Polyamine analog conjugates and quinone conjugates as...

Details Polyamine analog conjugates and quinone conjugates as... Polyamine analog conjugates and quinone conjugates as...

2000-04-27

2003-11-18

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C514S019300, C514S653000, C514S654000, C514S659000, C514S671000, C514S674000, C530S331000, C530S345000, C544S169000, C560S041000, C560S169000, C564S367000, C564S372000, C564S509000, C564S512000

Reexamination Certificate

active

06649587

ABSTRACT:

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH
Not applicable
TECHNICAL FIELD
This invention relates to therapeutic compositions in which a cytostatic or cytocidal compound, such as a polyamine analog or a quinone, is conjugated to a polypeptide recognized and cleaved by enzymes such as prostate specific antigen (PSA) and cathepsin B. This invention also relates to medicinal uses of these conjugates, such as uses in treating cancer, and uses in treating prostate diseases such as prostate cancer, prostatitis and benign prostatic hyperplasia (BPH).
BACKGROUND OF THE INVENTION
Despite advances in early diagnosis, prostate cancer remains a disease with high and increasing annual incidence and mortality. Prostate cancer is now the most frequently diagnosed cancer in men. This cancer is often 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 over 180,000 men in the U.S. each year, of which over 39,000 will die of the disease. In early stage cancers, metastasis occurs to lymph nodes. In late stage, metastasis to bone is common and often associated with uncontrollable pain.
In addition to cancer, two other significant diseases of the prostate are BPH and prostatitis. The cost of treating these three diseases is immense. The annual treatment of prostatic diseases in the U.S. requires about 4.4 million physician visits and 850,000 hospitalizations, and costs billions of dollars. Although treatments for prostatic diseases exist, these are generally only partially or temporarily effective and/or produce unacceptable side effects.
Benign prostatic hyperplasia (BPH) causes urinary obstruction, resulting in urinary incontinence. It occurs in almost 80% of men by the age of 80. BPH is often 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 BPH is the second most common cause of surgery in males. Unfortunately, a side-effect of TURP is the elimination of the ejaculatory ducts and the nerve bundles of the penis, resulting in impotence in 90% of patients.
An alternative therapy for prostate cancer 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. A combination of a radiating energy device integrated with a urinary drainage Foley type catheter has also been developed. U.S. Pat. No. 5,344,435. However, cancerous prostatic cells generally demonstrate a slow growth rate; few cancer cells are actively dividing at any one time. As a result, prostate cancer is generally resistant to radiation therapy.
This slow growth rate also makes prostate cancer resistant to chemotherapy, although several such methods are now in use or in development. Pharmacotherapy for the treatment of BPH is currently aimed at relaxing prostate smooth muscle (alpha, blockade) and decreasing prostate volume (androgen suppression). Clinical trials have been undertaken to evaluate selective alpha, blockers, antiandrogens, and 5-alpha reductase inhibitors for the treatment of BPH. Finasteride, a 5-alpha reductase inhibitor, has shown an ability to cause regression of the hyperplastic prostate gland in a majority of patients. Mocellini et. al. (1993)
Prostate
22:291; and Marberger (1998)
Urology
51:677-86.
Additional therapeutic techniques for prostate cancer include using 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. 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 steroidal nitrogen mustard derivative, was originally thought to be suitable for targeted drug delivery through conjugation of estrogen to toxic nitrogen mustard. Clinical trials, 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® (bicalutamide, Zeneca, Ltd.), a non-steroidal anti-androgen, 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.
An additional method for treating prostatic diseases involves administration of inhibitors of polyamine synthesis. Dunzendorfer (1985)
Urol. Int
. 40:241-250. Naturally-produced polyamines include spermidine and spermine and their precursor, diamine putrescine, which are secreted by the prostate gland and are abundant in the seminal fluid. Polyamines are required for cell division, and probably for differentiation. Spermine apparently stabilizes the DNA, which is tightly packed in the heads of sperm cells. Polyamines may be essential for stability of actin filament bundles and microtubules. However, polyamine biosynthesis inhibitors such as alpha-difluoromethylornithine (DFMO) cause toxicities, including severe hearing loss, these toxicities sometimes forcing the cessation of treatment. Splinter et al. (1986)
Eur. J. Cancer Clin. Oncol
. 22:61-67; and Horn et al. (1987)
Eur. J. Cancer Clin. Oncol
. 23:1103-1107. Another inhibitor, methylglyoxal-bis-guanylhydrazone (MGBG), caused side effects so extreme that, in one study, drug deaths occurred in over half of treated animals. Dunzendorfer (1985); and Herr et al. (1984)
Cancer
53:1294-1298.
A related type of therapy for prostate cancer involves using polyamine analogs, such as DENSPM (N1,N11-diethylnorspermine or BE-333). Mi et al. (1988)
Prostate
34:51-60. While the precise role(s) of naturally-produced polyamines have not been clearly defined, interactions with DNA and RNA have been convincingly implicated. Since the nature of these interactions is highly structure-dependent, polyamine analogs have been designed to effectively disrupt polyamine function by competition with naturally-occurring polyamines. Several polyamine analogs have been developed that exert marked inhibition of human tumor cell growth both in culture and in nude mice xenografts. Polyamine analogs such as BE-4444 [1,19-bis(ethylamino)-5,10,15-triazanonadecane], BE-373 [N,N′-bis(3-ethylamino)propyl)-1,7-heptane diamine], and BE-333 are particularly effective in inhibiting prostate xenograft tumors in nude mice. Zagaja et al. (1998)
Cancer Chem. Pharm
. 41:505-512; Jeffers et al. (1997)
Cancer Chem. Pharm
. 40:172-179; Feuerstein et al. (1991)
J. Cell. Biochem
. 46:37-47; and Marton et al. (1995)
Ann. Rev. Pharm. Toxicol
. 35:55-91. However, polyamine analogs can cause systemic toxicity. BE-333, for example, causes side effects such as headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia. Creaven et al. (1997)
Invest. New Drugs
15:227-34. In one test, administration of BE-333 caused labored breathing, convulsive movements and acute death in rats. Kanter et al. (1994)
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