WO2008088864A2 - Procédés associés à une métalloprotéinase-9 matricielle - Google Patents

Procédés associés à une métalloprotéinase-9 matricielle Download PDF

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WO2008088864A2
WO2008088864A2 PCT/US2008/000667 US2008000667W WO2008088864A2 WO 2008088864 A2 WO2008088864 A2 WO 2008088864A2 US 2008000667 W US2008000667 W US 2008000667W WO 2008088864 A2 WO2008088864 A2 WO 2008088864A2
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subject
agent
surgery
mmp
administered
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PCT/US2008/000667
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WO2008088864A3 (fr
WO2008088864A9 (fr
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Richard L. Whelan
Irena Kirman
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The Trustess Of Columbia University In The City Of New York
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 

Definitions

  • Colorectal adenocarcinoma is a leading cause of cancer- related death. Segmental colorectal resection remains the standard treatment. The rate of tumor recurrence after surgery is relatively high. Approximately one-third of patients are expected to experience recurrences post- operatively during the first 5 years. In this unfortunate subpopulation, despite resection, viable tumor cells persist after surgery in the abdominal cavity, in the bloodstream, or in tissue microfoci. Experimental data suggested that surgical trauma stimulates tumor growth early after surgery (1) . Surgical trauma, in theory, may accelerate the growth of tumor cells via surgery-associated immunosuppression or as a result of alterations in the balance of cell growth stimulatory/cell growth inhibitory substances.
  • IGFBP-3 insulin-like growth factors 1 and 2 as well as by IGF-binding protein-3 (IGFBP-3), which is an IGF-binding protein.
  • IGFBP-3 IGF-binding protein-3
  • the inhibitory growth effects of IGFBP-3 are exerted not only through binding and limiting the availability of IGFs, but also via its own direct pro- apoptotic effect for various types of tumor cells.
  • MMP matrix metalloproteinases
  • Lymphocytes also have been shown to produce MMP-9 (23) .
  • Leukocytes in response to mitogenic stimuli, increase proteinase production.
  • plant lectins and lipopolysaccharide have been shown to stimulate the production of proteinases by human leukocytes (5, 16) .
  • Surgical trauma is known to activate leukocytes, as evidenced by the release of multiple proinflammatory cytokines in the early postoperative period.
  • An increased level of MMP-9 has been found in the blood plasma and in surgical wound fluid (21) . Therefore, the possibility of a surgery-related increase in the postoperative production of MMPs exists. Summary of the Invention
  • This invention provides method for decreasing the degradation of insulin-like growth factor binding protein 3 (IGFBP-3) in a subject following open or laparoscopic surgery which comprises administering to the subject an amount of an agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) in the subject's plasma so as to thereby decrease the degradation of IGFBP-3 in the subject, wherein the agent is administered to the subject
  • This invention further provides a method for decreasing the degradation of insulin-like growth factor binding protein 3
  • IGFBP-3 in a subject following open or laparoscopic surgery which comprises administering to the subject an amount of an agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) -producing cells in the subject and/or inhibit the release of MMP-9 from such cells so as to thereby decrease the degradation of IGFBP-3 in the subject, wherein the agent is administered to the subject (a) prior to, (b) during or (c) after, the surgery, or any combination of (a) , (b) or (c) .
  • MMP-9 matrix metalloproteinase-9
  • This invention further provides a method for reducing the likelihood of tumor development or recurrence in a subject following open or laparoscopic surgery comprising administering to the subject an amount of an agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) in the subject's plasma so as to thereby reduce the likelihood of tumor development or recurrence in the subject, wherein the agent is administered to the subject (a) prior to, (b) during or (c) after, the surgery, or any combination of (a) , (b) or (c) .
