Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving hydrolase
Reexamination Certificate
1999-12-22
2004-11-02
Gitomer, Ralph (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving hydrolase
C435S024000
Reexamination Certificate
active
06811995
ABSTRACT:
BACKGROUND OF THE INVENTION
A class of disorders may be characterized as tissue remodelling-associated conditions, and includes cancers, arthritic conditions, obstructive disorders, degenerative disorders, and problematic wound-healing and ulcerative disorders. Paradigmatic among these is prostate cancer (CaP), the leading source of new cases of cancer in men in this country, and the second leading cancer cause of cancer death after lung cancer. Over 40,000 Americans are estimated to have died of CaP in 1995, and about 244,000 new cases of prostate cancer were detected (Cancer Facts and Figures —1995
, American Cancer Society, Inc.,
1995) and these numbers have increased annually at an alarming rate. Further, the rate of appearance of prostate cancer in African-American men is 37% higher than for their white counterparts (Jaroff, L. (Apr. 1, 1996), Time).
The current primary diagnostic tool for disorders of the prostate is measurement of the level of prostate-specific antigen (PSA) in blood, which in normal men ranges from 0 to 4 nanograms/milliliters. Prostate enlargement, a condition known as benign prostatic hyperplasia (BPH), is found in about half of men over age 45. With BPH, PSA levels rise in proportion to prostate size, possibly obscuring diagnosis of CaP. In addition, a significant proportion of men with CaP have normal PSA levels. The PSA test is somewhat non-specific for distinguishing CaP and BPH, and produces a degree of false negative results (Garnick, M., (1993),
Am. Inst. Med.,
118:804-818). Further, the PSA test is somewhat invasive, requiring the subject to give a blood sample, a procedure that requires trained personnel, in the setting of a doctor's office or clinic. The PSA test, a major advance over previous procedures, thus leaves much to be desired.
CaP is treated by surgery, radiation therapy, cryotherapy or implantation of radioactive seeds, or a combination of these procedures. In choosing one of these treatments, consideration is also taken of possible sequelae that impact negatively on quality of life, such as temporary or long-term incontinence and impotence. Further, following surgical or chemotherapeutic treatment, production of testosterone is suppressed hormonally, to discourage metastases in the CaP patient. Hormonal suppression is found to be effective for several years duration, however cancer cells that have metastasized eventually become resistant to the drugs of hormonal suppression. CaP metastasis to other sites is inevitably fatal. Only a small percent of men with microscopically-detectable CaP progress to metastatic cancer and actually die of this disease. A current medical approach, particularly for the elderly, is “watchful waiting”, wherein tumors are not treated but rather monitored for progression.
SUMMARY OF THE INVENTION
The present invention provides biological markers to non-invasively monitor the diagnosis and prognosis of prostate disorders and other tissue remodelling-associated conditions. This invention provides methods and kits using non-invasive procedures for detection of tissue remodelling-associated conditions in subjects and patients, for diagnosis of diseases such as prostate cancer, breast cancer, ovarian cancer, brain tumors, arthritic conditions, obstructive conditions, and ulcerative conditions. The primary screens use biological fluid samples that may be obtained by personnel without medical training, and do not require visiting a clinic or hospital. The statistical association between positive results and occurrence of tissue remodelling-associated conditions are applied to early diagnoses of the appearance of these conditions, and to prognoses of changes in these conditions.
The present invention features non-invasive methods for facilitating diagnosis of a subject for a tissue remodelling-associated condition. The method involves obtaining a biological sample from that subject and detecting an enzyme in that sample, facilitating the diagnosis. The non-invasive method was based at least in part, on the observation of full length, active intact enzymes that are normally associated with the process of tissue remodelling, in urine samples from patients with certain conditions. For example, gelatin-degrading matrix metalloproteinases and other proteases have been found in the urine of cancer patients. Further, high statistical associations between presence of prostate cancer and appearance of certain enzymes in urine, and between metastatic cancer and certain enzymes in urine, have been found.
The tissue remodelling conditions that can be monitored by the methods of this invention include a variety of types of cancer, moreover, the enzymes are suitable for diagnosis of other tissue remodelling conditions, such as arthritis, degenerative conditions, and obstructive conditions. The invention provides non-invasive methods for diagnosing these conditions by assay for enzymes in biological fluids.
More preferably, the methods of this invention embody detection of enzymes in urine, for diagnosis and prognosis of cancer, and most preferably, prostate cancer. The invention also relates to diagnosis and prognosis of metastatic prostate cancer. The varieties of cancer suitable for diagnosis by the methods of this invention include, among others, cancers of epithelial origin, for example, cancers of the nervous system, breast, retina, lung, skin, kidney, liver, pancreas, genito-urinary tract, ovarian, uterine and vaginal cancers, and gastrointestinal tract cancers, which form in cells of epithelial origin. Using the methods described here, cancers of mesodermal and endodermal origin, for example, cancers arising in bone or in hematopoietic cells, are also diagnosed.
In a preferred embodiment, the enzymes that are detected are matrix-digesting enzymes, more preferably, enzymes that are proteinases, and most preferably, enzymes that are metalloproteinases. In a different aspect, the methods of this invention involve enzymes that are full-length active enzymes, and they are matrix metalloproteinases. In another aspect, the method involves removal of low molecular weight contaminants from urine prior to the detection step; preferably, the urine is dialyzed to remove low molecular contaminants prior to the detection step.
Another aspect of the methods features a fully non-invasive means for facilitating the diagnosis of a subject for a disorder of the prostate. A urine sample is obtained from the subject, and a prostate disorder-associated enzyme is detected in the urine sample, facilitating the diagnosis of that subject for the prostate disorder. More preferably, the prostate disorder-associated enzyme is a matrix-digesting enzyme, most preferably, a proteinase which is a metalloproteinase. The disorders of the prostate include benign prostatic hyperplasia, “problematic” prostatic hyperplasia, organ-defined prostate cancer, this cancer which may previously have been treated surgically or chemically, and particularly, situations in which metastatic cancer is suspected. The method encompasses diagnosis of subjects who are being treated hormonally with agents that block testosterone.
The invention facilitates diagnosis of subjects for prostate cancer, using a urine sample from such subjects, and detecting one or more prostate cancer-associated enzymes. Enzymes of the matrix metalloproteinase class are among those that are diagnostic, and in the case of prostate cancer, the method involves detection of gelatinase A, gelatinase B, and related activities. More preferably, the detected metalloproteinase enzyme has a molecular weight approximately equal to 72 kDa, 92 kDa, or equal to or greater than approximately 150 kDa. Yet another feature of the invention is a method for prognosis of metastatic prostate cancer, by obtaining a biological sample from a subject and detecting a metastatic prostate cancer-associated enzyme in that biological sample facilitating the prognosis of metastatic prostate cancer. In the preferred embodiment for detecting these enzymes, low molecular weight contaminants are removed from the urine prior
Freeman Michael R.
Moses Marsha A.
Wiederschain Dmitri
Children's Medical Center Corporation
Gitomer Ralph
Nixon & Peabody LLP
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