MXPA00009129A - A method for chemoprevention of prostate cancer - Google Patents
A method for chemoprevention of prostate cancerInfo
- Publication number
- MXPA00009129A MXPA00009129A MXPA/A/2000/009129A MXPA00009129A MXPA00009129A MX PA00009129 A MXPA00009129 A MX PA00009129A MX PA00009129 A MXPA00009129 A MX PA00009129A MX PA00009129 A MXPA00009129 A MX PA00009129A
- Authority
- MX
- Mexico
- Prior art keywords
- prostate
- further characterized
- prostate cancer
- pharmaceutical preparation
- toremifene
- Prior art date
Links
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Abstract
This invention provides the chemoprevention of prostate cancer and, more particularly, to a method of administering to a subject an effective dose of a chemopreventive agent, toremifene and analogs or metabolites thereof, to prevent recurrence of, suppress or inhibit prostate carcinogenesis. The present invention provides a safe and effective method for suppressing or inhibiting latent prostate cancer and is particularly useful for treating subjects having an elevated risk of developing prostate cancer, for example, those having benign prostatic hyperplasia, prostate intraepithelial neoplasia (PIN), or an abnormally high level of circulating prostate specific antibody (PSA), or who have a family history of prostate cancer.
Description
A METHOD FOR THE CHEMIOPREVENTION OF PROSTATE CANCER
Field of the Invention The present invention relates to the chemoprevention of prostate cancer, and more particularly, to a method of administering to a subject, an effective dose of an agent to prevent the recurrence of, suppression or inhibition of prostate carcinogenesis.
Antecedents of the Invention Prostate cancer is one of the cancers that occurs most frequently among men in the United States, with hundreds of thousands of new cases diagnosed each year. Unfortunately, about 60% of newly diagnosed cases of prostate cancer are pathologically advanced, without cure and with a disastrous prognosis. One method for this problem is to find prostate cancer early through screening programs, and thereby reduce the number of patients with advanced prostate cancer. However, another strategy is to develop medicines to prevent prostate cancer. One third of all men around 50 years of age have a latent form of prostate cancer that can be activated in the form of clinical prostate cancer treated for life. The frequency of latent prostate tumors has been shown to increase substantially with each decade of life from 50 years (5-3 / 14%) to 90 (40-80%). The number of people with latent prostate cancer, is the same in all cultures, ethnic groups and races and even the frequency of clinically aggressive cancer is markedly different, this suggests that environmental factors can play an important role in the activation of cancer of latent prostate. Therefore, the development of chemoprevention strategies against prostate cancer, can have a great general impact both medical and economically against prostate cancer. Due to the high incidence and mortality from prostate cancer, it is imperative to develop chemoprevention strategies against this devastating disease. By understanding the factors that contribute to prostate carcinogenesis including the initiation, promotion and progression of prostate cancer, molecular mechanistic clues will be provided for the appropriate points of intervention, to avoid or stop the carcinogenic process. New methods are urgently needed in both basic science and clinical levels to decrease the incidence of prostate cancer, as well as to stop or cause regression of latent prostate cancer. Since the frequency of prostate cancer scales dramatically in the ages in which men face other important causes of mortality, simply decreasing the progression of prostate adenocarcinoma can be a more appropriate and cost-effective health strategy. Several methods have been taken for the chemoprevention of prostate cancer. Greenwald, in the publication "Expanding 5 Horizons in Breast and Prostate Cancer Prevention and Early
Detection "in J. Cancer Education 1993 Vol. 8, No. 2, pp. 91-1 07, mentions the test of 5a-reductase inhibitors such as finasteride for the prevention of prostate cancer." Brawley and associates, "Chemoprevention of Prostate Cancer "in Urology, 1994, 10 Vol. No. 5, also mentions 5a-reductase inhibitors, as well as
• Difloromethylornithine and retinoids as potential chemopreventive agents. Kelloff and associates, "in Journal of Cellular Biochemistry, 1992, supplement 16H: 1-8, describe the preclinical studies of the National Cancer Institute of seven agents: all-trans-N- (4-hydroxyphenyl) retinamide, difluoromethylornithine, dehydroepiandrosterone ,
Marozola, lovestatin, oltipraz, and finasteride. • Lucia and associates in "Chemopreventive activity of
Tamoxifen, N- (4-Hydroxyphenyl) Retinamide, and Vitamin D 20 Analog Ro24-553 1 for Vesicular Androgen Promoted Carcinomas
Seminal and Rat Prostate "in Cancer Research, 1995, Vol 55, p 5621 -5627, reports the prevention of prostate carcinomas in rats
Lobund-Wistar using tamoxifen, a estrogen response modifier.
As mentioned by Potter and associates, "A mechanistic hypothesis for the formation of DNA adductor by tamoxifen, following the hepatic oxidative metabolism" in carcinogenesis 1994, Vol. 15, pages 439 to 442, tamoxifen causes carcinogenicity
• 5 of the liver in rats which is attributed to the formation of covalent DNA adductors. This reference also reports that the analogous toremifene of tamoxifen, which showed a very low level of liver DNA adductor formation, compared to tamoxifen, is non-carcinogenic. 10 Toremifene is an example of a triphenylalkene compound
• described in U.S. Patent Nos. 4,696,949 and 5,491, 173 to Toivola and associates, the descriptions of which are incorporated herein by reference. Parenteral and topical administration to mammals of formulations that
contain toremifene, US Pat. No. 5,571,543 to Jalonen et al., In US Pat. No. 5,605,700 to Gregory et al.