  • MMP-9 matrix metalloproteinase-9
  • this invention provides a method for reducing the likelihood of tumor development or recurrence in a subject following open or laparoscopic surgery comprising administering to the subject an amount of an agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) -producing cells in the subject and/or inhibit the release of MMP-9 from such cells so as to reduce the likelihood of tumor development or recurrence in the subject, wherein the agent is administered to the subject (a) prior to, (b) during or (c) after the surgery, or any combination of (a) , (b) or (c) .
  • MMP-9 matrix metalloproteinase-9
  • Gelatinases in patients with colon cancer undergoing open (OS) or laparoscopically assisted (LS) surgery are evaluated.
  • MMP-9 recombinant human matrix metalloproteinase-9
  • the predominant plasma 92-kDa gelatinase corresponds to a proform of MMP-9 monomer, whereas a high- molecular-weight protease is its dimmer.
  • OS Patient A preoperatively (pre-OP) (lane 1) and on postoperative day (POD) 1 (lane 2), patient B pre-OP (lane 3) and POD 2 (lane 4) .
  • LS Patient C at pre-OP (lane 7) and on POD 1 (lane 6), and patient D at pre-OP (lane 7) and on POD 2 (lane 8) .
  • Recombinant human MMP-9 (lane 9) .
  • C. Western blot analysis confirms that a 92-kDa gelatinase is MMP-9.
  • Lane 1 recombinant human MMP-9.
  • Lanes 2 and 3 MMP-9 from human plasma.
  • MMP-9 Matrix metalloproteinase-9 enzyme-linked immunoassay
  • OS open
  • LS laparoscopically assisted
  • MMP-9 ELISA assay was performed on preoperative (pre-OP) and postoperative days (POD) 1 to 3 samples, as described in the materials and methods section. A statistically significant difference was found between POD 1 and pre-OP values in OS, but not in LS, patients. *p ⁇ 0.003.
  • Tissue inhibitor of metalloproteinase-1 enzyme- linked immunoassay in plasma samples from patients with colon cancer undergoing open or laparoscopically assisted surgery.
  • TIMP-I ELISA assay was performed on preoperative (pre-OP) and postoperative day (POD) 1 to 3 samples, as described in the materials and methods section. **p ⁇ 0.0003. *p ⁇ 0.01.
  • administering an agent can be effected or performed using any of the various methods and delivery systems known to those skilled in the art.
  • the administering can be performed, for example, intravenously, orally, nasally, via the cerebrospinal fluid, via implant, transmucosally, transdermally, intramuscularly, and subcutaneously .
  • the following delivery systems, which employ a number of routinely used pharmaceutically acceptable carriers, are only representative of the many embodiments envisioned for administering compositions according to the instant methods.
  • Injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can comprise excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA' s).
  • Implantable systems include rods and discs, and can contain excipients such as PLGA and polycaprylactone.
  • Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc).
  • excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.
  • Transmucosal delivery systems include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid) .
  • solubilizers and enhancers e.g., propylene glycol, bile salts and amino acids
  • other vehicles e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid
  • Dermal delivery systems include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions, liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids) , and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone) .
  • the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer.
  • Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, zanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine) , preservatives and antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid) , anti-caking agents, coating agents, and chelating agents (e.g., EDTA).
  • suspending agents e.g., gums, zanthans, cellulosics and sugars
  • humectants e.g., sorbitol
  • solubilizers e.g., ethanol, water, PEG and propylene glyco
  • Agent shall mean any chemical entity, including, without limitation, a glycomer, a protein, an antibody, a lectin, a nucleic acid, a small molecule, and any combination thereof .
  • Antibody shall include, by way of example, both naturally occurring and non-naturally occurring antibodies.
  • this term includes polyclonal and monoclonal antibodies, and antigen-binding fragments (e.g., Fab fragments) thereof. Furthermore, this term includes chimeric antibodies (e.g., humanized antibodies) and wholly synthetic antibodies, and antigen-binding fragments thereof.
  • Subject shall mean any organism including, without limitation, a mammal such as a mouse, a rat, a dog, a guinea pig, a ferret, a rabbit and a primate. In the preferred embodiment, the subject is a human being.
