Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of...
Reexamination Certificate
2000-09-06
2003-11-25
Yucel, Remy (Department: 1636)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
C435S326000, C435S344100
Reexamination Certificate
active
06653129
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a method for the isolation and detection of normal, benign hyperplastic, and cancerous prostate epithelial cells from semen, using a magnetic activated cell sorter (MACS).
BACKGROUND OF THE INVENTION
In spite of improved treatments for certain forms of cancer, it is still a leading cause of death in the United States. Since the chance for complete remission of cancer is, in most cases, greatly enhanced by early diagnosis, it is very desirable that physicians be able to detect cancers before a substantial tumor develops. However, the development of methods that permit rapid and accurate detection of many forms of cancer continues to challenge the medical community. One such illustrative form of cancer is prostate cancer.
Prostate cancer is the most common cancer in men with an estimated 317,000 cases in 1996 in the United States. It is the second leading cause of death among men who die from neoplasia with an estimated 40,000 deaths per year. Prompt detection and treatment is needed to limit mortality caused by prostate cancer.
Screening tests (i.e., digital rectal examination and prostatic specific antigen levels) are widely used for early detection of potentially curable prostatic cancer, but an accurate cytologic or histologic assessment is necessary to confirm the proper and accurate diagnosis. A prostatic needle biopsy is specific, but invasive and has a significant false negative rate (Stroumbakis, N. et al.,
Urology
, 49 (Suppl. 3A):113-118 (1997)). Furthermore, this procedure is associated with a significant level of morbidity, such as infection and bleeding.
Detection of Prostate Cancer
When it metastasizes, prostatic cancer has a distinct predilection for bone and lymph nodes (Saitoh et al.,
Cancer
, 54:3078-3084 (1984)). At the time of clinical diagnosis, as many as 25% of patients have bone metastasis demonstrable by radionuclide scans (Murphy, G. P., et al.,
J. Urol.
, 127:928-939 (1982)). Accurate clinical evaluation of nodal involvement has proven to be difficult. Imaging techniques such as computed tomography (“CT”) or magnetic resonance (“MR”) imaging are unable to distinguish metastatic prostate cancer involvement of lymph nodes by criterion other than size (i.e., >1 cm). Therefore, by definition, these imaging modalities are inherently insensitive in the detection of small volume (<1 cm) disease as well as non-specific in the detection of larger volume adenopathy. A recent study assessed the accuracy of MR in patients with clinically localized prostate cancer (Rifkin et al.,
N. Engl. J. Med
., 323:621-626 (1990)). In this study, 194 patients underwent a MRI examination and 185 of these patients had a lymph node dissection. Twenty-three (13%) of the patients had pathologically involved lymph nodes. MRI was suspicious in only 1 of these 23 cases, resulting in a sensitivity of 4%. Similar results have also been noted with CT scans (Gasser et al.,
N. Engl. J. Med
. (
Correspondence
), 324(7):49-495 (1991)).
The elevation of serum acid phosphatase activity in patients having metastasized prostate carcinoma was first reported by Gutman et al.,
J. Clin. Invest
., 17:473 (1938). In cancer of the prostate, prostatic acid phosphatase is released from the cancer tissue into the blood stream with the result that the total serum acid phosphatase level can be greatly increased above normal values. Numerous studies of this enzyme and its relation to prostatic cancer have been made since that time, e.g. Yan,
Amer. J. Med
., 56:604 (1974). However, the measurement of serum acid phosphatase is elevated in about 65-90 percent of patients having carcinoma of the prostate with bone metastasis; in about 30 percent of patients without roentgenological evidence of bone metastasis; and in about only 5-10 percent of patients lacking clinically demonstrable metastasis.
Prior art attempts to develop a specific test for prostatic acid phosphatase have met with only limited success, because techniques which rely on enzyme activity on a so-called “specific” substrate cannot take into account other biochemical and immunochemical differences among the many acid phosphatases which are unrelated to enzyme activity of prostate origin. In the case of isoenzymes, i.e., genetically defined enzymes having the same characteristic enzyme activity and a similar molecular structure but differing in amino acid sequences and/or content and, therefore, immunochemically distinguishable, it would appear inherently impossible to distinguish different isoenzyme forms merely by the choice of a particular substrate. It is, therefore, not surprising that none of these prior art methods is highly specific for the direct determination of prostatic acid phosphatase activity (
Cancer
5:236 (1952);
J. Lab. Clin. Med
., 82:486 (1973);
Clin. Chem. Acta
, 44:21 (1973); and
J. Physiol. Chem
., 356:1775 (1975)).
In addition to the aforementioned problems of non-specificity, which appear to be inherent in many of the prior art reagents employed for the detection of prostate cancer phosphatase, there have been reports of elevated serum acid phosphatase associated with other diseases, which further complicates the problem of obtaining an accurate clinical diagnosis of prostatic cancer. For example, Tuchman et al. noted that serum acid phosphatase levels appear to be elevated in patients with Gaucher's disease (Tuchman et al.,
Am. J. Med
., 27:959 (1959)).
Due to the inherent difficulties in developing a “specific” substrate for prostate acid phosphatase, several researches have developed immunochemical methods for the detection of prostate acid phosphatase. However, the previously reported immunochemical methods have drawbacks of their own which have precluded their widespread acceptance. For example, Shulman et al. described an immunodiffusion test for the detection of human prostate acid phosphatase (Shulman et al.,
Immunology
, 93:474 (1964)). Using antisera prepared from a prostatic fluid antigen obtained by rectal massage from patients with prostatic disease, no cross-reactivity precipitin line was observed in the double diffusion technique against extracts of normal kidney, testicle, liver, and lung. However, this method has the disadvantages of limited sensitivity, even with the large amounts of antigen employed, and of employing antisera which may cross-react with other, antigenically unrelated serum protein components present in prostatic fluid.
WO 79/00475 to Chu et al. describes a method for the detection of prostatic acid phosphatase isoenzyme patterns associated with prostatic cancer which obviates many of the above drawbacks. However, practical problems are posed by this method, such as the need for a source of cancerous prostate tissue from which the diagnostically relevant prostatic acid phosphatase isoenzyme patterns associated with prostatic cancer are extracted for the preparation of antibodies thereto.
In recent years, considerable effort has been spent to identify enzyme or antigen markers for various types of malignancies with the view towards developing specific diagnostic reagents. Previous investigators have demonstrated the occurrence of human prostate tissue-specific antigens. The ideal tumor marker would exhibit, among other characteristics, tissue or cell-type specificity.
Use of Monoclonal Antibodies in Prostate Cancer Detection and Treatment
Theoretically, radiolabeled monoclonal antibodies (“mAbs”) offer the potential to enhance both the sensitivity and specificity of detecting prostatic cancer within lymph nodes and elsewhere. While many mAbs have previously been prepared against prostate related antigens, none of these mAbs were specifically generated with an imaging objective in mind. Nevertheless, the clinical need has led to evaluation of some of these mAbs as possible imaging agents (Vihko et al.,
Biotechnology in Diagnostics
, 131-134 (1985); Babian et al.,
J. Urol
., 137:439-443 (1987); Leroy et al.,
Cancer
, 64:1-5 (1989); Meyers et al.,
The Prostate
, 14:209-220 (1989)).
In some cases, the monocl
Bander Neil H.
Glode Leonard Michael
Suh Chang In
Fish & Richardson P.C.
Sandals William
The Regents of the University of Colorado
Yucel Remy
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