Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-12-09
2003-01-21
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C530S350000, C530S352000, C530S386000, C530S850000, C530S851000, C530S853000
Reexamination Certificate
active
06509316
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to pharmaceutical compositions, methods and kits that provide for the early diagnosis and treatment of lung cancer. More particularly, the present invention relates to pharmaceutical compositions containing uteroglobin for treating or inhibiting metastasis of lung epithelial tumor cells and methods of using the same to treat or inhibit metastasis of lung epithelial tumor cells. The present invention also relates to methods and kits for early diagnosis of metastatic lung cancer by assaying for uteroglobin and comparing the results against control cells.
2. Description of the Prior Art
Cancers develop from uncontrolled multiplication of cells. All cancers are life threatening, and lung cancer remains the major cause of cancer death among both males and females.
There are four types of lung cancer found in humans: squamous, adeno, small cell, and large cell. Each tumor expresses specific differentiation features or surface phenotype determinants, all of which distinguish these cells form normal cells. The development of monoclonal antibody diagnostic techniques has greatly enhanced the production of reagents capable of differentiating normal cells from cancer cells and differentiating between cancer cell types. However, none of these markers have been able to provide information concerning when a tumor cell or cells will become metastatic.
The major cause of morbidity and mortality for cancer in humans is metastatic disease. As a consequence, there has been much interest in the mechanisms involved in invasion of cells and metastasis. Several enzyme systems have been implicated in the metastatic process: metalloproteinases, cysteine proteases, and serine proteases. Yagel, S. A. et al., 49
Cancer Research
3553 (1989), Dickson, R. B., 41
J. Steroid Biochem. Molec. Biol.
389 (1992) and Zucker S. et al., 45
Cancer Research
6168 (1985). Inhibitors of metalloproteinases, especially of the collagenases, have been the focus of intense study. DeClerck A. et al., 52
Cancer Research
701 (1992).
However, metastatic cancers have proven to be particularly difficult to treat. These cancers pose the highest risk to patients and, for optimal prognosis, often must be treated by aggressive methods that present increased risks of deleterious side-effects. Most treatments now available have severe toxic side effects to the human body such as nausea, vomiting, hair loss and fatigue.
Therefore, there is a great need for methods that accurately distinguish those tumors that are likely to metastasize from those that are unlikely to do so. Furthermore, since currently available methods of treating metastatic cancers often are inadequate, there also is a clear need for improved anti-metastatic agents and methods to treat metastatic cancers, and metastatic lung cancers in particular.
Metastatic cancers originate from a primary tumor. Metastasis of the primary tumor produces secondary tumors and disseminated cancer. It is well known that both primary and secondary tumors shed large numbers of cells.
The shed cells can spread through the body. For instance, a primary tumor may damage the surrounding lymph or circulatory vessels, allowing entry of shed cells into the lymph or circulatory systems, and hastening their spread in the body. Moreover, shedding of cells by cancerous tumors increases during surgery and radiotherapy.
Most shed cells do not form new tumors. To do so such cells must surmount a series of physical and physiological barriers. In fact, a series of distinct events must occur for metastasis to occur.
The primary tumor physically must (i) invade interstitial space of the primary tissue. In particular, it must (ii) penetrate the basement membrane of the tissue. For most metastases, the tumor must damage the endothelial cell wall of lymphatic or vascular vessels to provide access to shed cells. Cells that enter the lymph or blood must (iii) survive hemodynamic stress and host defenses in the circulation and, furthermore, (iv) the cells must lodge at a new site in the circulatory system, a process that apparently involves aggregated platelets. A cell then must (v) extravasate out of the vessel into the interstitial space. Finally, it must (vi) invade the interstitial space of the secondary organ and proliferate in the new location. Although the process of metastasis is physiologically complex, the overall pattern of metastasis is general to many types of cancers including lung cancers.
The metastatic process also clearly involves complex intracellular mechanisms that alter cancerous cells and their interactions with surrounding cells and tissues. Currently, it is thought that proliferation of many cancerous cells depends upon specific ligand-receptor interactions. Thus far, however, it has not been possible to develop a therapy that prevents or effectively inhibits metastasis of metastatic cancers.
The complexity of the processes involved in metastasis, and the lack of understanding of underlying molecular mechanisms, have made it particularly difficult in some cases to distinguish tumors that are likely to metastasize from those that are unlikely to do so.
The inability to discern the metastatic potential of tumors precludes accurate prognosis and leads, inevitably, to the therapeutic intervention that either is too aggressive or insufficiently aggressive. Furthermore, for all types of cancers it has been difficult or impossible thus far to develop treatments that inhibit or prevent the spread of metastatic tumors. Clearly, there remains a great need for methods to accurately determine the metastatic potential of tumors and for effective anti-metastatic compositions and methods.
The development of monoclonal antibody techniques for differentiating normal cells from cancer cells and differentiating one type of cancer cell from another has greatly enhanced lung cancer detection but does not yield information regarding metastatic potential of a neoplastic, dysplastic, or tumor cell.
Mulshine et al., U.S. Pat. No. 5,455,159, discloses early diagnosis of lung cancer by using monoclonal antibodies to detect cells that express antigens whose increased levels correlates with the development of lung cancer.
Mulshine et al., U.S. Pat. No. 4,569,788, discloses monoclonal antibodies which can be used to detect non-small cell lung cancer and distinguish non-small cell cancer from other cancers and normal cells.
Hirohashi et al., U.S. Pat. No. 4,683,200, discloses IgM class monoclonal antibody which is reactive with human lung cancers.
Loor et al., U.S. Pat. No. 4,690,890, discloses a process for detecting two antigens using an immunometric dual sandwich assay.
Tanswell et al., U.S. Pat. No. 4,624,930, discloses a process for detecting polyvalent antigens using a three receptor reaction.
However, none of the prior art techniques utilize uteroglobin or antibodies which react with the same. None of the prior art techniques disclose the use of proteins which are down-regulated or which exhibit decreased expression of the normal protein during neoplastic development. In contrast, the prior art has generally relied upon the up-regulation of cellular proteins to support the detection of these tumor markers. Further, the prior art does not disclose aberrantly processed proteins leading to aberrant protein structure and function, nor does the prior art provide for the ability to inhibit the metastatic process by administering the missing normal protein, thus re-creating positive feedback mechanisms within the cellular machinery.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions, methods and kits that provide for the early diagnosis and treatment of lung cancer. More particularly, the present invention relates to pharmaceutical compositions containing uteroglobin protein of SEQ ID NO. 1 for treating or inhibiting metastasis of lung epithelial tumor cells and methods of using the same to treat or inhibit metastasis of lung epithelial tumor cells. The present invention also relates to methods an
Manyak Michael J.
Patierno Steven R.
Canella Karen A.
Caputa Anthony C.
George Washington University
Heiman Lee C.
Juneau Todd L.
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