  • This invention provides a method for decreasing the degradation of insulin-like growth factor binding protein 3
  • IGFBP-3 in a subject following open or laparoscopic surgery which comprises administering to the subject an amount of an agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) in the subject's plasma so as to thereby decrease the degradation of IGFBP-3 in the subject, wherein the agent is administered to the subject
  • the subject is a human.
  • the agent is a PPAR-alpha agonist or a PPAR- gamma agonist.
  • PPAR-alpha and PPAR-gamma agonists include, without limitation, Ragaglitazar, Pioglitazone, Rosiglitazone and Bezafibrate.
  • the agent is fenofibrate.
  • the agent is a protease inhibitor, such as a tissue inhibitor of metalloproteinase-1 (TIMP-I) .
  • Other protease inhibitors include, without limitation, tissue inhibitor of metalloproteinase-2 (TIMP-2), tissue inhibitor of metalloproteinase-3 (TIMP-3), aproteinin and leupeptin.
  • the effective amount of the agent is from about 1 mg/day/kg body weight to about 500 mg/day/kg body weight. In another embodiment, the effective amount of the agent is about 100 mg/day/kg body weight. In further embodiments, the effective amount of the agent is from about 1 mg/day/kg body weight to about 10 mg/day/kg body weight, from about 10 mg/day/kg body weight to about 100 mg/day/kg body weight, from about 100 mg/day/kg body weight to about 500 mg/day/kg body weight, from about 50 mg/day/kg body weight to about 200 mg/day/kg body weight, from about 10 mg/day/kg body weight to about 200 mg/day/kg body weight and from about 1 mg/day/kg body weight to about 200 mg/day/kg body weight.
  • the agent is administered to the subject (a) prior to, (b) during and (c) after, the surgery.
  • the agent is administered to the subject prior to surgery.
  • the agent is administered during the surgery.
  • the agent is administered after the surgery.
  • the agent is administered to the subject daily commencing about one month prior to the surgery and continuing until about three weeks after the surgery.
  • the agent is administered intravenously or orally.
  • the open surgery is open abdominal surgery.
  • open surgery means surgery wherein the incision length is at least about 10 cm.
  • decreasing the level of MMP-9 in plasma means decreasing such level by at least 5%. In another embodiment, decreasing the level of MMP-9 in plasma means decreasing such level by at least 10%, 20% or 50%.
  • decreasing degradation of IGFBP-3 means decreasing such degradation by at least 5%. In another embodiment, decreasing degradation of IGFBP-3 means decreasing such degradation by at least 10%, 20% or 50%.
  • This invention further provides a method for decreasing the degradation of insulin-like growth factor binding protein 3 (IGFBP-3) in a subject following open or laparoscopic surgery which comprises administering to the subject an amount of an agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) -producing cells in the subject and/or inhibit the release of MMP-9 from such cells so as to thereby decrease the degradation of IGFBP-3 in the subject, wherein the agent is administered to the subject (a) prior to, (b) during or (c) after, the surgery, or any combination of (a) , (b) or (c) .
  • IGFBP-3 insulin-like growth factor binding protein 3
  • the subject is a human.
  • the agent is an anti-MMP-9 antibody.
  • the agent is an antibody that recognizes an MMP-9-producing cell, such as a monocyte.
  • MMP-9-producing cells include, without limitation, granulocytes and lymphocytes.
  • the agent is administered to the subject (a) prior to, (b) during and (c) after, the surgery. In another embodiment, the agent is administered to the subject prior to surgery. In another embodiment, the agent is administered during the surgery. In another embodiment, the agent is administered after the surgery. In another embodiment, the agent is administered to the subject daily commencing about one month prior to the surgery and continuing until about three weeks after the surgery. In another embodiment, the agent is administered intravenously or orally.
