Synthetic inhibitor of matrix metalloproteinases (batimastat) reduces prostate cancer growth in an orthotopic rat model

Lein, Michael; Jung, Klaus; Le, Dinh K.; Hasan, Tayyaba; Ortel, Bernhard; Borchert, Dietmar; Winkelmann, Bjoern; Schnorr, Dietmar; Loenings, Stefan A.

doi:10.1002/(sici)1097-0045(20000501)43:2<77::aid-pros1>3.0.co;2-q

Cited by 28 publications

(14 citation statements)

References 25 publications

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“…These in vitro data are in close agreement with our previous studies using the MMP inhibitor Batimastat in this cell line (Lein et al, 2000a). Similarly, Batimastat had an e ect on cell proliferation only at very high concentrations.…”

Section: Discussionsupporting

confidence: 92%

“…Pharmacological inhibitors of MMPs could be an innovative class of therapeutic agents to control tumor progression and metastases (Lein et al, 2000a;Eccles et al, 1996;Price et al, 1999). In the past few years, synthetic MMP inhibitors have undergone rapid clinical development.…”

Section: Introductionmentioning

confidence: 80%

“…Side e ects and limited bio-availability prevented further clinical application. Our own data supported the e ect of the broad spectrum MMP inhibitor Batimastat in a previous study in Dunning tumors, too (Lein et al, 2000a). In this study, we showed that Batimastat is capable of limiting orthotopic rat tumor progression by up to 50%.…”

Section: Discussionmentioning

confidence: 99%

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The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model

et al. 2002

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The therapeutic e cacy of synthetic inhibitors of matrixmetalloproteinases (MMPs) in various cancers has been demonstrated. A novel inhibitor, Ro 28-2653, with high selectivity for MMP2, MMP9 and membrane type 1-MMP was evaluated in an orthotopic prostate cancer rat model. E cacy was determined by recording tumor growth and survival endpoints. Prostate cancer was induced by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral lobe of the prostates of 148 Copenhagen rats. Daily oral treatment with Ro 28-2653 (10 ± 300 mg/kg per day) was started on day 1 or on day 6 after tumor cell injection. Animals were sacri®ced on day 20 for determination of tumor weights. For survival studies, rats received daily oral Ro 28-2653 (100 mg/kg per day) or vehicle for up to 30 days. Tumor induction was successful in 100% of the animals. Ro 28-2653 reproducibly reduced the tumor weights by up to 90% in a dose-dependent manner. In addition, an inhibitory e ect in rats with established tumors (treatment start at day 6) was shown. A signi®cantly prolonged survival of Ro 28-2653-treated rats was also demonstrated. Selective inhibition of MMP activity is a novel therapeutic approach, which bears promise for studies in patients with prostate cancer.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 80%

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The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model

et al. 2002

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“…Many synthetic MMP inhibitors, such as Batimastat (BB-94), Marimastat, and Prinomastat, have been developed and evaluated. Although the anti-tumor e ects of some MMPIs were con®rmed in animal models (Lein et al, 2000;Wylie et al, 1999;Prontera et al, 1999;Low et al, 1996;Wojtowicz-Praga et al, 1997;Shalinsky et al, 1999), many MMPIs have met bad fate in clinical trials. Marimastat is the ®rst orally bioavailable MMPI entered clinical trials in the ®eld of oncology.…”

Section: Clinical Application and Future Directionsmentioning

confidence: 99%

Complex roles of tissue inhibitors of metalloproteinases in cancer

2002

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Matrix metalloproteinases (MMPs) is tightly associated with extracellular matrix (ECM) turnover, which plays a very active role in tumor invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) plays a critical role in the homeostasis of ECM by regulating the activity of MMPs. TIMPs are well-known for their ability to inhibit MMP activity thereby inhibiting tumor growth and metastasis. However, many evidences suggest that TIMPs are multifunctional proteins, which regulate cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis. These e ects may be through MMPdependent or MMP-independent pathways. Recent data indicate that TIMPs have many paradoxical roles in tumorigenesis. In particular, both inhibitory e ect and stimulatory e ect on tumorigenesis have been demonstrated in many animal models in which TIMPs were overexpressed in cancer cells or in mice. Elevated TIMP levels are reported in association with cancer progression and identi®ed as poor prognostic indicators in several human tumor types. Herein, we review the complex roles of TIMPs in cancer growth and metastasis.

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“…Scale bars represent 50 μm suppression by BB-94 was accompanied by a reduced proliferation rate, an increased apoptosis, and a decrease in vascularity. Although the means by which BB-94 inhibited tumor growth have not been established in other experimental studies, cytostatic and/or anti-angiogenic activity of the drug has been suggested [6,7,18,20,32,37,40,47]. Ten years ago, we found that TNP-470, a fumagillin analog, inhibited tumor growth in the same experimental model of a pituitary adenoma also through the inhibition of cell proliferation and angiogenesis [35].…”

Section: Discussionmentioning

confidence: 93%

Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat

et al. 2007

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The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. Pituitary tumors were induced in male F344 rats by s.c. implantation of Silastic tubes containing diethylstilbestrol (DES). The effects of chronic treatment with BB-94 (30 mg/kg b.w.) on pituitary weight, cell proliferation, apoptosis and vascular density were evaluated. We have stated that chronic treatment with batimastat caused a significant reduction in the pituitary weight. Batimastat has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. A marked increase in the apoptotic index within the pituitary was observed in the study group. Moreover, the density of microvessels identified by CD31 was reduced in the group treated with BB-94. The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma. The ability of BB-94 to suppress established pituitary tumor growth suggests a possible application of MMPIs in the treatment of pituitary adenomas.

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Synthetic inhibitor of matrix metalloproteinases (batimastat) reduces prostate cancer growth in an orthotopic rat model

Cited by 28 publications

References 25 publications

The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model

The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model

Complex roles of tissue inhibitors of metalloproteinases in cancer

Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat

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