breast cancer cell lines

Reduced metastasis of Polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice

Contact Info

Product

Resources

About