  • the method further comprises administering to the subject an amount of a second agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) in the subject's plasma, wherein the second agent is administered to the subject (a) prior to, (b) during or (c) after, the surgery, or any combination of (a) , (b) or (c) , and does not decrease the level of MMP-9-producing cells in the subject or inhibit the release of MMP-9 from such cells.
  • the second agent can be, for example, aproteinin or any other MMP-9 inhibitor.
  • This invention further provides a method for reducing the likelihood of tumor development or recurrence in a subject following open or laparoscopic surgery comprising administering to the subject an amount of an agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) in the subject's plasma so as to thereby reduce the likelihood of tumor development or recurrence in the subject, wherein the agent is administered to the subject (a) prior to, (b) during or (c) after, the surgery, or any combination of (a) , (b) or (c) .
  • MMP-9 matrix metalloproteinase-9
  • the subject is a human.
  • the agent is a PPAR-alpha agonist or a PPAR- gamma agonist.
  • the agent is fenofibrate.
  • the agent is a protease inhibitor, such as a tissue inhibitor of metalloproteinase-1 (TIMP-I) .
  • the effective amount of the agent is from about 1 mg/day/kg body weight to about 500 mg/day/kg body weight. In another embodiment, the effective amount of the agent is about 100 mg/day/kg body weight.
  • the agent is administered to the subject (a) prior to, (b) during and (c) after, the surgery.
  • the agent is administered to the subject prior to surgery.
  • the agent is administered during the surgery.
  • the agent is administered after the surgery.
  • the agent is administered to the subject daily commencing about one month prior to the surgery and continuing until about three weeks after the surgery.
  • the agent is administered intravenously or orally.
  • the tumor is a colorectal tumor.
  • the tumor is any solid tumor.
  • this invention provides a method for reducing the likelihood of tumor development or recurrence in a subject following open or laparoscopic surgery comprising administering to the subject an amount of an agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) -producing cells in the subject and/or inhibit the release of MMP-9 from such cells so as to reduce the likelihood of tumor development or recurrence in the subject, wherein the agent is administered to the subject (a) prior to, (b) during or (c) after the surgery, or any combination of (a) , (b) or (c) .
  • MMP-9 matrix metalloproteinase-9
  • the subject is a human.
  • the agent is an anti-MMP-9 antibody.
  • the agent is an antibody that recognizes an MMP-9-producing cell, such as a monocyte.
  • the agent is administered to the subject (a) prior to, (b) during and (c) after, the surgery. In another embodiment, the agent is administered to the subject prior to surgery. In another embodiment, the agent is administered during the surgery. In another embodiment, the agent is administered after the surgery. In another embodiment, the agent is administered to the subject daily commencing about one month prior to the surgery and continuing until about three weeks after the surgery. In another embodiment, the agent is administered intravenously or orally.
  • the method further comprises administering to the subject an amount of a second agent effective to decrease the level of matrix metalloproteinase-9 (MMP-9) in the subject's plasma, wherein the second agent is administered to the subject (a) prior to, (b) during or (c) after, the surgery, or any combination of (a) , (b) or (c) , and does not decrease the level of MMP-9-producing cells in the subject or inhibit the release of MMP-9 from such cells.
  • the tumor is a colorectal tumor.
  • each embodiment above i.e., relating to PPAR agonists, protease inhibitors, agents and therapeutically effective amounts of agents, open surgery, MMP-9-producing cells, decreasing MMP-9 levels, IGFBP-3 levels and likelihood of tumor development and recurrence, and tumor types
  • PPAR agonists i.e., relating to PPAR agonists, protease inhibitors, agents and therapeutically effective amounts of agents, open surgery, MMP-9-producing cells, decreasing MMP-9 levels, IGFBP-3 levels and likelihood of tumor development and recurrence, and tumor types
  • IGFBP-3 insulin-like growth factor binding protein-3
  • OS major open surgery
  • LS laparoscopic surgery
  • Plasma 1 to 3. Plasma was isolated and stored at -80 0 C until the analyses were performed.
