Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
1999-03-10
2002-02-26
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S007100, C435S007400, C435S007720, C435S810000, C436S064000
Reexamination Certificate
active
06350571
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel methods for detecting and evaluating bladder cancer, utilizing hyaluronic acid (HA) and hyaluronidase (HAase).
2. Description of Related Art
Bladder carcinoma is the most common cancer of the urinary tract, accounting for 51,000 new cases and 11,000 deaths each year in the United States. Transitional cell carcinomas (TCCs) account for ≈90% of the bladder tumors. These tumors are heterogeneous in their ability to progress. For example, some TCCs behave in a benign fashion (low-grade, G1 tumors) whereas others are intermediate (G2 tumors) to highly aggressive (G3 tumors and carcinoma in situ (CIS)). The high-grade tumors generally metastasize quickly; indeed, at the time of clinical presentation (e.g., hematuria, irritative voiding symptoms etc.), invasive disease already exists for many patients with high-grade bladder tumors.
The two most important prognostic factors for TCCs are grade and stage (which indicates the depth of invasion) (American Joint Committee on Cancer: Staging of cancer at genito-urinary sites. In: Manual for Staging Cancer, 3
rd
edition, pp. 194-195, J. B. Lippincott Co., Philadelphia, 1988). Low-grade (G1) tumors are mostly confined to the mucosa (stage Ta) and have a <2% chance of progression (Heney, Natural history of superficial bladder cancer. Urol. Clin. North Am., 19: 429-435, 1992; Heney and Flanagan, Superficial bladder cancer progression and recurrence. J. Urol., 130: 1083-1086, 1983). Intermediate-grade (G2) tumors range from being non-invasive (Ta) to invasive (stages T1-T4). The G2, Ta tumors have ~11% chance of progression (Heney, Natural history of superficial bladder cancer. Urol. Clin. North Am., 19: 429-435, 1992). With the exception of carcinoma in situ (CIS), most high-grade tumors are initially detected at least at stage T1 (invading lamina propria) and are thus invasive. Muscle invasion (stage T2) by the tumor is ominous, as 50% of these patients develop distant metastasis within two years of diagnosis despite radical surgery, and 60% of them die within 5 years, however treated (Heney and Flanagan, Superficial bladder cancer progression and recurrence. J. Urol., 130: 1083-1086, 1983; Friedell et al., Summary of workshop on carcinoma-in-situ of the bladder. J. Urol., 136: 1047-1048, 1986; Soloway, Invasive bladder cancer: Selection of primary treatment. Semin. Oncol., 17: 551-554, 1990). Due to the malignant nature of high-grade TCCs, their early detection prior to muscle invasion, is crucial for a favorable prognosis.
Thus, it is not only important to detect the presence of tumor early, it is also crucial to identify the high-grade tumors which present with such a grim prognosis. Tumor recurrence is also a characteristic of bladder carcinoma. Therefore, despite a complete remission of the original tumor, patients must be closely followed in order to monitor the treatment efficacy and recurrence (Heney, Natural history of bladder cancer. Urol. Clin. North Am., 19: 429-433, 1992).
The current methods for bladder cancer detection involve cystoscopy, bladder washings, and biopsy. These procedures are invasive and require some form of anesthesia. Urine cytology use is possible but its specificity is low due to its subjective nature. A few other markers such as DNA ploidy, p53 mutations, microsatellite DNA, &bgr;-glucuronidase, basic-FGF levels, autocrine motility factor receptor etc. have been shown to be associated with bladder cancer (Sidransky and Messing, Molecular genetics and biochemical mechanisms in bladder cancer. Urol. Clin. North Am., 19: 629-639, 1992; Mao et al., Molecular detection of primary bladder cancer by microsatellite DNA. Science, 271: 659-662, 1996; Nguyen et al., Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J. Natl. Cancer Inst., 85: 241-242, 1993; Esrig et al., Accumulation of nuclear p53 and tumor progression in bladder cancer. N. Engl. J. Med., 331: 1259-1264, 1994; Ho, Urinary &bgr;-glucuronidase in screening and follow up of primary urinary tract malignancy. J. Urol., 154: 1335-1338, 1995; Korman et al., Autocrine motility factor receptor as a possible urine marker for transitional cell carcinoma of the bladder. J. Urol., 154: 347-349, 1995). However, most of these have not yet been used clinically as diagnostic markers.
