Search results
Items: 6
1.
Mühlebach MD, Schaser T, Zimmermann M, Armeanu S, Hanschmann KM, Cattaneo R, Bitzer M, Lauer UM, Cichutek K, Buchholz CJ.
Cancer Res. 2010 Oct 1;70(19):7620-9. doi: 10.1158/0008-5472.CAN-09-4650. Epub 2010 Sep 21.
Abstract
Primary
and secondary cancers of the liver are a significant health problem
with limited treatment options. We sought here to develop an oncolytic measles
virus (MV) preferentially activated in liver tumor tissue, thus
reducing infection and destruction of healthy tissue. We documented that
in primary tumor tissue, urokinase-type plasminogen activator and
especially matrix
metalloproteinase-2 (MMP-2) are significantly more active than in
adjacent nontumorous tissue. We then generated variants of the MV fusion
protein by inserting different MMP substrate motifs at the protease
cleavage site and identified the motif PQGLYA as the most efficient
cleavage site as determined by syncytia formation on protease-positive
tumor cells. The corresponding MMP-activatable oncolytic MV-MMPA1 virus
was rescued and shown to be strongly restricted on primary human
hepatocytes and healthy human liver tissue, while remaining as effective
as the parental MV in the tumor tissue sections. Our findings underline
the clinical potency of the MMP activation concept as a strategy to
generate safer oncolytic viruses for the treatment of primary and
secondary cancers of the liver.
2.
Beineke A, Puff C, Seehusen F, Baumgärtner W.
Vet Immunol Immunopathol. 2009 Jan 15;127(1-2):1-18. doi: 10.1016/j.vetimm.2008.09.023. Epub 2008 Oct 4. Review.
- PMID:
- 19019458
3.
Ichiyama T, Matsushige T, Siba P, Suarkia D, Takasu T, Miki K, Furukawa S.
J Infect. 2008 May;56(5):376-80. doi: 10.1016/j.jinf.2008.02.014. Epub 2008 Apr 18.
Abstract
OBJECTIVES:
To investigate the brain inflammation and damage in subacute sclerosing panencephalitis (SSPE), the cerebrospinal fluid (CSF) concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were determined in SSPE patients.
METHODS:
CSF MMP-9 and TIMP-1 levels were measured in 23 patients with SSPE in Papua New Guinea by ELISA.
RESULTS:
CSF MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients were significantly higher than controls (p<0 .001="" and="" between="" controls.="" csf="" differences="" in="" levels="" no="" p="" patients="" respectively="" significant="" sspe="" there="" timp-1="" were="">CONCLUSIONS:
Previous studies suggested that CSF MMP-9 levels reflect inflammatory damage to the brain. Our findings suggest that the MMP-9 level in CSF is an indicator of inflammatory damage to the brain in SSPE.
To investigate the brain inflammation and damage in subacute sclerosing panencephalitis (SSPE), the cerebrospinal fluid (CSF) concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were determined in SSPE patients.
METHODS:
CSF MMP-9 and TIMP-1 levels were measured in 23 patients with SSPE in Papua New Guinea by ELISA.
RESULTS:
CSF MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients were significantly higher than controls (p<0 .001="" and="" between="" controls.="" csf="" differences="" in="" levels="" no="" p="" patients="" respectively="" significant="" sspe="" there="" timp-1="" were="">CONCLUSIONS:
Previous studies suggested that CSF MMP-9 levels reflect inflammatory damage to the brain. Our findings suggest that the MMP-9 level in CSF is an indicator of inflammatory damage to the brain in SSPE.
4.
Ichiyama T, Siba P, Suarkia D, Takasu T, Miki K, Kira R, Kusuhara K, Hara T, Toyama J, Furukawa S.
J Neurol Sci. 2007 Jan 15;252(1):45-8. Epub 2006 Nov 22.