  • Plasma samples (3 ⁇ l/sample) diluted with loading buffer were electrophoretically separated on gelatine zymogram precast gels (Invitrogen, Carlsbad, CA, USA). After separation, the samples were renatured according to the manufacturer's instructions, stained with Coomassie Blue
  • Enzyme-linked immunoassay 96-well plates (Corning Incorporated, Corning, NY, USA) were coated with a monoclonal antibody to human MMP-9 (R&D Systems, Minneapolis, MN, USA) . After several washes, the plates were blocked with a 3% milk solution, and serial dilutions of human plasma were applied in duplicates with a starting dilution of 1:10. Subsequently, the plates were washed and then incubated with polyclonal biotinylated antibodies to human MMP-9 (R&D Systems) and streptavidin-peroxidase (BD Pharmingen, San Jose, CA, USA) .
  • ELISA Enzyme-linked immunoassay
  • the reaction was developed with teteramethylbenzidine solution (Sigma Chemical, St. Louis, MO, USA) and stopped with a sulfuric acid solution (Sigma) .
  • a recombinant human MMP-9 (R&D Systems) was used as a standard.
  • the reaction was evaluated using an ELX800 microplate reader (Bio-Tek Instruments, Inc., Winooski, VT, USA) .
  • the membrane then was blocked with 3% milk, incubated first with the monoclonal mouse antibody to human MMP-9 (R&D Systems) , and then incubated with peroxidase-labeled antimouse antibody (Pierce, Rockford, IL, USA) . Finally, the membrane was developed via chemiluminescent reaction using West Pico Luminol Supersignal solution (Pierce). Tissue Metalloproteinase-I ELISA
  • the method is similar to that described above for the MMP-9 ELISA.
  • 96-wel plates were coated with a monoclonal antibody to human tissue inhibitor of metalloproteinase-1 (TIMP-I) (R&D Systems) . After several washes, the plates were blocked with a 3% milk solution, and several dilutions of plasma were added.
  • the plates were washed and then incubated with polyclonal biotinylated antibody to human TIMP-I (R&D Systems) as well as streptavidin-peroxidase (BD Pharmingen, San Jose, CA, USA) .
  • the reaction was developed with tetramethylbenzidine solution (Sigma Chemical) and stopped with a sulfuric acid solution (Sigma Chemical) .
  • Recombinant human TIMP-I was used as a standard. The reaction was evaluated using an ELx ⁇ OO microplate reader (Bio-Tek Instruments).
  • results are expressed as mean ⁇ standard deviation.
  • the difference between pre- and postoperative values within a group was analyzed using the Wilcoxon' s test. A p value of 0.05 or less was considered statistically significant.
  • the concentration of MMP-9 was comparable in samples taken preoperatively (259.9 ⁇ 242.6 ng/ml), on POD 1 (246.1 ⁇ 254.0 ng/ml) , on POD 2 (230.8 ⁇ 172.3 ng/ml), and on POD 3 (212.4 ⁇ 213.9 ng/ml) (Fig. 2).
  • 30% of LS patients had a 1.5-fold or more increase in MMP-9 levels after surgery.
  • TIMP-I The concentration of TIMP-I was determined in plasma samples from OS and LS patients. In OS patients, a dramatic increase in the level of TIMP-I was found on POD 1 (245.7 ⁇ 136.0 ng/ml), as compared with the mean pre-OP value (105.5 ⁇ 78.2 ng/ml; p ⁇ 0.0003). A lesser but still significant elevation in TIMP-I concentration also was found on POD 2 (141.6 ⁇ 62.7 ng/ml; p ⁇ 0.01) (Fig. 3) in the OS group.
  • the LS patients showed a less impressive, yet significant, increase in mean TIMP-I levels on both POD 1 (147.5 ⁇ 96.8 ng/ml; p ⁇ 0.01) and POD 2 (154.3 ⁇ 148.2 ng/ml; p ⁇ 0.01), as compared with the mean pre-OP value (109.4 ⁇ 96.5 ng/ml).
