WO2010085511A1 - Method for treating prostate cancer - Google Patents
Method for treating prostate cancer Download PDFInfo
- Publication number
- WO2010085511A1 WO2010085511A1 PCT/US2010/021552 US2010021552W WO2010085511A1 WO 2010085511 A1 WO2010085511 A1 WO 2010085511A1 US 2010021552 W US2010021552 W US 2010021552W WO 2010085511 A1 WO2010085511 A1 WO 2010085511A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- testosterone
- prostate cancer
- prostate
- dutasteπde
- dht
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
Definitions
- This invention relates to a method of treating prostate cancer with 5 ⁇ -reductase inhibitors BACKGROUND
- Androgens male hormones stimulate prostate growth, and ultimately can lead to the development of prostate cancer, by activating the androgen receptor, which in turn leads to the production of growth factors that cause cell proliferation (see, for example, Tmdall and Rittmaster, J Urol 179 1235-42, 2008) Androgens arise mainly from the testes in men, although the adrenal gland makes androgen precursors which can be converted to active androgens in the prostate and elsewhere In order to be active at stimulating prostate growth, testosterone, the major androgen in the blood, must be converted to dihydrotestosterone (DHT), by the enzyme 5 ⁇ -reductase At least two forms of 5 ⁇ -reductase, type 1 and type 2, exist in prostate tissue and both forms can convert testosterone to DHT Because of the stimulatory effect of androgens on the prostate, testosterone treatment has been contramdicated in men who are thought to have prostate cancer (Bhasin S et al, J CIm Endocrinol Metab 91 1995-2010, 2006)
- prostate cancer When prostate cancer is diagnosed and is contained within the prostate, it is often treated with either surgery to remove the prostate or radiation therapy (Hammad F, Ann NY Acad Sci 1138 267-77, 2008) If the cancer recurs or has spread beyond the prostate, and therefore is not curable, treatment usually consists of androgen ablation (Ip C, Endocrinol Metab CIm N Am 36 421-34, 2007) This involves suppressing testosterone secretion, either through surgical removal of the testes (castration) or through medicines that turn off the testes (gonadotropm-releasmg hormone analogues) Other drugs which block androgen action (antiandrogens) or adrenal enzyme inhibitors are sometimes added to block the remaining androgens that arise from the adrenal glands Prostate cancer
- CRPC castrate resistant prostate cancer
- DHT actually have different effects on the prostate DHT causes cell division (proliferation), whereas testosterone causes cell maturation (differentiation) (Dadras SS Gene Expr 9 183-94, 2001)
- testosterone causes cell maturation (differentiation)
- differentiated cells lose the ability to proliferate
- testosterone when given to men, it rapidly is converted to DHT by the high levels of 5 ⁇ -reductase in the prostate, thereby stimulating prostate cancer cell proliferation
- Inhibitors of 5 ⁇ -reductase reduce the amount of DHT in the prostate and are currently approved to treat benign prostate hyperplasia (BPH) (Rittmaster R, Best Pract Res Clin Endocrinol Metab 22 389-402, 2008) Two such inhibitors are currently marketed, finasteride (Proscar ® ) and dutaste ⁇ de (Avodart ® ) Finasteride is selective for 5 ⁇ -reductase type 2, whereas dutaste ⁇ de blocks both forms of the enzyme Neither drug is approved for treatment of prostate cancer
- the concept that a high testosterone/low DHT environment within the prostate could control prostate cancer growth comes from a study using a 5 ⁇ -reductase inhibitor after initial androgen ablation for treatment of prostate cancer in a mouse model (Eggener et al, The Prostate 66 495-502, 2006)
- dutaste ⁇ de used to treat BPH is 0 5 mg daily When given to men with normal testosterone levels, this dose of dutaste ⁇ de reduces DHT levels in the prostate by 94% (Rittmaster R et al, Urology 72 808-812, 2008) When a higher dose of dutaste ⁇ de is given (3 5 mg daily), DHT levels are reduced by 99% (Gleave M et al, The Prostate 66 1674-85, 2006) Finasteride, because it only inhibits one form of 5 ⁇ - reductase, decreases DHT in the prostate by 68-85% (different degrees of DHT suppression with finasteride have been seen in different studies) (Rittmaster R et al, Urology 72 808-812, 2008) Conversely, 5 ⁇ -reductase inhibitors increase mtraprostatic testosterone levels by blocking testosterone to DHT conversion In a published study, 3 5 mg daily of dutaste ⁇ de alone, when added to androgen ablation, did not appear to be effective in treating men
- PCT publication WO2006/104762 claims a method for treating Alzheimer's disease, Parkinson's disease or sexual dysfunction comprising administration of a testosterone supplement together with a 5-alpha-reductase inhibitor
- the present describes a method of treating prostate cancer in male human patients by the administration of a testosterone supplement and dutaste ⁇ de
- the inventor postulates that this novel method will be useful for treating prostate cancer and in particular, to treat CRPC, because a testosterone supplement, plus dutaste ⁇ de to block testosterone to DHT conversion, will create a high testosterone/low DHT environment within the prostate that will induce prostate cancer cells to differentiate and not proliferate
