Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice

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

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

Background: Matrix metalloproteinases (MMPs) are involved in the invasion and metastasis of human cancers by mediating the degradation of extracellular matrix components. Therefore, these enzymes constitute promising targets in the development of anticancer therapies. Batimastat ([{4-N-hydroxyamino}-2R-isobuty1-3S-{thieny1-thiomethy1}succiny1]-L-phenyl-alanine-N-methylamide) is one of a new class of agents designed to inhibit MMP activity. Purpose: We asked whether batimastat, given as adjuvant therapy after primary tumor resection, could inhibit local-regional tumor regrowth and the formation of lung metastases in a human breast cancer xenograft model. We also explored possible effects of batimastat on breast cancer cell viability and on the accumulation of specific messenger RNAs (mRNAs). Methods: Human MDA-MB-435 breast cancer cells were treated in vitro for 6 days with batimastat at concentrations ranging from 0.1 to 10.0 μM, and then viable cell counts were performed. The activity of collagenases, directly associated with cultured MDA-MB-435 cells or released into their culture fluids, was assessed by gelatin zymography after 1 and 3 days of batimastat treatment (drug range, 0.2-2.0 μM). Athymic nude mice were given daily intraperitoneal injections of batimastat (30 mg/kg body weight) after resection of MDA-MB-435 primary tumors grown in their mammary fat pads; the volumes of tumor regrowths and the numbers and volumes of lung metastases were calculated; neovascularization in the regrowths was assessed by immunohistochemical analysis with an antibody directed against CD31, an endothelial cell antigen. The effect of batimastat treatment on the accumulation of mRNAs encoding specific MMPs and the tissue inhibitor of metalloproteinases-2 (TIMP-2) in cultured cells, primary tumors, and tumor regrowths was measured by RNA dot blotting and hybridization with complementary probes. Linear regression analysis, Student's tests, and chi-squared analysis were used to evaluate the data. Results: The viability of cultured MDA-MB-435 cells was not affected by treatment with batimastat; however, measured activities for the 72-kd and 92-kd collagenases released by these cells were reduced after batimastat treatment. Intraperitoneal injection of batimastat significantly inhibited the local-regional regrowth of resected MDA-MB-435 tumors in athymic nude mice (in comparison with control mice, P =.035), and it reduced the incidence (P

Original languageEnglish (US)
Pages (from-to)1546-1551
Number of pages6
JournalJournal of the National Cancer Institute
Volume87
Issue number20
DOIs
StatePublished - Oct 18 1995
Externally publishedYes

Fingerprint

Regrowth
Matrix Metalloproteinase Inhibitors
Metastasis
Breast Cancer
Nude Mice
Inhibitor
Mouse
Tumors
Tumor
Breast Neoplasms
Neoplasm Metastasis
Cell
Cells
Lung
Viability
Messenger RNA
Therapy
Neoplasms
Injection
Collagenases

ASJC Scopus subject areas

  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging
  • Oncology
  • Cancer Research

Cite this

Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. / Sledge, George W.; Qulali, Mona; Goulet, Robert; Bone, Elisabeth A.; Fife, Rose.

In: Journal of the National Cancer Institute, Vol. 87, No. 20, 18.10.1995, p. 1546-1551.

Research output: Contribution to journalArticle

Sledge, George W. ; Qulali, Mona ; Goulet, Robert ; Bone, Elisabeth A. ; Fife, Rose. / Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. In: Journal of the National Cancer Institute. 1995 ; Vol. 87, No. 20. pp. 1546-1551.
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AU - Qulali, Mona

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AU - Bone, Elisabeth A.

AU - Fife, Rose

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