• descriptions are incorporated herein by reference. In US Pat. No. 4,990,538 to Harris et al., The disclosure of which is incorporated herein by reference, formulations containing toremifene are disclosed to reverse the reference to multiple medicaments of cancer cells to a cytotoxic medicament.
US Patent Nos. 5,595,722 and 5,599,844 to Grainger and associates, the descriptions of which are incorporated herein by reference, describe methods for identifying agents that increase TGF levels, and for oral administration of formulations containing
• 5 activators of TGFP and stimulators of TGFP production, to avoid or treat conditions characterized by a normal proliferation of soft muscle cells, for example, vascular trauma. The people described to increase the levels of TGFP include tamoxifen and its analogous toremifene. 10 The North American Patents Numbers 5,629,007 and 5,635, 197
• of Audia and associates, whose descriptions are incorporated into the present invention, as a reference, describe a method to prevent the development of prostate cancer at risk of developing said cancer, for example, a patient who has
benign prostatic hyperplasia, administering to the patient an octahydrobenzo (f) quinoline-3-one compound. U.S. Patent Number 5,595,985 to Labrie, whose
• description is incorporated into the present invention as a reference also describes a method for treating hyperplasia of
benign prostate, using a combination of 5a-reductase inhibitor and a compound that binds and blocks access to androgen receptors. Flutamide is an example of a compound that blocks androgen receptors. The North American Patents Numbers 4,474,813 of Neri and
associates, the descriptions of which are incorporated herein by reference, describe pharmaceutical preparations comprising flutamide to delay and / or prevent the establishment of carcinoma in the prostate. The preparation may be in the form of a capsule, tablet, suppository or elixir. TO
• Despite these developments, there is a continuing need for effective agents and methods to prevent prostate cancer. The present invention is directed to satisfy this need.
Summary of Invention 10 The present invention provides chemoprevention of
• prostate cancer, and more particularly, a method of administering to a subject an effective dose of a chemopreventive agent, toremifene and analogues or metabolisms thereof, to prevent recurrence, treatment, suppression or
inhibition of prostate carcinogenesis. The present invention is directed to a method for preventing prostate carcinogenesis. The present invention comprises the
• administration to a mammal of a pharmaceutical preparation of a chemopreventive agent having the formula:
wherein Ri and R2, which may be the same or different, are H or OH, R3 OCH2CH2NR R5, wherein R4 and R5, which may be the same or different, are H or an alkyl group of from 1 to about 4 carbon atoms. • And its pharmaceutically acceptable carriers, diluents, salts, esters or N-oxides or mixtures thereof. The present invention provides a safe and effective method for suppressing or inhibiting latent prostate cancer, and is particularly useful for treating subjects who have a high risk of developing prostate cancer, for example, those who have
• benign prostatic hyperplasia, prostatic intraepithelial neoplasia (PIN), or an abnormally high level of prostate-specific antibody in the circulation (PSA), or those who have a family history of prostate cancer. 15 Brief Description of the Drawings Figure 1: A graph illustrating the chemopreventive examples of toremifene in the TRAMP model. Figures 2A-2C: Sections H &E illustrating ventral prostate cells in normal mice and carcinoma in TRAMP mice, included in the study. Figure 3: Effect of Toremifene on the development of ventral prostate in mouse TRAMP. Figure 4: Effect of Toremifene on the occurrence in TRAMP mice.
Figure 5: Effect of Toremifene on tumor development in the TRAMP model. Figure 6A-6B: Comparison of the effects of placebo versus toremifene on tumor growth. • 5 Detailed Description of the Invention The present invention provides a method for preventing prostate carcinogenesis; 2) methods to suppress or inhibit prostate cancer; 3) methods to reduce the risk of development 10 of prostate cancer; 4) methods to increase the range of
• Survival of a subject using the chemopreventive agent of prostate, toremifene, analogues and metabolisms thereof. As demonstrated in the present invention, toremifene is a prostate chemopreventive agent. In the experiments known in the present invention, the prostates were dissected and evaluated both histologically and by complete analysis. Likewise, toremifene was tested for the treatment of prostate cancer by treating LNCaP xenografts in shaved mice. As shown, the data are somewhat dramatic, 20 not since toremifene not only has an inhibited growth but actually had the ability to produce the regression of tumors. The present invention is directed to a method for preventing prostate carcinogenesis. The present invention comprises administering to a mammal a pharmaceutical preparation of a chemopreventive agent having the formula:
wherein Ri and R2, which may be the same or different, are H or OH, R3 is OCH2CH2NR R5, wherein R4 and R5, which may be the same or different, are H or an alkyl group of about 1 to about 4 carbon atoms; and its pharmaceutically acceptable carrier, diluents, salts, esters or N-oxides and mixtures thereof. The present invention provides the use of a pharmaceutical composition to prevent recurrence of suppression or inhibition of prostate carcinogenesis, or increase the range of survival in a subject having prostate cancer, comprising a chemopreventive agent having the formula:
wherein Ri and R2, which may be the same or different, are HO, or R3 is OCH2CH2NR R5 > wherein R 4 and R 5, which may be the same or different, are H or an alkyl group of 1 to about 4 carbon atoms; and its transporter,
• Pharmaceutically acceptable diluent, salts or esters or N-oxides and mixtures thereof. The present invention provides a safe and effective method for suppressing or inhibiting latent prostate cancer, and particularly useful for treating subjects at high risk.
