Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-05-01
2004-03-23
Nguyen, Dave T. (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C430S320000, C424S094100, C536S024500
Reexamination Certificate
active
06710037
ABSTRACT:
All references cited herein are incorporated in their entirety by reference.
TECHNICAL FIELD OF INVENTION
The present invention relates to methods of using polypeptides or polynucleotides that encode polypeptides which enhance inactivation of active androgens for the treatment of androgen-dependent disorders. Specifically, the present invention relates to methods of treating conditions wherein androgen activity is implicated such as prostate cancer, benign prostatic hyperplasia and other androgen-dependent disorders such as androgenic alopecia.
BACKGROUND OF THE INVENTION
An androgen-dependent disorder refers to any disorder that can benefit from a decrease in androgen stimulation and includes pathological conditions that depend on androgen stimulation. An androgen-dependent disorder can result from an excessive accumulation of testosterone or other androgenic hormone; increased sensitivity of androgen receptors to androgen; or an increase in androgen-stimulated transcription. Examples of androgen-dependent disorders include prostate cancer, benign prostatic hyperplasia, acne vulgaris, seborrhea, female hirsutism, androgenic alopecia (which includes female and male pattern baldness), and polycystic ovary syndrome. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of androgen-dependent disorders resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4′-nitro-3′-trifluoromethyl-isobutyranilide. See Neri et al., “A Biological Profile of a Nonsteroidal Antiandrogen, SCH 13521 (4′-Nitro-3′-Trifluoromethylisobutyranilide)”,
Endocrinology
, 91(2):427-437 (1972). Unfortunately, even though these products are largely devoid of direct hormonal stimulatory effects, they compete with all natural androgens for receptor sites. Hence these products have a tendency to feminize a male host or the male fetus of a female host and/or initiate feedback effects that cause hyperstimulation of the testes with increased androgen production.
Growth of prostate tissue is androgen-dependent in benign prostatic hyperplasia (BPH) and early stage prostate cancer. Commonly, treatment of prostate cancer is based on surgery and/or radiation therapy, but these methods also have deleterious side effects and are ineffective in a significant percentage of cases. For example, radical prostatectomy is often accompanied by a period of dysfunction. Likewise, radiation therapy not only invokes acute adverse effects but at times also leads to long-term complications that can be debilitating or even life threatening, requiring more invasive treatments or hospitalization.
Cytotoxic chemotherapy is largely ineffective in treating prostate cancer. Even though recently developed cytotoxic agents (e.g., paclitaxel, docetaxel, and vinorelbine) have been shown to decrease prostate-specific antigen (PSA) and the pain secondary to cancer, the majority of studies using chemotherapy have failed to improve the duration of overall survival when compared to appropriate controls. Plus, the toxicity associated with these agents is unsuitable for treating elderly patients.
Luteinizing hormone-releasing hormone (LHRH) receptor agonists, and more recently antagonists, are widely used for treatment of hormone-sensitive prostate cancer. But the testicular atrophy and the loss of libido, muscle mass and erectile function that results from decreased gonadotropin levels is only tolerable for life-threatening indications. Similarly, surgical castration is an alternative for decreasing serum androgens to treat advanced prostate cancer, but the loss of function which results can only be considered for life-threatening conditions.
5&agr;-reductase inhibitors, such as finnsteride, that inhibit reduction of testosterone to the more active androgen 5&agr;-dihydrotestosterone (DHT) are used for the treatment of BPH. But 5&agr;-reductase inhibitors are only marginally effective in treatment of BPH and often require at least six months of treatment before efficacy may be observed. This marginal activity may be due to prostatic accumulation of active testosterone to eight times the normal level (Wright et al., “Relative Potency of Testosterone and Dihydrotestosterone in Preventing Atrophy and Apoptosis in the Prostate of the Castrated Rat”,
J. Clin. Invest
., 98(11):2558-2563 (1996)).
An alternative approach involves gene therapy, that is, the introduction of a gene into cells for therapeutic purposes. As with more conventional therapies, the success of gene therapy relies on targeting cells selectively and effectively without adversely affecting other cells. For example, gene therapy using E-cadherin, a polypeptide involved in cell-cell and cell-matrix interactions, was proposed as a means of limiting the metastasis of cancerous cells. This approach, however, has been unsuccessful; apparently because other cadherins are also involved in the metastasis of cancerous cells. In another study, patients were treated with autologous genetically modified tumor cells that secreted granulocyte-macrophage colony-stimulating factor (GM-CSF) in an effort to elicit an immune response against prostate cancer antigens. Unfortunately, only a small fraction of these patients responded to the treatment by producing antibodies; and of those antibodies produced, none appeared to be prostate-specific.
The present inventors have responded to the above needs by developing novel approaches for the treatment of androgen-dependent disorders. In contrast to other approaches such as castration, LHRH agonists, LHRH antagonists and 5&agr;-reductase inhibitors which focus on decreasing synthesis of active androgens to decrease androgen stimulation, the present invention focuses on enhancing inactivation of active androgens, by increasing their degradation or elimination. Surprisingly, the present invention has resulted in tumor regression in human tumor (e.g., LNCaP tumor) xenograft studies in mice, whereas approaches that decreased androgen synthesis failed to induce tumor regression in this model. Additionally, the present invention may be practiced locally thereby decreasing androgen stimulation in the target tissue and thus avoiding systemic side effects.
SUMMARY OF THE INVENTION
The present invention provides a method for treating an androgen-dependent disorder comprising administering to a patient suffering from the androgen-dependent disorder an effective amount of polypeptide or a polynucleotide encoding the polypeptide which enhances inactivation of an active androgen.
In a preferred embodiment, the androgen-dependent disorder includes but is not limited to prostate cancer, benign prostatic hyperplasia, acne vulgaris, seborrhea, female hirsutism, androgenic alopecia, and polycystic ovary syndrome.
In one preferred embodiment, the polypeptide reduces 5&agr;-dihydroxytestosterone (DHT) to 5&agr;-androstane-3&agr;-17&bgr;-diol (3&agr;-diol). In a more preferred embodiment, the polypeptide is a 3&agr;-hydroxysteroid dehydrogenase (3&agr;-HSD) enzyme. More preferably, the polypeptide is a 3&agr;-HSD type 1 (3&agr;-HSD1), a 3&agr;-HSD type 2 (3&agr;-HSD2), or a 3&agr;-HSD type 3 (3&agr;-HSD3) enzyme.
In another preferred embodiment, the polypeptide reduces 5&agr;-dihydroxytestosterone (DHT) to 5&agr;-androstane-3&bgr;-17&bgr;-diol (3&bgr;-diol). In a more preferred embodiment, the polypeptide is a 3&bgr;-hydroxysteroid dehydrogenase (3&bgr;-HSD) enzyme.
In yet another preferred embodiment, the polypeptide oxidizes testosterone to androst-4ene-3,17-dione or oxidizes DHT to 5&agr;-androstane-3,17-dione (5&agr;-dione). In a more preferred embodiment, the polypeptide is an oxidative 17&bgr;-hydroxysteroid dehydrogenase (17&bgr;-HSD) enzyme. More preferably, the polypeptide is a 17&bgr;-HSD type 2 (17&bgr;-HSD2), a 17&bgr;-HSD type 4 (17&bgr;-HSD4), or a 17&bgr;-HSD type 6 (17&bgr;-HSD6) en
Bond Richard W.
Pachter Jonathan A.
Wang Lynn
Angell Jon Eric
Nguyen Dave T.
Schering Corporation
Zaradic Sandy
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