- the inventor postulates that the method of the present invention will only be successful with a dose of dutaste ⁇ de significantly higher than that currently used to treat BPH
- the method of the present invention has the dual benefit of controlling prostate cancer growth and improving quality of life for the patient by avoiding low androgen levels (hypogonadism)
- the daily dose of dutaste ⁇ de is significantly greater than the current dose of 0 5 mg per day
- the daily dose is at least 2 0 mg per day, more preferably at least 3 0 mg per day
- 3 5 mg per day may be the ideal dose in order to maximally block testosterone to DHT conversion and will create a maximal testosterone DHT ratio within the prostate
- the method of this invention can use different doses of a testosterone supplement, and the testosterone supplement can be administered by any method currently used in clinical practice (for example, injections, patches, gels, or oral medication)
- Suitable doses of testosterone supplement include, for example, testosterone and testosterone ester derivatives, for example 200 to 400 mg testosterone enanthate (Delatestryl ® ) intramuscularly weekly or 5 to 15 mg testosterone gel (Androgel ® ) daily
- testosterone supplements include testosterone, testosterone enanthate, and testosterone propionate This list is not meant to exclude other androgen formulations that can be 5-alpha-reduced to a more active androgen
- the dose of testosterone supplement should be sufficient to maintain serum testosterone levels of at least 500 ng/dl (17 4nmol/L) Higher doses may provide additional benefit
- the method of this invention is applicable for use in men with any stage of prostate cancer
- the optimal patient may be one with castrate resistant prostate cancer
- dutaste ⁇ de and testosterone supplements are well known by those in the art and are readily available In addition, dutaste ⁇ de can be made as described, for example in US patent 5,565,467
- dutaste ⁇ de and the testosterone supplement may be administered separately or in a combined administration
Abstract
A method for treating prostate cancer in a male human patient that includes administering dutasteride and a testosterone supplement to the patient is described.
Description
METHOD FOR TREATING PROSTATE CANCER
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U S Provisional Application No 61/146,048 filed on January 21, 2009, which is incorporated herein in its entirety
FIELD OF THE INVENTION
This invention relates to a method of treating prostate cancer with 5α-reductase inhibitors BACKGROUND
Androgens (male hormones) stimulate prostate growth, and ultimately can lead to the development of prostate cancer, by activating the androgen receptor, which in turn leads to the production of growth factors that cause cell proliferation (see, for example, Tmdall and Rittmaster, J Urol 179 1235-42, 2008) Androgens arise mainly from the testes in men, although the adrenal gland makes androgen precursors which can be converted to active androgens in the prostate and elsewhere In order to be active at stimulating prostate growth, testosterone, the major androgen in the blood, must be converted to dihydrotestosterone (DHT), by the enzyme 5α-reductase At least two forms of 5α-reductase, type 1 and type 2, exist in prostate tissue and both forms can convert testosterone to DHT Because of the stimulatory effect of androgens on the prostate, testosterone treatment has been contramdicated in men who are thought to have prostate cancer (Bhasin S et al, J CIm Endocrinol Metab 91 1995-2010, 2006)
When prostate cancer is diagnosed and is contained within the prostate, it is often treated with either surgery to remove the prostate or radiation therapy (Hammad F, Ann NY Acad Sci 1138 267-77, 2008) If the cancer recurs or has spread beyond the prostate, and therefore is not curable, treatment usually consists of androgen ablation (Ip C, Endocrinol Metab CIm N Am 36 421-34, 2007) This involves suppressing testosterone secretion, either through surgical removal of the testes (castration) or through medicines that turn off the testes (gonadotropm-releasmg hormone analogues) Other drugs which block androgen action (antiandrogens) or adrenal enzyme inhibitors are sometimes added to block the remaining androgens that arise from the adrenal glands Prostate cancer
almost always responds to such treatment at first, but many advanced prostate cancers eventually escape the effects of androgen ablation and resume growth When this happens the cancer is called castrate resistant prostate cancer (CRPC) Such growth is demonstrated either by a rise in blood levels of prostate specific antigen (PSA), a marker of prostate cancer, or by demonstration of tumor growth by radiological imaging
It used to be thought that in CRPC, the cancer evolved to grow using mechanisms other than androgens and the androgen receptor However, it is now known that in many such cancers, the cells over express both 5α-reductase and the androgen receptor, as well as other enzymes necessary for androgen synthesis (Stanbrough M, Cancer Research 66 2815-25, 2006) In essence, these cancers appear not to be resistant to the action of androgens, but stimulated by the enhanced production of androgens within the cancer cells themselves Nevertheless, in spite of increasing attempts to block androgen production and action, these cancers usually escape the initial growth suppression induced by androgen ablation There is now evidence from studies in prostate cancer cells that testosterone and