of prostate cancer development, for example, those that have
• benign prostatic hyperplasia, intrahepitelial prostate cancer (PI N) or an abnormally high level of prostate-specific antibodies in the circulation (PSA), or those who have a family history of prostate cancer. The compound 4-chloro-1,2-diphenyl-1 - [4- [2- (N, N-dimethylamino) ethoxy] phenyl] -1-butene of the formula (1), wherein R1 and R2 are each one H and R4 and R5 are each methyl, is called toremifene. Toremifene has been shown to be safe and effective as an antitumor compound and exhibits hormonal effects as a
estrogen or as an anti-agent. estrogen, depending on the dose used. In administration, toremifene has several metabolites that are also biologically active. The present invention also provides the use of toremifene analogues or metabolisms thereof, which are known
by the experts in the art. Other examples of chemopreventive agents of the formula (1) are the following: 4-chloro-1,2-diphenyl-1 - [4- [2- (N-methylamine) ethoxy] phenyl] -1- buteno; 4-chloro-1, 2-diphenyl-1 - [4- [2- (N, N- (diethylamine) ethoxy] phenyl] -1-butane; 4-chloro-1,2-diphenyl-1 - [4- ( aminoethoxy) phenyl] -1-butane; 4-chloro-1 - (4-hydroxyphenyl) -1 - [4- [2- (N, N-dimethylamine) ethoxy] phenyl] -2-phenyl-1-butane; 4-chloro-1 - (4-hydroxyphenyl) -1 - [4- [2- (N-methylamine) ethoxy] phenyl] -2- phenyl-1-butane, and 4-chloro-1,2-bis (4 -hydroxyphenyl) -1 - [4- [2- (N, N-dimethylamine) ethoxy] phenyl] -1-butane.
The present invention comprises pure isomers (Z) - and (E) - of
• the compounds and mixtures thereof and as well as pairs of enantiomers (RR.SS) - and (RS.SR) - pure and mixtures thereof. The compounds of the agent of the formula (1) can be prepared according to the procedures described in
North American Patents Numbers. 4,696,949 and 5,491, 173 of Toivola and associates mentioned above. The present invention includes salts of amino compounds
• pharmtically acceptable substitutes with organic and inorganic acids, for example, citric acid and hydrochloric acid. The
The present invention also includes N-oxides of the amino substituents of the compounds of the formula (1). The pharmtically acceptable salts can also be prepared from the phenolic compounds, by treatment with inorganic bases, for example, sodium hydroxide. Likewise,
esters of phenolic compounds can be made with aliphatic and aromatic carboxylic acids, for example, ic acid and benzoic acid esters. As used in the present description, a "pharmtical composition" means therapeutically effective amounts of the
# 5 agent together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or transporters. A "therapeutically effective amount" as used in the present invention, refers to the amount which provides a therapeutic effect for a given condition and regimen.
Administration, said compositions, are liquid formulations, or
• freeze-dried, or otherwise dried, including diluents of various regulator contents (eg, Tris-HCl., ate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent surfabsorption, detergents, (for
For example, Twen 20, Twen 80, Pluronic F68, salts of bile acid), solubilizing agents (for example, glycerol, glycerol polyethylene), antioxidants (for example ascorbic acid, sodium metadisulfite),
• preservatives (for example, salt, benzyl alcohol, parabens), thickening substances or tonicity modifiers (for example,
lactose, mannitol), covalent adhesion to the protein of polymers such as glycol polyethylene, complexity with metal ions, or incorporation of the material into or on the particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels etc, or in liposomes , microemulsions,
micelles, unilamellar or multilamellar vesicles, erythrocytes
anonymous or spheroplast Said compositions will influence the physical state, solubility, stability, range of release in vivo and range of space in vivo. The sustained release compositions are sustained, include a formulation in hypophilic deposits (eg, fatty acids, waxes, oils). Also contemplated by the present invention are particulate compositions coated with polymers (eg, poloxamers or polaxamines). Other embodiments of the compositions of the present invention incorporate protective covers of shapes
particulates, protease inhibitors or augmentation
• Permeability for different routes of administration, including parenteral, pulmonary, nasal and oral. In one embodiment, the pharmaceutical composition is administered parenterally, for canceral, transmucosal, transdermal, intramuscular, intravenous,
intradermal, subcutaneous, intraperitoneal, intraventricular, intracranial and intratumural. In addition, as used in the present description, a
• "pharmaceutically acceptable carrier"; it is well known to those skilled in the art, and includes, but is not limited to, 0.01 -0.1 M and
preferably 0.05M of phosphate or saline regulator at 0.8%. in addition, said pharmaceutically acceptable carriers can be solutions, suspensions of aqueous or non-aqueous emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and
injectable organic esters such as ethyl oleate. Aqueous carriers include water, solutions, emulsions or alcohol / aqueous suspensions, including saline and regulated media. Parenteral vehicles include a solution of sodium chloride, Ringer's dextrose, dextrose and sodium chloride, 5 fixed or fixed Ringef's oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, the like. Conservatives and other additives may also be present, such as, for example, antimicrobial agents, antioxidants, and
of collation, inert gases and the like. • The term "adjuvant" refers to a compound or mixture that improves the immune response to an antigen. An adjuvant can serve as a deposit of tissue that slowly releases the antigen, and also as a lymphoid system activator that improves
non-specific way the immune response (Hood and associates, immunology, Second Edition, 1984, Benjamin / Cummings: Menlo PARK, California, page 384). Often, a major challenge with
• an atigeno alone, is the absence of an adjuvant, which will fail to elicit a humoral or cellular immune response. The adjuvant
includes but is not limited to Freud's complete adjuvant incomplete Freud's adjuvant, saponin, mineral gels such as aluminum dioxide, surface active substances such as lysolecithin, pluronic polyols, polyanions such as peptides, oil or hydrocarbon emulsions. , hemocyanins, impedance of endoplasty, dinitrophenol, and
potentially useful human adjuvant such as BCG (Bacillus Calmette.Guerin) and corinebacterium parvum. Preferably, the adjuvant is pharmaceutically acceptable. Sustained or sustained release compositions include formulation in lifofilic deposits (eg, fatty acids, waxes, oils). Also contemplated by the present invention are particulate compositions coated with polymers (eg, poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue-specific receptors, binders or antigens, or coupled to ligands of specific receptors of
tissue. • Other embodiments of the compositions of the present invention incorporate protective covers of particulate forms, protease inhibitors or permeability enhancers for different routes of administration, including pareneral, pulmonary,
nasal and oral. Compounds modified by the covalent adhesion of water-soluble polymers such as glycol polyethylene, glycol polyethylene copolymers and glycol polypropylene, and carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone or polyproline, are known to exhibit half lives
substantially longer in the blood, following the intravenous injection, than the half lives of corresponding modified compounds (Abuchowski et al., 1981: Newmark and associates, 1982; and Katre and associates., 1987). These modifications also increase the solubility of the compound in a solution
, eliminate aggregation, improve the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound. As a result, the desired biological activity in vivo can be achieved by administering said polymer compound abductors less frequently or at lower doses than with the unmodified compound. In yet another embodiment, the pharmaceutical composition can be modified in a controlled release system. For example, the agent can be administered using intravenous infusion, a
implantable osmotic pump, a transdermal patch, liposomes or
• other modes of administration. In one embodiment, a pump can be used (see Langer, supra, Sefton, CRC Crit Ref Biomed Eng 14: 201 (1987), Buchwald and associates, Surgery 88: 507 (1980), Saudek and associates. with New England, J. Med. 321: 574 (1989).