Abstract
We determined the relationship between the serum concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases
1 (TIMP-1) in 33 patients with subacute sclerosing panencephalitis
(SSPE) to investigate the function of the blood-brain-barrier (BBB) in
SSPE. Serum MMP-9 and TIMP-1 levels were measured by ELISA. Serum MMP-9
levels and MMP-9/TIMP-1 ratios of SSPE patients in Papua New Guinea (n =
24), and those in Japan (n = 9) were significantly higher than the each
control (MMP-9, p = 0.0390, and p = 0.0023, respectively; MMP-9/TIMP-1,
p = 0.0319, and p = 0.0009, respectively). Serum MMP-9 levels and
MMP-9/TIMP-1 ratios of SSPE patients with Jabbour stage III (n = 13)
were significantly higher than those with Jabbour stage II (n = 18) (p =
0.003, and p = 0.0412, respectively). There were no significant
differences of serum TIMP-1 levels between the SSPE patients and
controls. High serum MMP-9 and MMP-9/TIMP-1 levels will promote brain
invasion through the BBB by immunocompetent cells in the blood. Our
findings suggest that the balance of serum MMP-9 and TIMP-1 levels
modulate the inflammatory cascade of SSPE.
5.
Springfeld C, von Messling V, Frenzke M, Ungerechts G, Buchholz CJ, Cattaneo R.
Cancer Res. 2006 Aug 1;66(15):7694-700.
Abstract
Cancer cells secrete matrix metalloproteinases (MMP) that degrade the extracellular matrix
and are responsible for some hallmarks of malignant cancer. Many
viruses, including a few currently used in oncolytic virotherapy
clinical trials, depend on intracellular proteases to process their
proteins and activate their particles. We show here for measles
virus (MV) that particle activation can be made dependent of proteases
secreted by cancer cells. The MV depends on the intracellular protease
furin to process and activate its envelope fusion (F) protein. To make F
protein activation cancer cell specific, we introduced hexameric
sequences recognized by an MMP and identified the mutant proteins most
effective in fusing MMP-expressing human fibrosarcoma cells (HT1080). We
showed that an MMP inhibitor interferes with syncytia formation
elicited by mutant F proteins and confirmed MMP-dependent cleavage by
Edman degradation sequence analysis. We generated recombinant MVs
expressing the modified F proteins in place of furin-activated F. These
viruses spread only in cells secreting MMP. In nude mice, an
MMP-activated MV retarded HT1080 xenograft growth as efficiently as the
furin-activated MV vaccine strain. In MV-susceptible mice, the
furin-activated virus caused lethal encephalitis upon intracerebral
inoculation, whereas the MMP-activated did not. Thus, MV particle
activation can be made dependent of proteases secreted by cancer cells,
enhancing safety. This study opens the perspective of combining
targeting at the particle activation, receptor recognition, and
selective replication levels to improve the therapeutic index of MV and
other viruses in ongoing clinical trials of oncolysis.
6.
Agafonov AP, Kameneva SN, Agafonova OA, Neverov AA, Ignat'ev GM.
Vestn Ross Akad Med Nauk. 2004;(8):3-6. Russian.
Abstract
The level of specific antibodies to viruses of measles,
parotitis, type-6 herpes, Epstein-Barr, tick-borne encephalitis and
Borrelia burgdorferi as well as presence of genetic samples and antigens
of the above infectious antigens were studied in patients with multiple
sclerosis (MS). The cytokines Th1 and Th2 parameters were investigated
in blood serum of patients at different MS stages. The titer of
antibodies to measles
virus was noted to be increasing in MS patients with age and disease
aggravation. The level of antibodies to any of the studied infectious
agents, except for the type-6 herpes virus, was not dynamically changing
for as long as 9 months. The viral genetic samples (measles
RNA) were detected just once in 2 patients; the detection time
coincided in both cases with MS aggravation. The cytokines dynamics
failed to correlate with MS aggravation or exacerbation while the total
index of all studied cytokines was decreased. A high MMPw 9 content in
blood serum correlated with MS exacerbation in 1 patient.
Matrix metalloproteinase-3 (MMP-3) also known as stromelysin-1 and transin (EC 3.4.24.17) cleaves a number of substrates including cartilage proteoglycan, collagen types II, III, IV, V and IX, fibronectin, laminin, and can activate MMP 1. MMP-3 is secreted as 57 and 59 kDa proenzymes and can be activated in vitro by organomercurials (e.g., 4 aminophenylmercuric acetate, Enzymes MMP 3
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