DHT actually have different effects on the prostate DHT causes cell division (proliferation), whereas testosterone causes cell maturation (differentiation) (Dadras SS Gene Expr 9 183-94, 2001) In most organs, including the prostate, differentiated cells lose the ability to proliferate Unfortunately, when testosterone is given to men, it rapidly is converted to DHT by the high levels of 5α-reductase in the prostate, thereby stimulating prostate cancer cell proliferation
Inhibitors of 5α-reductase reduce the amount of DHT in the prostate and are currently approved to treat benign prostate hyperplasia (BPH) (Rittmaster R, Best Pract Res Clin Endocrinol Metab 22 389-402, 2008) Two such inhibitors are currently marketed, finasteride (Proscar®) and dutasteπde (Avodart®) Finasteride is selective for 5α-reductase type 2, whereas dutasteπde blocks both forms of the enzyme Neither drug is approved for treatment of prostate cancer
The concept that a high testosterone/low DHT environment within the prostate could control prostate cancer growth comes from a study using a 5α-reductase inhibitor after initial androgen ablation for treatment of prostate cancer in a mouse model (Eggener et al, The Prostate 66 495-502, 2006) The mice, which earned tumors from the LNCaP
prostate cancer cell lme, were all castrated After the tumors regressed, the mice were randomized to receive vehicle (continued castration), finasteride alone, testosterone alone, or a combination of testosterone plus finasteride Tumors rapidly re-grew in all mice except the group that received the combination of testosterone and finasteride, suggesting that the high testosterone/low DHT environment prevented tumor re-growth
Further support of the benefits of creating a high testosterone/low DHT environment comes from a retrospective study of the use of finasteride during intermittent androgen ablation for treatment of prostate cancer (Scholz MC et al, J Urology 175 1673-8, 2006) In this form of treatment, rather than giving continual androgen ablation with medications, the androgen ablation is only given long enough to suppress PSA to low levels (Rashid MH et al , Oncologist 9 295-301 , 2004) The androgen ablation is then stopped, and testosterone levels usually return to normal, allowing for an improved quality of life for patients Eventually PSA levels rise, and when this occurs, another cycle of androgen ablation is given In the Scholz study, finasteride was given during the "off period" of intermittent androgen ablation and was shown to prolong the time until another course of androgen ablation was needed Although the investigators assumed that finasteride was acting by reducing DHT levels, the use of finasteride created the high testosterone/low DHT levels in the prostate that might maximally control prostate cancer growth However, supplemental testosterone was not given, and this may be necessary to optimally inhibit tumor growth
The dose of dutasteπde used to treat BPH is 0 5 mg daily When given to men with normal testosterone levels, this dose of dutasteπde reduces DHT levels in the prostate by 94% (Rittmaster R et al, Urology 72 808-812, 2008) When a higher dose of dutasteπde is given (3 5 mg daily), DHT levels are reduced by 99% (Gleave M et al, The Prostate 66 1674-85, 2006) Finasteride, because it only inhibits one form of 5α- reductase, decreases DHT in the prostate by 68-85% (different degrees of DHT suppression with finasteride have been seen in different studies) (Rittmaster R et al, Urology 72 808-812, 2008) Conversely, 5α-reductase inhibitors increase mtraprostatic testosterone levels by blocking testosterone to DHT conversion In a published study, 3 5 mg daily of dutasteπde alone, when added to androgen ablation, did not appear to be effective in treating men with CRPC In the study, two of
25 men with CRPC had a partial PSA response to 3 5 mg dutasteπde, and the median time to PSA progression was 1 9 months (Shah S et al, Journal of Urology 181 621-6, 2009)
PCT publication WO2006/104762 claims a method for treating Alzheimer's disease, Parkinson's disease or sexual dysfunction comprising administration of a testosterone supplement together with a 5-alpha-reductase inhibitor
BRIEF DESCRIPTION OF THE INVENTION
Briefly, in one aspect, the present describes a method of treating prostate cancer in male human patients by the administration of a testosterone supplement and dutasteπde
Although not specifically suggested by publications, the inventor postulates that this novel method will be useful for treating prostate cancer and in particular, to treat CRPC, because a testosterone supplement, plus dutasteπde to block testosterone to DHT conversion, will create a high testosterone/low DHT environment within the prostate that will induce prostate cancer cells to differentiate and not proliferate
In particular, the inventor postulates that the method of the present invention will only be successful with a dose of dutasteπde significantly higher than that currently used to treat BPH The inventor postulates that only when the DHT levels are maximally reduced will the method truly be successful and that this will require a dutasteπde dose of at least 2 0 mg/day