modality, polymeric materials can be used, even in another modality a controlled release system can be placed near the therapeutic target, for example, the brain, requiring
• in this way only a fraction of the systemic dose (see, for example, Goodson in medical release applications)
controlled, supra, vol. 2, pages from 1 15 to 138 (1984). Preferably, a controlled release device is introduced into a subject, next to the site of inappropriate immune activation or a tumor. In Langer's review (Science 249: 1527-1533 (1990).) Other controlled release systems are mentioned.
The method of the present invention for preventing prostate carcinogenesis comprises administering to a mammal a pharmaceutical preparation comprising a chemopreventive agent or a metabolite or salt thereof. The pharmaceutical preparation may comprise the chemopreventive agent alone, or may additionally include a pharmaceutically acceptable carrier, and may be in solid or liquid form such as tablets, powders, capsules, pills, solutions, suspensions, elixirs, emulsions, gels, creams or suppositories, including rectal suppositories and
urethral. Acceptable acceptable transformers include
• gums, starches, sugars, cellulose materials and their mixture. The pharmaceutical preparation containing the chemopreventive agent can be administered to a subject, for example, by subcutaneous implantation of a pill; in a modality
In addition, the pill provides controlled release of the chemopreventive agent over a period of time. The preparation can also be administered by an intravenous injection,
• intraarterial, or intramuscular liquid preparation, oral administration of a liquid or solid preparation by
topical application. Administration can also be carried out by using a rectal suppository or a urethral suppository. The pharmaceutical preparation can also be a parenteral formulation; In one embodiment, the formulation comprises a liposome that includes a complex of a chemopreventive agent such as,
For example, toremifene and a cyclodextrir compound such as
described in U.S. Patent Number 5,571, 534 of Jalonen and associates mentioned above. The pharmaceutical preparations of the present invention can be prepared by known processes of dissolution,
• 5 mixing, granulation or tablet formation. For oral administration, the chemopreventive agents or their physiologically tolerated derivatives such as salts, esters, N-oxide and the like, are mixed with customary additives for this purpose, such as vehicles, stabilizers or inert diluents,
and are converted by the usual methods in a way
• suitable for administration such as tablets, coated tablets, soft hard gelatin capsules, aqueous solutions of alcohol or oily. Examples of suitable inert carriers are conventional tablet bases such as lactose, sucrose, or starch
of corn in combination with binders such as acacia, corn starch, gelatin or with disintegrating agents such as corn, potato starch, alginic acid or a stearic acid
• similar lubricant or magnesium stearate. Examples of suitable vehicles or oily solvents are vegetable oils or
animals such as sunflower oil or cod liver oil. The preparations can be made in the form of both dry and wet granules. For parenteral administration (subcutaneous, intravenous, intraarterial or intramuscular injection) chemopreventive agents or their physiologically tolerated derivatives such
as salts, esters, N-oxides and the like, become a
solution, suspension or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other auxiliaries. Examples are: sterile liquids such as water and oils with or without the addition of a
• 5 surfactant or other pharmaceutically acceptable adjuvants. The illustrative oils are those of animal, vegetable or synthetic origin oil, for example, peanut oil, soybean oil or mineral oil. In general, water, saline, aqueous dextrose, and related sugar solutions and glycols such as glycols
propylene or polyethylene glycol, are liquid carriers
• preferred, particularly for injectable solutions. The preparation of pharmaceutical compositions containing an active component is well known in the art. Typically, said compositions are prepared as a polypeptide aerosol
supplied to the nasofarinx or as injectables, either as liquid solutions or suspensions, however, they can also be prepared in solid forms suitable for solution in or suspension in liquid before injecting. The preparation can also be emulsified. The active therapeutic ingredient is often mixed
with excipients, which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like or combinations thereof. In addition, if desired, the composition may contain minor amounts of substances
auxiliaries such as wetting or emulsifying agents,
pH regulating agents which improve the effectiveness of the active ingredient. An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms. The pharmaceutically acceptable salts include the acid addition salts (formed with the aminolibres of the polypeptide or antibody molecule) and which are formed with inorganic acids, such as, for example, hydrochloric or phosphoric acids, or said organic acids as acetic, oxalic,
tartaric,. Mandelico and similar. The salts formed from
