A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours

Hirte, Hal W.; Goel, Rakesh; Major, Pierre; Seymour, Leonard W.; Huan, S.; Yau, Jonathan C.; Arnold, Andrew; Holohan, S.; Waterfield, B.; Bates, Susan E.; Bennett, Katherine; Walsh, William R.; Elias, Ileana

doi:10.1023/a:1008347630465

Cited by 33 publications

(16 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In preclinical studies, growth inhibitory activity and reduction in the number of metastases were shown in various tumor models, with elevation of transaminase levels and mild depression of erythropoiesis as the principal toxic effects in animals [51][52][53][54]. Four phase I studies including a total of 89 patients have been performed [55][56][57][58][59]. Dose levels studied ranged from 100-1,600 mg/day.…”

Section: Phase I Studiesmentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors: Current Developments and Future Perspectives

2001

View full text Add to dashboard Cite

The Oncologist 2001;6:415-427 www.TheOncologist.com Correspondence: Ronald Hoekstra, M.D., Department of Medical Oncology, University Hospital Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Fax: 31-10-463-4627; e-mail: hoekstra@oncd.azr.nl Received May 25, 2001; accepted for publication August 7, 2001. ©AlphaMed Press 1083-7159/2001 INTRODUCTIONThe importance of proteinases in tumor invasion was first recognized in 1925 when Fischer found that a lytic substance from sarcoma cells could degrade the fibrin stroma. Later it was found that the serine proteinase plasminogen activator (PA) played an important role in activating plasminogen to plasmin. Apart from PAs, proteinases such as serine, cysteine, and metalloproteinases have been associated with cancer [1]. It is important to realize that high levels of extracellular proteolytic activity are not restricted to the malignant phenotype, but are also seen in a number of physiological processes such as embryo implantation, wound healing, and angiogenesis. A common feature in these processes is the breaching of histological barriers with the degradation of the extracellular matrix (ECM) composed of basement membrane and extracellular stroma.Matrix metalloproteinases (MMPs) are enzymes able to degrade most components of the ECM such as collagens, laminins, fibronectins, elastins, and the protein core of proteoglycans. At this moment more than 20 different MMPs have been identified and classified. They show a consistent sequence homology and in general share a pre-domain, which is a signal peptide for secretion, a pro-domain, important for maintaining latency, a catalytic domain with a highly

show abstract

Section: Phase I Studiesmentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors: Current Developments and Future Perspectives

2001

View full text Add to dashboard Cite

show abstract

“…However, as far as we are aware, no clinical trial has so far achieved satisfying results. Although chemical components, clinical trial design, and patient selection might be important factors, a better understanding of the role of MMPs in the pathophysiology of malignant tumors may be needed [4]. In this study, we measured the activity of MMP-2, -9 and -7 in tumor tissues of early-stage non-small cell lung cancer (NSCLC).…”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase Activity in Early-Stage Lung Cancer

et al. 2013

View full text Add to dashboard Cite

Background: The matrix metalloproteinases (MMPs)-2, -9 and -7 are thought to be associated with tumor invasion, metastasis, and angiogenesis. However, their possible roles in early-stage lung cancer are not clear. We measured the activity of MMP-2, -7 and -9 in early-stage lung cancer tissues. Material and Methods: Normal lung tissues and cancer tissues were collected from 60 consecutive stage-I non-small cell lung cancer (NSCLC) patients. The activities of MMP-2 and MMP-9 were determined by gelatin zymography, and the activity of MMP-7 was determined by casein zymography. Furthermore, the ratio of the active form of MMP-2 in tumor tissue (T) compared with normal tissue (N) was determined, and the survival in the groups with different MMP-2 T:N ratio was compared. Results: The activity of both MMP-2 and MMP-9 was detected in all cancer and normal tissues. Interestingly, MMP-9 activity was significantly reduced, whereas MMP-2 activity was significantly increased, in cancer tissues compared to normal tissues. The survival rate of the MMP-2 T:N ratio > 2.5 group was 57.45%, which was significantly reduced compared with that of the T:N ratio ≤ 2.5 group (86.78%). Conclusion: Our findings suggest that MMP-2, but not MMP-9 and MMP-7, may be implicated in early-stage tumor invasion, metastasis, and angiogenesis in NSCLC.

show abstract

“…Several agents have been developed that block the MMPs and prevent them from interacting with the molecules directing their activities to the cell surface or inhibiting their enzymatic activity. It can also be reduced indirectly, by inhibition of the signal-transduction pathways that induce MMP transcription by inhibiting tyrosine kinase receptor signaling [30-33]. …”

Section: Discussionmentioning

confidence: 99%

Optimizing the Diagnostic Role of Alpha-Fetoprotein and Abdominal Ultrasound by Adding Overexpressed Blood mRNA Matrix Metalloproteinase-12 for Diagnosis of HCV-Related Hepatocellular Carcinoma

Elshimi

Sakr

Morad

et al. 2018

Gastrointest Tumors

View full text Add to dashboard Cite

Background and Aims: Matrix metalloproteinase-12 (MMP-12) is involved in tumor invasiveness and metastasis and significantly overexpressed in hepatocellular carcinoma (HCC) tissues. We aimed to investigate the diagnostic and prognostic value of blood mRNA MMP-12 overexpression in patients with HCC. Patients and Methods: From January 2017 to June 2017, 100 patients with HCC (HCV-related cirrhosis) and 100 patients with HCV-related cirrhosis (without HCC) were included in this study. All patients were subjected to triphasic CT abdomen when indicated, liver profile, alpha-fetoprotein (AFP), and molecular characterization of metalloproteinase-12 expression. Results: There were no statistically significant differences between both groups regarding CBC parameters and liver profile (p value > 0.05). There was a statistically significant difference between patients with and without HCC regarding blood mRNA MMP-12 overexpression (p value < 0.01), blood mRNA MMP-12, and/or AFP (sensitivity 84.0%, specificity 60.0%, PPV 51.2%, and NPP 88.2%). The accuracy of mRNA MMP-12 and/or AFP in detection of HCC was 68.0%. Conclusion: Blood mRNA MMP-12 has a good sensitivity and a bad specificity but is accurate in HCC diagnosis. Adding blood mRNA MMP-12 to AFP optimizes the current screening program to improve early diagnosis of HCC and hence better prognosis.

show abstract

A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours

Abstract: The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent.

Cited by 33 publications

References 10 publications

Matrix Metalloproteinase Inhibitors: Current Developments and Future Perspectives

Matrix Metalloproteinase Inhibitors: Current Developments and Future Perspectives

Matrix Metalloproteinase Activity in Early-Stage Lung Cancer

Optimizing the Diagnostic Role of Alpha-Fetoprotein and Abdominal Ultrasound by Adding Overexpressed Blood mRNA Matrix Metalloproteinase-12 for Diagnosis of HCV-Related Hepatocellular Carcinoma

Contact Info

Product

Resources

About