Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1998-03-02
2001-03-06
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093600, C435S320100, C435S005000, C435S006120, C435S455000, C435S456000, C435S325000, C435S366000, C435S371000, C435S375000
Reexamination Certificate
active
06197293
ABSTRACT:
STATEMENT OF RIGHTS TO INVENTION MADE UNDER FEDERALLY SPONSORED RESEARCH
(Not applicable)
TECHNICAL FIELD
This invention relates to cell transfection using adenoviral vectors, especially replication-competent adenoviruses, and methods of their use. More specifically, it relates to cell-specific replication of adenovirus vectors in cells expressing the androgen receptor, particularly prostate carcinoma cells, through use of a probasin transcriptional regulatory element.
BACKGROUND OF THE INVENTION
There are three significant diseases of the prostate: benign prostate hyperplasia (BPH), prostate cancer, and prostatitis. The cost of treating these three diseases is immense. The annual treatment of prostate diseases in the U.S. required 4.4 million physician visits, 836,000 hospitalizations, and cost over $3 billion in 1985. Approximately one out of every four males above the age of 55 suffers from a prostate disease of some form or another. Prostate cancer is the fastest growing cause of cancer in men, with approximately 244,000 new cases diagnosed and about 44,000 deaths reported for 1995 in the United States. Due to the aging U.S. population, the incidence of BPH and prostate cancer is likely to increase.
BPH causes urinary obstruction resulting in urinary incontinence. It occurs in almost 80% of men by the age of 80. Unregulated dihydrotestosterone is believed to cause hyperplastic prostate growth. Pharmacotherapy for the treatment of BPH is currently aimed at relaxing prostate smooth muscle (alpha blockade) and decreasing prostate volume (androgen suppression). Phase III clinical trails are underway to evaluate selective alpha
l
blockers, antiandrogens, and 5-alpha reductase inhibitors for the treatment of BPH. The most promising of these is finasteride, which has shown an ability to cause regression of the hyperplastic prostate gland in a majority of patients. Mocellini et. al. (1993)
Prostate
22:291.
BPH is treated surgically with a transurethral resection of the prostate (TURP). This procedure is very common: 500,000 TURPs are performed in the U.S. each year and 25% of men will require surgery at some time in their lives to alleviate urinary obstruction. This makes BPH the second most common cause of surgery in males. The TURP procedure requires several days of hospitalization as well as the surgery itself. The average medical reimbursement cost of a TURP in 1987 dollars was $8,000; in 1993 dollars this is $14,000. Unfortunately, a side-effect of the TURP is the elimination of the ejaculatory ducts as well as the nerve bundles of the penis, resulting in impotence in 90% of patients. A TURP is prefaced by an outpatient biopsy procedure to determine if the enlargement of the prostate is benign or cancerous, which also adds to the cost. Hypertrophy may also be treated by transurethral insertion of a tubular stent or expandable dilation catheter to maintain the patency of the urethral lumen. U.S. Pat. No. 4,893,623, issued Jan. 16, 1990, to Rosenbluth et al.; and U.S. Pat. No. 5,527,336, issued Jun. 18, 1996, to Rosenbluth et al.
An alternative therapy for prostate diseases involves radiation therapy. A catheter has been developed which squeezes prostate tissue during microwave irradiation; this increases the therapeutic temperature to which the prostate tissue more distal to the microwave antennae can be heated without excessively heating nearby non-prostate tissue. U.S. Pat. No. 5,007,437, issued Apr. 16, 1991, to Sterzer et al. A combination of a radiating energy device integrated with an urinary drainage Foley type catheter has also been developed. U.S. Pat. No. 5,344,435, issued Sep. 6, 1994, to Turner et al.
Prostate cancer is now the most frequently diagnosed cancer in men. Prostate cancer is latent; many men carry prostate cancer cells without overt signs of disease. Autopsies of individuals dying of other causes show prostate cancer cells in 30% of men at age 50; by age 80, the prevalence is 60%. Further, prostate cancer can take up to 10 years to kill the patient after initial diagnosis. Prostate cancer is newly diagnosed in slightly over 100,000 men in the U.S. each year, of which over 40,000 will die of the disease. There is also high morbidity. Cancer metastasis to bone (late stage) is common and often associated with uncontrollable pain. Metastasis also occurs to lymph nodes (early stage).
The disease progresses from a well-defined mass within the prostate, to a breakdown and invasion of the lateral margins of the prostate, to metastasis to regional lymph nodes, to metastasis to the bone marrow. The aggressiveness of prostate tumors varies widely. Some tumors are relatively aggressive, doubling every six months, whereas other are extremely slow-growing, doubling once every five years. As a consequence of the slow growth rate, few cancer cells are actively dividing at any one time. As a result, prostate cancer is generally resistant to radiation and chemotherapy, although both therapeutic modalities are widely used. Surgery is the mainstay of treatment but it too is largely ineffective and also removes the ejaculatory ducts, resulting in impotence.
Unfortunately, in 80% of cases, diagnosis of prostate cancer is established when the disease has already metastasized to the bones. Of special interest is the observation that prostate cancers frequently grow more rapidly in sites of metastasis than within the prostate itself, the site of the primary cancer.
At this stage there is no effective cytotoxic chemotherapy for prostate cancer. Current therapeutic techniques include the use of chemical forms of medical castration by shutting down androgen production in the testes, or directly blocking androgen production in the prostate. For the treatment of prostate cancer oral estrogens and luteinizing releasing hormone analogs are used as well as surgical removal of glands that produce androgens (orchiectomy or adrenalectomy). However, estrogens are no longer recommended because of serious, even lethal, cardiovascular complications, Luteinizing hormone releasing hormone (LHRH) analogs are used instead. However, hormonal therapy invariably fails with time with the development of hormone-resistant tumor cells. It is not known whether these cells develop as a mutation of the original hormone sensitive cells, or a separate class of cells. Furthermore, since 20% of patients fail to respond to hormonal therapy, it is believed that hormone-resistant cells are present at the onset of therapy.
Estramustine, a steriodal nitrogen mustard derivative, was originally thought to be suitable for targeted drug delivery through conjugation of estrogen to toxic nitrogen mustard. Clinical trails, however, have been disappointing when survival is used as an endpoint. Finasteride, a 4-aza steroid (Proscar® from Merck & Co.), inhibits the enzyme responsible for the intracellular conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate. Casodex® is thought to inhibit cellular uptake of testosterone by blocking androgen receptors in the nucleus. However, almost all advanced cancer prostate cells fail to respond to androgen deprivation. Indolocarbazole derivatives such as K-252a have also recently been developed to treat prostate diseases. U.S. Pat. No. 5,516,771, issued May 14, 1996, to Dionne.
None of these techniques for treating prostate diseases has been universally sucessful. Following localized therapy, up to 40% of patients with advanced disease, and a large proportion of all patients, eventually develop metastatic disease. Treatment for advanced disease initially involving hormonal manipulations and palliative radio therapy have demonstrated symptomatic relief, but no long-term disease-free survival. The use of cytotoxic agents in the management of hormone-resistant advanced prostate cancer remains poorly defined. A few single agents have become “standard therapy”, although demonstration of their efficacy, by contemporary standards, is lacking. Combination chemotherapy is frequently employed, although its contribution to overall patient management is lar
Henderson Daniel R.
Schuur Eric R.
Yu De-Chao
Calydon, Inc.
Guzo David
Morrison & Forester LLP
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