  • the concentration of TIMP-I 132.4 ⁇ 81.7 ng/ml did not significantly differ from pre-OP levels .
  • MMP-9 The protease most affected by surgical trauma was MMP-9.
  • MMP-2 the other principal protease found in both pre- and postoperative plasma samples, was not appreciably altered by colon resection.
  • the plasma concentration of MMP-9 was determined via ELISA for both OS and LS patients.
  • MMP-9 known to be an IGFBP-3 cleaving enzyme, is the protease responsible for the previously reported surgery-related IGFBP-3 depletion noted early after major abdominal procedures (10). Furthermore, MMP-9 is capable of cleaving a number of other important proteins. For example, MMP-9 has been shown to modulate the activity of chemokines (25) and to cleave metastasis suppressor gene product kisspeptin (KiSS-I) protein/metastin (20), insulin (4), transforming growth factor ⁇ (TGF- ⁇ ) binding protein (3), interleukin-2 receptor (IL-2R ⁇ ) (17), matrix proteins (11), and other vital molecules.
  • chemokines (25)
  • KiSS-I metastasis suppressor gene product kisspeptin
  • TGF- ⁇ transforming growth factor ⁇
  • IL-2R ⁇ interleukin-2 receptor
  • MMP-9 levels in OS patients after surgery may prove to be a risk factor not only for tumor reccurences, by virtue decreased IGFBP-3 levels, but also for other insulin-dependent and immune functions.
  • elevated MMP-9 levels after surgery may increase chances of anastomotic leakage attributable to alterations in the integrity of extracellular matrix proteins (18).
  • MMP production is thought to be MMP production (24) .
  • MMP-9 production and its overexpression are dependent on leukocytes (15). Tumor cells may induce release of MMP-9 from human mononuclear cells (19). Inhibition of MMP has been shown to delay the growth of tumors and prolonged survival of animals in experimental studies (2, 12).
  • MMP-9 levels were similar before and after surgery for the LS group as a whole, in fact, 30% of the laparoscopic cancer patients had increased MMP-9 levels after surgery. This was more often the case for patients with advanced disease. Other reasons for increased MMP-9 levels in the closed surgery setting remain to be elucidated. Further studies are needed to determine the clinical importance, if any, of the short-lived increase in plasma MMP-9 levels noted after colectomy. Likewise, additional studies are needed to identify MMP regulatory agents in this setting.
  • TIMP-I levels were about 135% greater than the mean preoperative level for the patients in both OS and LS groups (significant difference for both groups) .
  • POD 3 in the OS group a significant increase in TIMP-I levels (mean value, 167% of the mean preoperative level) was noted, wherein as in the LS group, a mild but nonsignificant elevation in TIMP levels was recorded.
  • TIMP-2 production after surgery may serve as a feedback mechanism that regulates MMP-9 levels.
  • Serum TIMP-I concentration is reported to be elevated in patients with colorectal cancer (7), although the clinical significance of elevated levels in this patient population remains unclear. In patients with lung cancer, however, increased TIMP-I levels have been associated with a poor prognosis (26) . With regard to renal cell carcinoma, increased expression of MMP-9, MMP-2, TIMP-I and TIMP-2 were noted to be associated with other indicators of poor prognosis (8 ) .
  • IGFBP-3 insulin-like growth factor binding protein 3
  • mice were divided into three groups. Sham Laparotomy (SL), CO 2 Pneumoperitoneum (PP) and Anesthesia Control (AC).
  • SL Sham Laparotomy
  • PP CO 2 Pneumoperitoneum
  • AC Anesthesia Control
  • mice were hIGFBP-3 transgenics on a CD-I background.
