Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of...
Reexamination Certificate
1999-09-07
2002-06-04
Nashed, Nashaat T. (Department: 1652)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
C435S320100, C435S252330, C435S219000, C435S226000, C536S023100, C536S023200, C536S023500
Reexamination Certificate
active
06399371
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to therapeutic and diagnostic agents in cancer and inflammatory diseases. More specifically, the present invention relates to polynucleotide sequences encoding matrix metalloprotease proteins, as well as methods which utilize these sequences, which are useful for the detection, diagnosis, staging, monitoring, prognosis, prevention, or treatment of cancer or inflammatory diseases.
2. Description of the Related Art
The matrix metalloproteases (MMPs) are a multi-enzyme family capable of completely degrading the components of the extracellular matrix (ECM), their natural substrates (W. B. Ennis, and L. M. Matrisian,
J. Neuro
-
Oncology
, 18: 105-109 (1994)). The ECM is a meshwork of cells and various types of collagens and proteoglycans, collectively called connective tissue, which provides mechanical support and helps to maintain the structural integrity of tissues and organs. The function of the ECM is particularly apparent in articular cartilage where it provides cushioning and ease of movement between bones in joints. The MMPs are secreted by the cellular components of the ECM (fibroblasts, chondrocytes and synoviocytes) and inflammatory cells (neutrophils and macrophages) in inactive forms (zymogens) which are converted extracellularly to the active enzymes by various proteinases. Normally MMPs function in a highly regulated fashion as part of the physiological turnover of the ECM, effectively renewing and remodeling the ECM. However, in the clinical features of several diseases, the ECM is degraded and there is much evidence to support that MMPs play a significant pathological role in ECM degradation.
At least fourteen members of the MMP family have been identified and most assigned EC numbers; several more have been discovered recently. They can be classified generally according to four subgroups based on substrate preference or cellular localization; e.g., collagenases prefer Type I and II collagen, gelatinases prefer Type IV collagen, and stromelysins prefer proteoglycans (L. M. Matrisian,
Bio. Essays
14: 455-463 (1992)). The fourth subgroup are the membrane type MMPs (mtMMPs) which are characterized by the presence of a hydrophobic transmembrane domain near the C-terminus for anchoring the protein in the cell membrane. All of the other MMPs are secreted into the extracellular milieu.
Most of the known MMPs contain zinc in their catalytic sites and require calcium for activity. The major human MMPs have been cloned and exhibit greater than 50% homology. They contain a leader sequence for signaling their secretion by cells; a highly conserved pro-enzyme sequence removed upon activation; a catalytic site with a highly conserved zinc binding domain; and a carboxy terminal region containing a conserved sequence similar to hemopexin, a heme binding protein. Although MMPs can be readily activated in vitro using mercurial compounds or trypsin, the precise mechanism for propeptide removal and activation of MMPs in vivo is not understood. Some MMPs can undergo an autoactivation process, while recent evidence indicates that membrane type MMPs may function as activators of other MMPs.
A growing line of evidence implicates the MMPs as important enzymes in cancer metastasis. Although different cancer cell lines have been shown to express various MMPs when grown in culture, gelatinase A in particular has been the focus of a number of recent studies which demonstrates its role in the invasiveness of cancer cells (W. G. Stetler-Stevenson, et al.,
FASEB J
. 7: 1434-1441 (1993)). For example, gelatinase A is found in the urine of bladder cancer patients and specific monoclonal antibodies have been used to detect the enzyme in breast tumor sections (I. M. Margulies, et al., 1: 467-474 (1992)). The enzyme is expressed in an invasive prostate cancer cell line (PC-3 ML) and cells transfected with the gelatinase A gene are capable of extravasation when injected into mice (M. E. Stearns, and M. Wang,
Oncology Res
. 6: 195-201 (1994)). These studies and others implicate the involvement of gelatinase A in tumor metastasis, and suggest that inhibitors of this enzyme may offer therapeutic potential in certain forms of cancer. A broad spectrum matrix metalloproteinase inhibitor has been shown to decrease the tumor burden of mice bearing ovarian carcinoma xenographs (B. Davies, et al.,
Cancer Res
. 53: 2087-2091 (1993)). This compound (BB-94, batimastat) is currently being evaluated in clinical trials for malignant ascites (S. A. Watson, et al.,
Cancer Research
, 55: 3629-3633 (1995)); however, its poor bioavailability necessitates parental administration. Gelatinase A selective succinyl hydroxamates have been suggested as anti-cancer agents as well, yet these compounds possess the same peptidic backbone as batimastat (Porter, J. R.; Beeley, N. R. A.; Boyce, B. A.; Mason, B.; Millican, A.; Millar, K.; Leonard, J.; Morphy, J. R.; O'Connell, J. P. Potent and selective inhibitors of gelatinase A 1. Hydroxamic acid derivatives.