• free caboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides and organic bases such as propylamine, trimethylamine, ethanol2-histidine, procaine, and the like. For topical administration to body surfaces using, for example, creams, gels, drops, and the like, chemopreventive agents or their physiologically tolerated derivatives such
• as, salts, esters N-oxides and the like, are prepared and applied in the form of solutions, suspensions or emulsions in
a physiologically acceptable diluent with or without a pharmaceutical carrier. In another embodiment, the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249: 1527-1533 (1990); Treat and associates, in liposomes in therapy
of infectious diseases and cancer, López-Berestein, and Fildler (eds.), Liss, New York, pages 353 to 365 (1989); López Berestein, ibid, pages from 317 to 327; see generally ibid). The pharmaceutical compositions of the present invention are particularly useful for treating a subject having a high risk of developing prostate cancer. High-risk subjects include, for example, those who have benign prostatic hyperplasia, prostatic intraepithelial neoplasia (PIN), or an abnormally high level of prostate specific antibody in the circulation (PSA), or who have a family history of 10 prostate cancer. In addition, the prostate chemopreventive agent can be administered in combination with other cytokines or growth factors, including but not limited to: IFN and a, IFN-β; Interleukin (IL) 1 L-2, IL-4, IL-6, IL-7, IL-12, tumor necrosis factor (TNF) a, TNF-β, granule-colony stimulation factor (G) -CSF), granulosite / macrophage CSF (GM-CSF); accessory molecules, including members of the superfamily and
• integral members of the Ig superfamily such as, but not limited to, the stimulatory molecule of LFA-1 cells. LFA-3, CD22, and 20 B7-1, B7-2, and ICAM-1 T. The chemopreventive agent may precede or follow an agent treatment of DNA damage, by intervals within the range of minutes to weeks. The protocols and methods are known to those skilled in the art. The agents or
Factors that damage DNA are known to those skilled in the art, and means any chemical compound or method of treatment that induces DNA damage when applied to a cell. Such agents and factors include radiation and waves that induce DNA damage such as gamma-radiation, X-rays, and UV-radiation, microwaves,
• 5 electronic and similar emissions. A variety of chemical compounds, also described, "chemotherapeutic agents", function to induce DNA damage, which are intended to be used in combination treatment methods described in the present invention. The chemotherapeutic agents contemplated for
used, include, for example, adriamycin, 5-fluorouracil (5FU),
• etoposide (VP-16), camptothecin, actinomycin-D, mitomycin C, cisplatin (CDDP) and even hydrogen peroxide. The present invention also comprises the use of a combination of one or more agents to damage DNA, whether based on radiation or on
real compounds, such as, the use of X-rays with cisplatin or the use of cisplatin with etoposide. In another embodiment, the localized tumor site can be irradiated with radiation damage to DNA, such as X-rays, ultraviolet light, gamma rays or even microwaves. Alternatively,
The tumor cells may be in contact with the DNA damage agent by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a DNA-damaging compound, such as adriamycin, 5-fluorouracil, etoposide, casmptothecin, actinomycin-D, mitomycin C, or more
Preferably cisplatin. Agents that damage DNA also include compounds that interfere with DNA replication, mitosis, and chromosomal segregation. Said therapeutic compounds, include adriamycin, also known as doxorubicin, etoposide, verapamil, polofilotoxin and the like. • 5 Other factors that cause DNA damage and that have been widely used influence what are commonly known as gamma-rays, X-rays and / or other targeted delivery of radioisotopes to tumor cells. Other forms of DNA damage factors, such as microwaves and
UV-irradiation. Most likely, all these factors
• perform a wide range of DNA damage, DNA precursors, DNA replication and repair, and the assembly and maintenance of chromosomes. As will be readily appreciated by an expert in the art,
The methods and pharmaceutical compositions of the present invention are particularly suitable for administration to mammals, preferably humans. The intermediate endpoint biomarkers are biological alterations that can be measured in tissues, which occur between
the initiation and development of frank neoplasia. It is considered that the modulation of one or more biomarkers of intermediate endpoint by a chemopreventive agent, may reflect a real inhibition of carcinogenesis. A biomarker would be validated if the endpoint, incidence of cancer, were also reduced by
the putative chemopreventive agent. Intermediate biomarkers in cancer can be classified into the following groups: histological, proliferation, differentiation, and biochemical markers. In any strategy of chemoprophylaxis, the availability of precancerous lesions histologically recognizable and accepted, 5 constitute an important starting point. For the prostate, a possible histological marker is prostatic intraepithelial neoplasm (PIN), which is a precancerous precursor of prostate adenocarcinoma. The PIN appears as an abnormal proliferation within the ducts of the premalignant foci prostate.
