Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-12-09
2001-09-11
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C436S064000, C530S350000, C530S352000, C530S386000
Reexamination Certificate
active
06288039
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 breast cancer. More particularly, the present invention relates to pharmaceutical compositions containing uteroglobin for treating or inhibiting metastasis of breast epithelial tumor cells and methods of using the same to treat or inhibit metastasis of breast epithelial tumor cells. The present invention also relates to methods and kits for early diagnosis of metastatic breast 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 breast cancer remains the major cause of cancer death among females.
It will be appreciated by those skilled in the art that there exists a need for effective treatments and a more sensitive and less invasive method of early detection and diagnosis of breast cancer than those treatments and methods currently in use.
Breast cancer presents inherent difficulties in regard to the ease with which it is detected and diagnosed. This is in contrast to detection of some other common cancers, including skin and cervical cancers, the latter of which is based on cytomorphologic screening techniques.
There have been several attempts to develop improved methods of breast cancer detection and diagnosis. In the attempts to improve methods of detection and diagnosis of breast cancer, numerous studies have searched for oncogene mutations, gene amplification, and loss of heterozygosity in invasive breast cancer (Callahan, et al., 1992; Cheickh, et al., 1992; Chen, et al., 1992; and Lippman, et al. 1990). However, few studies of breast cancer have analyzed uteroglobin, uteroglobin mutations and/or altered uteroglobin gene expression in cancer or in pre-invasive neoplastic conditions. Further, none of the studies have developed treatments and methods directly responsive to both pre-invasive conditions and metastatic cancers.
Pre-invasive Conditions
Ductal carcinoma in situ (DCIS) is one pre-invasive condition related to breast cancers. Investigators have demonstrated high levels of p53 protein in 13-40% of DCIS lesions employing a monoclonal antibody to p53, and subsequent sequencing demonstrated mutations in several cases (Poller et al., 1992). The neu/erbB2 gene appears to be amplified in a subset of DCIS lesions (Allred, et al., 1992; Maguire, et al., 1992).
Histologic analysis of DCIS cases suggests that mutations and altered gene expression events, as well as changes in chromatin and DNA content, occur predominantly in comedo DCIS (Bocker et al., 1992; Killeen, et al., 1991; and Komitowski, et al., 1990), which has a rapid rate of local invasion and progression to metastasis. Thus, there are presently few reliable marker genes for non-comedo DCIS (NCDCIS, hereafter).
Cancer in humans appears to be a multi-step process which involves progression from pre-malignant to malignant to metastatic disease which ultimately kills the patient. Epidemiologic studies in humans have established that certain pathologic conditions are “premalignant” because they are associated with increased risk of malignancy. There is precedent for detecting and eliminating pre-invasive lesions as a cancer prevention strategy: dysplasia and carcinoma in-situ of the uterine cervix are examples of pre-malignancies which have been successfully employed in the prevention of cervical cancer by cytologic screening methods. Unfortunately, because the breast cannot be sampled as readily as cervix, the development of screening methods for breast pre-malignancy involves more complex approaches than cytomorphologic screening now currently employed to detect cervical cancer.
Pre-malignant breast disease is also characterized by an apparent morphological progression from atypical hyperplasias, to carcinoma in-situ (pre-invasive cancer) to invasive cancer which ultimately spreads and metastasizes resulting in the death of the patient. Careful histologic examination of breast biopsies has demonstrated intermediate stages which have acquired some of these characteristics but not others. Detailed morphological studies have established that different morphologic lesions progress at different rates, varying from atypical hyperplasia (with a low risk) to comedo ductal carcinoma-in-situ which progresses to invasive cancer in a high percentage of patients (London et al., 1991; Page et al., 1982; Page et al., 1991; and page et al, 1978). Family history is also an important risk factor in the development of breast cancer and increases the relative risk of these pre-malignant lesions (Dupont et al., 1985; Dupont et al., 1993; and London et al., 1991). Of particular interest is non-comedo carcinoma-in-situ which is associated with a greater than ten-fold increased relative risk of breast cancer compared to control groups (Otteser et al., 1992; Page et al., 1982). Two other reasons besides an increased relative risk support the concept that DCIS is pre-malignant: 1) When breast cancer occurs in these patients, it regularly occurs in the same region of the same breast where the DCIS was found; and 2) DCIS is frequently present in tissue adjacent to invasive breast cancer (Ottensen et al., 1992; Schwartz et al., 1992). For these reasons, DCIS very likely represents a rate-limiting step in the development of invasive breast cancer in women.
DCIS
DCIS (sometimes called intraductal carcinoma) is a group of lesions in which the cells have grown to completely fill the duct with patterns similar to invasive cancer, but do not invade outside the duct or show metastases at presentation. DCIS occurs in two forms: comedo DCIS and non-comedo DCIS.
Comedo DCIS is often a grossly palpable lesion which was probably considered “cancer” in the 19th and early 20th century and progresses to cancer (without definitive therapy) in at least 50% of patients within three years (ottesen et al., 1992; Page et al., 1982). Most of the molecular alterations which have been reported in pre-malignant breast disease have been observed in cases of comedo DCIS (Poller et al., 1993; Radford et al., 1993; l and Tsuda et al., 1992).
Non-comedo DCIS is detected by microscopic analysis of breast aspirates or biopsies and is associated with a 10 fold increased risk of breast cancer, which corresponds to a 25-30% absolute risk of breast cancer within 15 years (Ottesen et al., 1992; Page et al., 1982; and Ward et al., 1992).
Widespread application of mammography has changed the relative incidence of comedo and non-comedo DCIS such that NCDCIS now represents the predominant form of DCIS diagnosed in the United States (Ottesen et al., 1992; Page et al., 1982; and Pierce et al., 1992). Both forms of DCIS generally recur as invasive cancer at the same site as the pre-malignant lesion (without definitive therapy). The precursor lesions to DCIS are probably atypical ductal hyperplasia and proliferative disease without atypia which are associated with lower rates of breast cancer development, but show further increased risk when associated with a family history of breast cancer (Dupont et al., 1985; Dupont et al., 1989; Dupont et al., 1993; Lawrence, 1990; London et al., 1991; Page et al., 1982; page et al., 1985; Page et al., 1991; Page et al., 1978; Simpson et al., 1992; Solin et al., 1991; Swain, 1992; Weed et al., 1990).
What is needed, then, is effective treatments for and sensitive methods of detection and diagnosis of breast cancer when the cancerous cells are still in the pre-invasive stage. To illustrate the usefulness in early breast cancer detection of a marker gene and its encoded protein, an analogous situation might be to consider the dramatic impact that prostate specific antigen has had on early stage prostate cancer. Treatments and methods of early detection and diagnosis of breast cancer are presently lacking in the prior art or have not proven to be effective in clinical settings.
Studies Showing Increased Risk o
Manyak Michael J.
Patierno Steven R.
George Washington University
Heiman Lee C.
Juneau Todd L.
Nath Gary M.
Seaman D. Margaret
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