Bioorg. Med. Chem. Lett
., 4: 2741-2746 (1994)). More recently, an orally active, broad spectrum, MMP inhibitor (BB-2516, marimastat) was reported to stop progression of colorectal, ovarian, prostatic and pancreatic cancer (R. P. Beckett, et al.,
D. D. T
., 1: 16-26 (1996)).
Several lines of evidence indicate that the unregulated activity of MMPs is responsible for the joint degradation observed in rheumatoid arthritis and osteoarthritis. In these human arthritides, activated forms of the MMPs and their products (glycosaminoglycans and collagen fragments) are found in synovial fluids and joint tissues in abnormally high amounts (see E. D. Harris Jr., Role of collagenase in joint destruction.
The Joints and Synovial Fluid
, Vol., 1, Sokologg, L., Ed., Orlando, Fla., Academic Press, 1977, T. E. Cawston, et al.,
Arthritis Rheum
., 27: 285-290 (1984), Cawston,
T. Ann. Rheumatic Diseases
., 52: 769-770 (1993), Y. L. Okada, et al.,
J. Biol. Chem
., 261: 14245-14255 (1986), D. L. Scott, et al.,
Molec. Aspects Med
., 12: 341-394 (1991), and E. D. Harris, et al.,
Arthritis Rheum
., 12: 92-102 (1992)). These arthritic tissues also show a greater-than-normal expression of MMPs (S. S. McCachren,
Arthritis and Rheumatism
, 34: 1085-1093 (1991), A. J. P. Docherty and G. Murphy,
Ann. Rheumat. Dis
., 49: 469-479 (1990)) which is induced by cytokines and growth factors, also found abundantly in these tissues (D. L. Scott, et al., (1991), supra, S. M. Frisch and H. E. Ruley,
J. Biol. Chem
., 262: 16300-16304 (1987)). In addition, the activities of MMPs in normal tissues are thought to be regulated by the presence of endogenous tissue inhibitors of MMPs, (TIMPs, see T. E. Cawston,
Curr. Med. Lit. Rheum
., 3: 127-0 (1984)). The ratio of the amounts of TIMP and MMPs is thought to maintain a balance between the rates of degradation and synthesis of ECM. In tissues from rheumatoid arthritics, an abnormally high expression of MMPs results in an imbalance of these enzymes and degradation of ECM (S. S. McCachren (1991) and T. E. Cawston (1984), supra). Thus in arthritis, inhibition of the exacerbated degradative activities of MMPs by specific agents could help restore this balance. In rodent models which mimic the biochemical features of arthritis, there is evidence that the combined action of proteoglycan loss (due to stromelysin activity) and cartilage degradation (due to collagenase) are early events in this disease (R. M. Hembry, et al.,
Am. J. Pathol
., 143: 628-642 (1993), K. A. Hasty, et al.,
Arthritis and Rheumatism
, 33: 388-397 (1990)). Several prototype inhibitors of MMPs have been shown to reduce cartilage degradation in these animal models (M. J. DiMartino, et al.,
J. Cell Biochem. suppl
., 19E: 179 (1991), P. Brown, et al., Orally active inhibitors of cartilage degradation. Abst. # 81, Abstracts of Inflammation '93, Vienna, Austria, p. 29. (1993)).
There is much evidence to suggest that MMPs mediate the migration of inflammatory cells into endothelium (D., Moscatel
Falduto Michael T.
Magnuson Scott R.
Morgan Douglas W.
Abbott Laboratories
Casuto Dianne
Nashed Nashaat T.
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