cell dysplasia and carcinoma in situ stromal invasion. The PIN and the
• histological prostate cancer, they are morphologically and phenotypically similar. Therefore, the development of high-grade PIN can represent an important step in the progression path, where the normal prostate develops PIN, prostate cancer
histological, invasive clinical prostate cancer and metastasis. The examples that follow are presented in order to illustrate more fully the preferred modalities
• of the present invention. However, these should not be constructed as limitations of wide scope in this
invention. Section of Experimental Details Example 1: Mouse Prostate with Transgenic Adenocarcinoma The study of chemoprevention of prostate cancer has been hampered by the lack of adequate animal models. He
The recent development of the mouse prostate model with transgenic adenocarcinoma (TRAMP) makes possible the study of chemoprevention. In the TRAMP model, which is described in Greenberg and associates, "Prostate cancer in a transgenic mouse" "Proc. Nati Acad. Sci. USA, 1995, Vol. 92, pages of the 3439 to the
• 5 3443, the large PB-SV40 antigen transgene T (PB-Tag), is expressed specifically in the epithelial cells of the murine prostate. As a result, this model has several advantages over the currently existing models: 1) mice develop progressive forms of prostatic epithelial hyperplasia, a
an age as early as 10 weeks and invasive adenocarcinoma
• at an age of about 18 weeks; 2) the metastatic expansion of the prostate cancer pattern resembles human prostate cancer being the common sites of lymph node metastasis, lung, kidney, adrenal gland and skeleton; 3) the development, as well
as a progression of prostate cancer can be followed within a relatively short period of 10 to 30 weeks; 4) tumors arise with 10% frequency; 5) Animals can be
• selected for the presence of the prostate cancer transgen before the onset of clinical prostate cancer for the treatment of
tests directly with chemopreventive agents that can alter prostate carcinogenesis. The TRAMP transgenic mouse model is an excellent live model to determine the mechanisms of initiation and promotion of prostate cancer, and to test the effectiveness of
potential chemopreventive agents. These mice develop in
progressive form epithelial prostatic hyperplasia, PIN, and subsequently prostate cancer within a short period (> 17 weeks). The chemopreventive treatment of hybrid TRAM mice begins 30 days after birth, using chemopreventive agents at a level of approximately 0.05-50 mg / kg body weight / day, preferably approximately 6-30 mg / kg body weight / day. The chemopreventive agents are processed conventionally in 21-day and 90-day pills (prepared by Innovative Research of America, Sarasota, FL) and delivered as subcutaneous implants. The control animals receive placebo implants. In each drug treatment group, the animals were sacrificed at an age of 5.7, 10, 15, 20, 25, 30, 40, and 50 weeks until the development of a palpable tumor. The blood is collected and collected by time point of treatment, to evaluate the changes in the serum of testosterone and estradiol. Prostate tissues are collected according to morphometric, histological, and molecular studies. The following test procedures are used: 1) A complete prostate scan is performed in series to detect changes in the morphology of the prostate ducts over time and without treatment; the examples are shown in Figure 2. Tissue sections are histologically evaluated by H & E and standard Masson-trichome staining.
The emergence of PIN is evaluated and classified (I-soft to III-severe). 2) serum levels of estradiol and total testosterone are measured (RIA) for each age range, to evaluate any change
• 5 in these hormones as a result of chemopreventive agents.
Example 2: Immunohistochemistry Data Analysis Microscopic images of each tissue are evaluated, using
a quantification of images (N I H-lmage 1 .6 PPC) with the help
• from a computer (computer and monitor (Mac 9500-2 32), using a Kodak DCS 460 camera in a Nikon Microphot-FX microscope and is quantified using a quantitative color image analysis system (I PLab Sprectrum 3.1,
Scanalytics, Inc., VA) which differentiates the color differences of the stained tissue sections. Threshold values are established to identify various tissue components of the prostate. The
• pixel densities of the corresponding area is taken out one of these tissue components are calculated for each complete selection of the
color monitor. A total of 5 selections are averaged per prostate section. Immunohistochemical imaging can be digitized and quantified to allow statistical evaluation by determining sample and probability correlation coefficients (2-tailed). 25 Example 3: Chemopreventive Activity Study A study was carried out to test the efficacy of chemopreventive agents in TRAMP transgenic animals (PBTag X FVBwt) (provided by Dr. Norman Greenberg.
• 5 College of medicine, TX). These mice preliminarily showed signs of cancer as early as 10 weeks. Transgenic TRAMP male litters were selected for the large T ag transgene, and positive males were used in the study. Toremifene atiestrogen, which was tested for its possible
chemopreventive effects, was incorporated into custom pills
• (Innovative Research of America, Sarasota, FL), and preventive treatment in mice started 30 days after birth (average mouse weight 14 grams). Each of each group of 10 to 12 animals, received subcutaneous implantations of pills with
Toremifene content with release in 90 days. The dosage of diffusable drug, adjusted for growth related to weight changes, was designed to deliver any dose
• low (6mg / kg) or high doses (30mg / kg) of toremifene. The control animals (n = IO) received placebo implants. The effectiveness of
Treatment was measured by absence of palpable tumor. Murine prostate tumors were collected and evaluated by molecular and histological techniques. Using the transgenic TRAMP model of prostate cancer in which each animal that inherits the prostate cancer gene
develops prostate cancer, it was shown that toremifene both increases latency and decreases the incidence of prostate cancer. As shown in Figure 1, the effects of a high and low dose of toremifene were equally effective. The formation
• 5 tumors in the ventral prostate of TRAMP mice were observed at week 17 for the placebo group (n = IO), and at week 19 for the group treated with high doses of toremifene (n = 12 =), and week 28 for the group treated with low doses of toremifene, (n = 12). Therefore, treatment with toremifene substantially increased
the latency period up to 1 1 weeks for the development of cancer
• in the ventral prostate in TRAMP mice. Since the animals treated with toremifene did not reach a 50% tumor development point during the study period, the time in which 25% of the animals that had tumors
compared between groups. The tumors were palpable in 25% of 10 animals, in week 23 in the placebo group and in weeks 30-31 in the groups with high and low doses of toremifene, a delay of 7-8 weeks. As shown in Table 1 below, both the low dose of toremifene and the
the high dose of toremifene vs. placebo, were significant by the registration classification and statistical analysis of Wilcoxon.