  • IGFBP-3 Intact IGFBP-3 levels were measured using a combination Western blot analysis and ELISA at each time point. Serum and intracellular levels
  • Plasma levels of intact IGFBP-3 were significantly lower post SL when compared to preoperative levels. A mean decrease of 76.6% was found after laparotomy (P ⁇ 0.05). Zymography analysis demonstrated significantly higher MMP- 9-related proteolytic activity post SL when compared to preoperative levels (78.5 RU vs. 42.3 RU, p ⁇ 0.05). In the PP and AC groups, no significant change was found between the preoperative and postoperative levels of intact plasma IGFBP-3 or MMP-9. Mononuclear intracellular levels of MMP- 9 were significantly lower post SL when compared to preoperative levels (3 RU vs. 37 RU) . Post-procedure intracellular levels of MMP-9 were not significantly decreased in the PP or AC groups.
  • Plasma levels of intact IGFBP-3 were found to be significantly decreased following SL. This decrease was not seen following PP. Depletion of intact IGFBP-3 following SL correlated with a rapid release of MMP-9 from mononuclear cells and an increase in circulating serum MMP-
  • MMP-9 may play an important role in IGFBP-3 proteolysis post surgical trauma and that circulating mononuclear cells are an important source.
  • PPARs matrix metalloproteinase-9
  • IGFBP-3 insulin-like growth factor binding protein-3
  • PPARs Peroxisome proliferator-activated receptors
  • mice A total of 20 mice were included in this study. All the mice were IGFBP-3 transgenic mice on a CD-I background. 10 mice were assigned to receive fenofibrate - 100mg/kg
  • mice received placebo (70% ethanol) according to the same time schedule.
  • day #4 all mice underwent a sham laparotomy (midline incision from xiphoid to pubis) . Retroorbital blood drawing took place prior to the administration of the drug/placebo, and 24 hours following laparotomy (day #5) .
  • Intact IGFBP-3 levels were measured using a combination of Western blot analysis and ELISA at each time point (48 hours pre-op and 24 hours post-op) . Serum levels of MMP-9 were measured at each time point using zymography.
  • PPAR alpha agonist fenofibrate inhibits the release of MMP- 9 and the depletion of intact IGFBP-3 normally seen following surgical trauma in mice. This inhibition may play a role in reversing the tumor-enhancing effects of surgical therapy seen in previous animal models. Although further studies are necessary, these results suggest that the perioperative administration of fenofibrate may be useful in the inhibition of tumor growth in the postoperative period.
  • TGF-beta latent transforming growth factor-beta
  • MMP-9 92 kDa type IV collagenase
  • Trocme, C, et al. "Human B lymphocytes synthesize the 92-kDa gelatinase matrix metalloproteinase-9," J. Biol. Chem. 273: 20677-20684 (1998).

Abstract

Cette invention propose un procédé pour diminuer la dégradation de la protéine 3 de liaison du facteur de croissance de type insuline (IGFBP-3) chez un sujet à la suite d'une chirurgie ouverte ou laparoscopique. Cette invention propose en outre un procédé pour diminuer la dégradation de la protéine 3 de liaison du facteur de croissance de type insuline (IGFBP-3) chez un sujet à la suite d'une chirurgie ouverte ou laparoscopique. Cette invention propose en outre un procédé pour réduire la probabilité d'un développement de tumeur ou d'une récurrence de tumeur chez un sujet à la suite d'une chirurgie ouverte ou laparoscopique. Enfin, cette invention propose en outre un procédé pour réduire la probabilité d'un développement de tumeur ou d'une récurrence de tumeur chez un sujet à la suite d'une chirurgie ouverte ou laparoscopique.
PCT/US2008/000667 2007-01-18 2008-01-18 Procédés associés à une métalloprotéinase-9 matricielle WO2008088864A2 (fr)

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US60/881,436 2007-01-18

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US8377443B2 (en) 2010-08-27 2013-02-19 Gilead Biologics, Inc. Antibodies to matrix metalloproteinase 9
US8501916B2 (en) 2010-08-27 2013-08-06 Gilead Biologics, Inc. Antibodies to matrix metalloproteinase 9
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