Currently, three non-invasive diagnostic tests for bladder cancer are under investigation in the United States. The hematuria home screening test has high sensitivity but low specificity due to the wide spectrum of benign genito-urinary (GU) conditions (kidney stones, benign prostatic hyperplasia etc) which give rise to false positives (Britton et al., A community study of bladder cancer screening by the detection of occult urinary bleeding. J. Urol., 148:788-790, 1992; Messing et al., Hematuria home screening: Repeat testing results. J. Urol., 154: 57-61, 1995). The second test is the Bard BTA Latex agglutination assay. A multi-center trial for this test was conducted in the United States to monitor bladder tumor recurrence. The results show that the sensitivity of this test to detect bladder tumors and, more importantly high-grade TCCs, is only ≈40-50% (Sarosdy et al., Results of a multicenter trial using the BTA test to monitor for and diagnose recurrent bladder cancer, J. Urol., 154: 379-384, 1995; U.S. Pat. No. 5,264,370). In another multicenter study involving 90 patients and the third test, Soloway et al. have shown that the NMP22 test has an overall sensitivity of 70% to detect bladder tumor recurrence (Soloway et al., Use of a new tumor marker NMP22 in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. J. Urol., 156: 363-367, 1996). Thus, to date, no non-invasive test exists that can detect bladder tumor and/or evaluate its grade with high sensitivity and specificity.
With the above problems in the art in mind, the inventors have developed non-invasive methods to detect bladder cancer by measuring the levels of certain “molecular determinants” specifically expressed in the biological fluids (such as urine specimens) of bladder cancer patients. More particularly, the methods of the invention are based on the inventors' discovery that levels of hyaluronic acid and hyaluronidase in a sample of biological fluid, especially urine, are associated with the presence and grade of bladder cancer.
Hyaluronic acid (also known in the art as hyaluronate and hyaluronan, and abbreviated as HA), is a glycosaminoglycan comprising a straight unbranched polysaccharide chain with alternating units of N-acetyl-D-glucosamine and D-glucuronic acid. HA is present ubiquitously in various types of biological material, including both bacteria and animals. In humans, HA is found in high concentrations in umbilical cords, vitreous humor of the eyes, cartilage and synovial fluid. Small amounts of HA are present in CSF, lymph, blood, serum and urine. Levels of HA have been associated with diseases such as rheumatoid arthritis, liver cirrhosis, and Wilms' tumor. HA is associated with non-specific tumors in general, but its use has not been applied heretofore to the discovery, therapy and management of particular clinical tumors.
HA has been known to play a role in several pathophysiological conditions including cancer. For example, HA levels have been shown to be elevated in certain animal tumor models (e.g., rabbit V2 carcinoma, Knudson et al., The role and regulation of tumor associated hyaluronan. In: The Biology of Hyaluronan (J. Whelan, ed.), pp. 150-169, New York, Wiley Chichister (Ciba Foundation Symposium 143), 1989) and human cancers (e.g., lung, Wilms' tumor, breast, etc., Knudson et al., ibid.).
In tumor tissues, HA expands upon hydration opening spaces for tumor cell migration (Knudson et al., The role and regulation of tumor associated hyaluronan. In: The Biology of Hyaluronan (J. Whelan, ed.), pp. 150-169, New York, Wiley Chichister (Ciba Foundation Symposium
Lokeshwar Vinata B.
Pham Henry T.
Caputa Anthony C.
Nickol Gary B
Whitlock Ted W.
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