Table 1 - Statistical Analysis Classification- Renk Wilcoxon
• 5 low doses of toremifene vs. placebo 0.0003 '0.0004 * High dose of toremifene vs. placebo 0.0017 * 0.0071 * * significance P <0.05
At week 33, a point when all control animals
had developed tumors, 72% of the animals treated with
• low dose of toremifene and 60% treated with high doses of toremifene, were still free of tumors. Therefore, treatment with toremifene at both high and low doses resulted in a significantly decreased incidence of tumors in
the ventral prostate of TRAMP mice. These results, obtained according to the present invention, had not been anticipated from those reported in the aforementioned documents of Lucia and associates, which describe the administration of two levels of administration of
tamoxifen, a close structural analogue of toremifene, for Lobund-Wistar rats that have prostate carcinomas induced by treatment with a combination of an initiator and a promoter. In the Lucia and associates reference, I report clinically 22-26% of the animals that receive lower doses, and only 32-50% of
those who receive higher doses of tamoxifen, remained free of tumors in the anterior prostate. It should be noted that the anterior prostate of a rodent, unlike its ventral prostate, has no corresponding segment in a human prostate. In Lucia and associates, it further manifests that the initiator-promoter combination employed in the described methods, while being effective in inducing cancer in the anterior prostate of the test animals, failed to reduce carcinomas in the ventral prostate. Therefore, there is no basis for expecting a chemopreventive effect in tumors in the ventral prostate, by administering tamoxifen to Lobund-Wistar rats or humans. As already mentioned, the administration of toremifene produces a substantial chemopreventive effect against tumors in the ventral prostate of TRAMP mice. This result is driven for a similar beneficial effect in humans, whose prostate includes a segment corresponding to the ventral prostate of rodents.
Example 4: Histological Examination of Prostate Tissue Tumors from groups treated with placebo and with high doses of toremifene, taken at the time of palpation, were evaluated histologically. Figure 2A is an H & E section of the ventral prostate of a normal adult 17-week-old mouse. Figure 2B, is a section of the ventral prostate of a TRAMP mouse treated with placebo of 16 weeks of age, and shows that unlike the normal prostate structure illustrated in Figure 2A, the ventral prostate of the mouse TRAMP is characterized by lamellae of undifferentiated anaplastic cells with a high mitotic index. In contrast, as shown in Figure 2C, the prostate of a TRAMP mouse treated with 30-week-old toremifene retains much of the normal glandular architecture and has 5 tumors with a more differentiated structure, the mitotic index being much lower. than that of the animal treated with placebo. These results indicate that toremifene, even at low doses, have the ability to suppress prostate carcinogenesis in the TRAMP model. 10 • Example 5: Use of Chemopreventive Efficacy of Toremifene against Prostate Cancer in the TRAMP Mouse Model. This experiment confirms and demonstrates the chemopreventive efficacy of toremifene. This study focuses on the
histological and molecular changes associated with the development of the prostate tumor in control animals and the mechanism and chemopreventive action of toremifene with TRAMP animals, which are
• bred, selected and treated with sustained-release medication pills. In predetermined times, they sacrificed
groups of 5 animals and their prostate were removed for analysis, the prostate glands were evaluated for the presence of the tumor by histology, complete divisions and immunohistochemistry of large antigen T. To date, the placebo and toremifene treatments have been completed for the time points, 7, 10, 15 and 20 weeks and the results are described below. Results: Complete amounts of prostate were completed during 7, 10,
• 5 15, and 20 weeks for the different groups. The full analysis revealed that mice treated with placebo developed prostate tumors 15 to 20 weeks of age similar to the previous pilot study. In addition, animals treated with toremifene had a delay in the onset of prostate cancer up to 20 weeks
(Figure 3). In week 20, there is a delay in the emergence of
• tumor in the group treated with toremifene for up to 35 weeks (Figure 4). These data confirm that even with a more sensitive assessment of tumorigenity, toremifene exhibited chemopreventive activity. Tissue samples were set for evaluation
histological, processed and embedded in parfine. Sections were cut (5 pM thick), and stained through a routine H & E method. Toremifene inhibited the development in the ducts and
• tissue differentiation (compare the 17-week TRAMP mouse prostate tumor vs the wild type (Figure 4);
prostate treated with toremifene vs. pacebo in 15 weeks (Figure 5). Qualitatively, the immunohistochemistry of the tissues treated with placebo and toremifene showed the presence of T-antigen in the ventral prostate. Therefore, the chemopreventive activity observed by toremifene is not appreciated by the
suppression of the probasin promoter in the TRAMP model.
Conclusions: The ability of toremifene to prevent the emergence of prostate cancer in the TRAMP model has been confirmed, using more sensitive techniques to evaluate tumor formation. The mechanism of chemopreventive effects of
• Toremifene, are not appreciated through the loss of the transgene for the large antigenic protein T.
