Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-02-18
2001-02-13
Eyler, Yvonne (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S004000, C435S007230, C436S063000, C436S064000
Reexamination Certificate
active
06187536
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds for and methods of identifying and imaging pancreatic cancer cells and identifying and treating individuals with pancreatic cancer.
BACKGROUND OF THE INVENTION
Pancreatic adenocarcinoma is the fifth leading cause of cancer death in the United States. The etiology of this malignancy is large unknown. Advancing age, male gender and smoking are established risk factors, while chronic pancreatitis and diabetes may be as well. The prognosis for patients with pancreatic cancer is poor, with reported 1 year survival rates between 5% and 10%.
There is considerable evidence to support a central role for cholecystokinin (CCK)* in human pancreatic cancer. The influence of endogenous hormones is well-described for several human malignancies including breast, ovary and prostate. Generally, the hormones implicated are important in both the health and disease of their target organ. CCK is an important mediator in the growth of the normal pancreas. Animal studies in which exogenous CCK was administered or endogenous CCK levels were manipulated documented pancreatic hyperplasia, dysplasia and the production of frank malignancies. Similar studies, following the induction of pancreatic tumors, suggest that CCK administration accelerates the growth of malignant compared to uninvolved tissue. In human cancer cell lines and xenografted human tumors, CCK promotes the growth of pancreatic adenocarcinoma.
Two CCK receptors have been characterized and cloned in animal and human studies, CCK-A and CCK-B. These receptors share structural homology and can be differentiated based on their binding affinities for CCK and another related gastrointestinal hormone, gastrin. The CCK-A receptor has an affinity for CCK which is 1000-fold greater than for gastrin while the CCK-B receptor exhibits equivalent affinities for either peptide.
The identification of a specific marker for pancreatic cancer would be of substantial diagnostic, and potentially therapeutic benefit. There remains a need for compositions, kits and methods for screening individuals and identifying pancreatic cancer cells. There remains a need for compositions and a method of imaging pancreatic cancer cells. There remains a need for compositions and methods for treating individuals who have pancreatic cancers.
SUMMARY OF THE INVENTION
The present invention arises out of the observation that, unlike normal human pancreas cells which express the holecystokinin receptor B (CCK B receptors)but not the holecystokinin receptor A (CCK A receptors), human ancreatic cancer cells express CCK A receptors. This finding allows for the targeting of CCK A receptors in diagnostic, imaging and therapeutic regimens related to human pancreatic cancer.
The expression of CCK A receptors in human pancreatic cancer cells may be used as a target to screen individuals for human pancreatic cancer. The CCK A receptor may serve as a human pancreatic cancer marker in samples which do not normally contain CCK A receptors from individuals, particularly those at risk of having pancreatic cancer. In patients, such as those who have been identified as having pancreatic cancer, CCK A receptors represents markers for metastatic disease.
CCK A receptors may be used as a target for imaging agents. The presence of CCK A receptors on cells can be detected in vivo using detectable ligands and the location of CCK A receptor-expressing cells can be used to determine both primary and metastic human pancreatic cancer.
The expression of CCK A receptors in human pancreatic cancer cells provides targets for delivering therapeutic compositions. The compositions may be compounds which effect the activity of CCK A receptors directly. The compositions may be or include components, portions or moieties that are ligands which selectively bind to the CCK A receptors to deliver cytotoxic or cytostatic therapeutic agents.
DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
As used herein, the term “CCK A receptor-specific ligand” and “CCK A receptor ligand” are used interchangeably and are meant to refer to compounds which bind to the human CCK A receptor at a greater affinity than they do to the human CCK B receptor.
As used herein, the term “CCK A receptor-specific antagonist” is meant to refer to compounds which bind to the human CCK A receptor at a greater affinity than they do to the human CCK B receptor and which when bound to the CCK A receptor, display less biological activity than endogenous CCK. Thus, a CCK A receptor specific antagonist competes with native CCK, and when the CCK A receptor specific antagonist is bound to CCK A receptor, either it does not transduce the signal which is transduced by CCK binding to CCK A receptor, or it transduces the signal but at a diminished level. Accordingly, the term CCK A receptor specific antagonist includes antagonists and weak agonists wherein weak a weak agonist is an agonist with less activity than endogenous CCK when bound to the CCK A receptor.
As used herein, the term “non-1,4-benzodiazepin-2-one CCK A receptor-specific antagonist” is meant to refer to CCK A receptor-specific antagonists other than those non-1,4-benzodiazepin-2-one CCK A receptor-specific antagonists disclosed in U.S. Pat. No. 4,994,258, which is incorporated herein by reference.
As used herein, the term “1,4-benzodiazepin-2-one CCK A receptor-specific antagonist” is meant to refer to CCK A receptor-specific antagonists disclosed in U.S. Pat. No. 4,994,258, which is incorporated herein by reference.
As used herein, the term “CCK A receptor-specific agonist” is meant to refer to compounds which bind to the human CCK A receptor at a greater affinity than they do to the human CCK B receptor and which when bound to the CCK A receptor, display qualitatively comparable biological activity as endogenous CCK. Thus, a CCK A receptor specific agonist competes with native CCK, and when the CCK A receptor specific antagonist is bound to CCK A receptor, either transduces the signal which is transduced by CCK binding to CCK A receptor, either to a greater, lesser or equal degree as that which is transduced by CCK. Accordingly, in some cases a CCK A receptor agonist mat be a CCK A receptor specific antagonist as defined herein provided that the agonist is a weak agonists.
As used herein, the term “active agent” is meant to refer to compounds that are therapeutic agents or imaging agents.
As used herein, the term “radiostable” is meant to refer to compounds which do not undergo radioactive decay; i.e. compounds which are not radioactive.
As used herein, the term “therapeutic agent” is meant to refer to chemotherapeutics, toxins, radiotherapeutics, targeting agents, radiosensitizing agents and antisense compounds.
As used herein, the term “chemotherapeutic” is meant to refer to compounds that, when contacted with and/or incorporated into a cell, produce an effect on the cell including causing the death of the cell, inhibiting cell division or inducing differentiation.
As used herein, the term “toxin” is meant to refer to compounds that, when contacted with and/or incorporated into a cell, produce the death of the cell.
As used herein, the term “radiotherapeutic” is meant to refer to radionuclides which when contacted with and/or incorporated into a cell, produce the death of the cell.
As used herein, the term “targeting agent” is meant to refer compounds which can be bound by and or react with other compounds. Targeting agents may be used to deliver chemotherapeutics, toxins, enzymes, radiotherapeutics, antibodies or imaging agents to cells that have targeting agents associated with them and/or to convert or otherwise transform or enhance co-administered active agents. A targeting agent may include a moiety that constitutes a first agent that is localized to the cell which when contacted. with a second agent either is converted to a third agent which has a desired activity or causes the conversion of the second agent into an agent with a desired activity. The result is the localized agent facilitates exposure of an agent with a
Barber Michael T.
Biswas Sanjoy
Waldman Scott A.
Weinberg David
Eyler Yvonne
Holleran Anne L.
Thomas Jefferson University
Woodcock Washburn Kurtz Mackiewicz & Norris
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