WO2008024026A2

WO2008024026A2 - Use of 9-oxoacridine-10-acetic acid, its salts and esters for the treatment, prophylaxis or relapse prevention of prostate cancer

Info

Publication number: WO2008024026A2
Application number: PCT/RU2007/000423
Authority: WO
Inventors: Kirill Gennadievich Surkov
Original assignee: Kirill Gennadievich Surkov
Priority date: 2006-07-31
Filing date: 2007-07-31
Publication date: 2008-02-28
Also published as: WO2008024026A3; RU2325160C1; RU2006127809A

Abstract

The present invention provides the use of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters, in combination with antiandrogenic hormonotherapy, for the treatment, prophylaxis and relapse prevention of prostate cancer. A method of treatment or prophylaxis of prostate cancer comprises the steps of (a) administration of an effective amount of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salt or ester to a patient in need thereof and (b) hormonotherapy aimed at decreasing androgen action. Further, a method of inducing or increasing the sensitivity of prostate cancer to hormone therapy aimed at decreasing androgen action is provided, wherein the method comprises administration of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salt or ester.

Description

USE OF 9-OXOACRIDINE-IO-ACETIC ACID, ITS SALTS AND ESTERS

FOR THE TREATMENT, PROPHYLAXIS OR RELAPSE PREVENTION OF PROSTATE CANCER

The invention relates to medicine, in particular, to the use of 9-oxoacridine-10- acetic acid, its salts and esters for the treatment, prophylaxis and relapse prevention of prostate cancer.

In 1941, Higgins and Hodges showed the hormone dependence of prostate cancer. Since then, hormonotherapy is the leading method of therapy of advanced forms of this tumor.

Typically, in all the cases of hormonotherapy use in the treatment of prostate tumors, its main objective is to reduce or completely eliminate the influence of endogenous male sex hormones (androgens) produced by the patient's body on tumor cells. For this purpose, hormones, their analogues, agonists or antagonists are used, as well as hormone synthesis stimulators or inhibitors.

Testosterone amounts to about 95% of all androgens and is produced by the testicles in response to the release of the hypothalamus luteinizing hormone-releasing hormone. About 5% of androgens are secreted by the adrenals, which under the adrenocorticotropic hormone stimulus produce androgens androstendion and dehydroepiandrosteron, which are transformed into testosterone in the peripheral tissues and in the prostate. In prostate cells, under the influence of 5α-reductase enzyme, testosterone turns into the more active androgen - dihydrotestosterone.

Most hormonotherapeutic methods for prostate cancer treatment aim at decreasing the blood testosterone level via depression of androgen synthesis in the testicles and in the adrenal cortex.

Attempts have been made to provide preparations and methods for increasing the efficacy of hormono- and/or chemotherapy focused on the decrease of androgen influence on cells. However, at present, no specific preparations are known that would be able to increase the sensitivity of tumor cells to hormonotherapy (hormone chemotherapy) focused on the decrease of androgen influence both on the individual clones of prostate cancer and on the whole tumor, and at the same time not being hormones, or its antagonists and having no hormonal activity. For example, lα^S-dihydroxycholecalciferol (calcitriol), biologically active form of vitamin D₃ (see WO 2004/087190, published on October 14, 2004, GENIX THERAPEUTICS INC.), is recommended for clinical use as a medication for prostate cancer therapy that increases the androgen therapy efficacy in treatment of prostate cancer. Calcitriol enhances the action of luteinizing hormone-releasing hormone agonist, which has the androgen-suppressing activity being the inhibitor of gonadotropin secretion (gonadotropin secretion inhibition leads to inhibition of testosterone production by testicles). In the same publication (WO 2004/087190), a method for the treatment of prostate cancer is disclosed, comprising co-administration of LHRH analogue and calcitriol to a patient. However, no factual data giving the evidence of efficacy of this medication and the method are presented in the publication.