Example 6: Toremifene Induced Regression of Tumors of Human Prostate Cancer Established in the Mouse Model
Shaved. • Prostate cancer is usually the most commonly diagnosed cancer in American men. However, questions remain regarding the etiology and treatment of this disease, especially in advanced forms. The therapy
hormones, remains the standard method of treatment for recurrent and advanced prostate cancer, despite the common development of the hormone refraction disorder. Therefore, it is necessary
• new methods for the prevention and treatment of prostate cancer, to accommodate the increasing number of men with
diagnosis of this disease. The experiments and results that follow show that toremifene suppresses the growth of hormone-sensitive LNCaP tumor in shaved athymic mice. Materials and Methods: a subcutaneous injection was
million LNCaP cells in matrigel, on each side of the mice
atimicos shaved. A total of 40 mice were injected. After approximately 3 to 4 weeks, visible tumors developed. After recording the size of the tumor in two dimensions, the mice were divided into placebo groups and
• 5 treatment, based on the equivalent load of the tumor. A single pill (placebo versus toremifene 35mg) was implanted subcutaneously between the shoulder blades of each mouse. The size of the tumor was recorded weekly. The tumor volume was calculated (tumor volume = 0.5 (L + W) x L x W x 0.5236, where
L = tumor length and W = tumor width). the volume of the tumor in
• the moment of the implantation of the pill, served as the point of reference for the future comparison of the variation of the size of the tumor. Variations in tumor size were recorded weekly, in the form of a percentage differentiation of the
original measurement in the implantation of the pill. Results: Two mice died immediately after the implantation of the pill, due to the fatal wounds of others
• mice. A mouse treated with toremifene was excluded from the study due to the development of hemorrhages and hematomas of the tumor
excessive. All mice developed visible tumors unilaterally or bilaterally. Each tumor was monitored regardless of the duration of the study. Twenty-four tumors were treated with placebo and 28 tumors were treated with toremifene. The results are shown in Table 2 and in Figure 6A and 6B. 25
Table 2 Placebo Group Week N =% Change in volume relative to day 0 of treatment f 5 3 1 1 9.44 8 1 15.27 8 271 .71 8 600.88
• Toremifene Week N =% Change in volume relative to day 0 of treatment 3 1 1 -34.58 15 4 7 -61 .01 5 7 -74.51 6 5 -61 .72 I
The follow-up interval will be extended in the population currently reported 20, and the additional animal data that is currently being collected. Conclusion: Toremifene inhibits in induced regression of established LNCaP tumors. Although the mechanism by which toremifene exerts this effect is not known, the ability to
producing these effects supports the use of toremifene, as a treatment for prostate cancer, and to prevent the recurrence of prostate cancer in high-risk patients, with micrometastasis of established prostate cancer.
•
•
•
Claims (18)
- CLAIMS Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: • 1 . A method for preventing prostate carcinogenesis comprising: administering to a mammal a pharmaceutical preparation comprising a chemopreventive agent, which 10 has the formula: wherein Ri and R2, which may be the same or different, are H or OH; R3 is OCH2CH2NR4R5, wherein R or R5, which may be the same or different, are H an alkyl group of from 1 to 20 about 4 carbon atoms; and their pharmaceutically acceptable salts, esters, or N-oxides and mixtures thereof.
- 2. The method as described in Claim 1, characterized in that said pharmaceutical preparation further comprises a pharmaceutically acceptable carrier.
- 3. The method as described in Claim 2, • 5 further characterized in that said carrier is selected from the group consisting of a gum, a starch, a sugar, a cellulose material and mixtures thereof.
- 4. The method as described in Claim 1, further characterized in that said administration comprises: • subcutaneous implantation in said subject of a pill containing said pharmaceutical preparation.
- 5. The method as described in Claim 4, 15 further characterized in that said pill provides controlled release of said pharmaceutical preparation for a period of time. •
- 6. The method as described in claim 1, further characterized in that said administration of intravenous, intraarterial or intramuscular injection in said subject is said pharmaceutical preparation in liquid form.
- 7. The method as described in Claim 1, characterized further by oral administration to said subject, is a liquid or solid preparation containing said pharmaceutical preparation.
- 8. The method as described in Claim 1, further characterized in that said administration in topical form applied to the surface of said subject is from said pharmaceutical preparation.
- 9. The method as described in Claim 1, 10 further characterized in that said pharmaceutical preparation is • selected from the group consisting of: a pill, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream and a suppository.
- 10. The method as described in Claim 9, further characterized in that said suppository is a rectal suppository or a urethral suppository. • eleven .
- The method as described in Claim 1, 20 further characterized in that said pharmaceutical preparation is a parenteral formulation.
- 12. The method as described in Claim 1 1, further characterized in that said parenteral formulation comprises a liposome comprising a complex of said chemopreventive agent and a cyclodextrin compound.
- 13. The method as described in Claim 1, • further characterized in that said chemopreventive agent comprises toremifene, its N-oxides pharmaceutically acceptable salts and mixtures thereof.
- 14. The method as described in Claim 1, 10 further characterized because the administration of said agent • Chemopreventive is carried out in a dosage of from approximately 0.5 mg / kg of body weight / day to approximately 50 mg / kg of body weight / day.
- 15. The method as described in Claim 14, further characterized in that administration of said chemopreventive agent is carried out from about 6 • mg / kg of body weight / day, up to approximately 30 mg / kg of body weight / day.
- 16. The method as described in Claim 1, further characterized in that said subject has a high risk of prostate cancer.
- 17. The method as described in Claim 16, further characterized in that said subject has benign prostatic hyperplasia, prostatic intraepithelial neoplasia (PI N) or an abnormally high level of prostate-specific antibodies in the prostate. • 5 circulation (PSA).
- 18. A method to prevent the recurrence of, suppression or inhibition of prostate carcinogenesis, or to increase the range of survival in a subject having prostate cancer, in Wherein said method comprises: administering to a mammal a • pharmaceutical preparation comprising a chemopreventive agent, which has the formula: 20 wherein R-i and R2, which may be the same or different, are H or OH; R 3 is OCH 2 CH 2 NR R 5, wherein R and R 5, which may be the same or different, are H an alkyl group of from 1 to about 4 carbon atoms; and its pharmaceutically acceptable salts, esters, or N-oxides and 25 mixtures thereof.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/084,602 | 1998-05-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00009129A true MXPA00009129A (en) | 2001-11-21 |
Family
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