The method of the present invention has the dual benefit of controlling prostate cancer growth and improving quality of life for the patient by avoiding low androgen levels (hypogonadism)
DETAILED DESCRIPTION OF THE INVENTION In one embodiment of the present invention the daily dose of dutasteπde is significantly greater than the current dose of 0 5 mg per day Preferably, the daily dose is at least 2 0 mg per day, more preferably at least 3 0 mg per day For example, the inventor believes that 3 5 mg per day may be the ideal dose in order to maximally block
testosterone to DHT conversion and will create a maximal testosterone DHT ratio within the prostate
The method of this invention can use different doses of a testosterone supplement, and the testosterone supplement can be administered by any method currently used in clinical practice (for example, injections, patches, gels, or oral medication) Suitable doses of testosterone supplement include, for example, testosterone and testosterone ester derivatives, for example 200 to 400 mg testosterone enanthate (Delatestryl®) intramuscularly weekly or 5 to 15 mg testosterone gel (Androgel®) daily
Possible testosterone supplements include testosterone, testosterone enanthate, and testosterone propionate This list is not meant to exclude other androgen formulations that can be 5-alpha-reduced to a more active androgen The dose of testosterone supplement should be sufficient to maintain serum testosterone levels of at least 500 ng/dl (17 4nmol/L) Higher doses may provide additional benefit
Although the method of this invention is applicable for use in men with any stage of prostate cancer, the optimal patient may be one with castrate resistant prostate cancer
Dutasteπde and testosterone supplements are well known by those in the art and are readily available In addition, dutasteπde can be made as described, for example in US patent 5,565,467
The dutasteπde and the testosterone supplement may be administered separately or in a combined administration
Claims
What is claimed is
1 A method for treating prostate cancer in a male human patient, comprising the administration of dutasteπde and a testosterone supplement, wherein said administration of dutasteπde is at least 2 mg/day
2 The method of Claim 1 wherein said administration of dutasteπde is at least 3 mg/day
3 The method of Claim 1 wherein said administration of dutasteπde is from 3 0 to 4 0 mg/day
4 The method of any preceding claim wherein said testosterone supplement is selected from the group consisting of testosterone, testosterone enanthate, testosterone propionate, testosterone cypionate, testosterone undecanoate, testosterone cyclodextπn, methyl testosterone, and fluoxy mesterone
5 The method of any of Claims 1-3 wherein said testosterone supplement is selected from the group consisting of testosterone and testosterone ester derivatives
6 The method of any of Claims 1-3 wherein said testosterone supplement is selected from the group consisting of testosterone, testosterone enanthate, and testosterone propionate
7 The method of any preceding claim wherein said prostate cancer is castrate-resistant prostate cancer
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14604809P | 2009-01-21 | 2009-01-21 | |
| US61/146,048 | 2009-01-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2010085511A1 true WO2010085511A1 (en) | 2010-07-29 |
Family
ID=42356188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2010/021552 WO2010085511A1 (en) | 2009-01-21 | 2010-01-21 | Method for treating prostate cancer |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2010085511A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2964323A1 (en) * | 2010-09-08 | 2012-03-09 | Jean Pierre Raynaud | Use of exogenous testosterone as neoadjuvant and/or adjuvant in a patient of androgenic deficit for treating the patient with localized prostate cancer, respectively before/after surgical or medical treatment of the patient |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050176692A1 (en) * | 2004-02-09 | 2005-08-11 | University Of Washington | Oral androgen therapy using modulators of testosterone bioavailability |
| WO2006104762A2 (en) * | 2005-03-25 | 2006-10-05 | Merck & Co., Inc. | Method of treating men with testosterone supplement and 5alpha-reductase inhibitor |
-
2010
- 2010-01-21 WO PCT/US2010/021552 patent/WO2010085511A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050176692A1 (en) * | 2004-02-09 | 2005-08-11 | University Of Washington | Oral androgen therapy using modulators of testosterone bioavailability |
| WO2006104762A2 (en) * | 2005-03-25 | 2006-10-05 | Merck & Co., Inc. | Method of treating men with testosterone supplement and 5alpha-reductase inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| XU ET AL.: "Pharmacologic Basis for the Enhanced Efficacy of Dutasteride against Prostatic Cancers.", CLINICAL CANCER RESEARCH, vol. 12, no. 13, 1 July 2006 (2006-07-01), pages 4072 - 4079 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2964323A1 (en) * | 2010-09-08 | 2012-03-09 | Jean Pierre Raynaud | Use of exogenous testosterone as neoadjuvant and/or adjuvant in a patient of androgenic deficit for treating the patient with localized prostate cancer, respectively before/after surgical or medical treatment of the patient |
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