DE 19536818 Al (March 21, 1997), Schering AG, discloses the use of interferon-β to increase the efficacy of antiandrogen therapy of prostate cancer. In the same publication (DE 19536818 Al), A method for treatment of prostate cancer disclosed in this publication comprises co-administration of an antiandrogen and interferon-β to a patient. The disadvantages of this method include numerous side effects, first of all associated with the properties of interferon preparations.

The above mentioned medications increase the efficacy of some medical preparations for the treatment of prostate cancer. However, the problem of the development of medications and methods for treatment and prevention of recurrent prostate cancer remains. In particular, in many cases of prostate cancer, the tumor looses the sensitivity to hormonotherapy (this condition is called hormonal refractoriness).

Nowadays, there are no effective methods of treatment and/or increasing the lifetime of patients with prostate cancer refractory to hormonal influence. The problem of prostate cancer hormone refractoriness is complicated by the presence of distant metastases in 50-70% of the newly diagnosed prostate cancer patients. In spite of the fact that primary prostate cancer is considered as hormone-sensitive a priori, from 20% to 30% patients with newly diagnosed advanced prostate cancer do not respond to hormonotherapy. It is necessary to note that in some period of time after commencement of the hormonotherapy of advanced prostate cancer, the appearance of hormone refractory form of the disease is observed, and a further progressing of the tumor process takes place. Until now, no effective remedies and methods of treatment are developed, that could prevent or delay the progress of hormone-refractoriness of prostate cancer that is initially sensitive to hormonotherapy, as well as no methods of treatment of patients with prostate cancer that is initially refractory to hormonotherapy are known. The treatment of patients with disseminated hormone- refractory prostate cancer is complicated because of the negligible possibilities of radiotherapy and surgical treatment, besides, prostate cancer with both initial hormone refractoriness and acquired hormone refractoriness has weak sensitivity to chemotherapy.

The object of present invention is to increase the efficacy of treatment and prevention of prostate cancer.

This object is solved by the use of the 9-oxoacridine-lO-acetic acid, its pharmaceutically acceptable salts and esters for the treatment and prevention of a prostate cancer.

In one aspect of the invention, 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters are proposed for inducing and increasing the sensitivity of prostate cancer to hormonotherapy, and also for increasing the efficacy of antiandrogenic hormonotherapy in treatment of prostate cancer and its relapse prevention. In some embodiments of the invention, 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters are used in combination with antiandrogenic hormonotherapy and may be applied in the combined therapy of prostate cancer and its relapse prevention, as a medication for induction or increasing prostate cancer sensitivity to hormonotherapy and a medication for overcoming hormone refractoriness in prostate cancer. The inventive medication proposed for use in combined (complex) therapy for treatment and prevention of prostate cancer provides the enhancement in comparison to the conventional hormonotherapy.

In another aspect of the invention, use of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and its esters is provided for the manufacture of a medical preparation for prostate cancer therapy and its relapse prevention, and, further, a medical preparation for inducing or increasing the prostate cancer sensitivity to hormonotherapy and a medical preparation for overcoming the hormone refractoriness of prostate cancer.

In still another aspect of the invention, the use of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and its esters, is provided in combination with antiandrogenic hormonotherapy. According to the present invention, a pharmaceutical composition for the treatment, prophylaxis or relapse prevention of prostate cancer, is provided, comprising (a) a compound selected from the group including 9-oxoacridine-lO-acetic acid, its pharmaceutically acceptable salt and ester, and (b) at least one antiandrogen agent, in amounts that together are efficient for the said treatment, prophylaxis or relapse prevention, and (c) a pharmaceutically acceptable carrier or excipient.

In accordance with present invention, the following methods are proposed as well.

A method of prostate cancer treatment comprising the steps of: (a) administration of an effective amount of 9-oxoacridine — 10 — acetic acid, its pharmaceutically acceptable salt or ester to a patient in need thereof, and (b) hormonotherapy aimed at decreasing androgen action.

A method of prostate cancer relapse prevention, comprising the steps of (a) administration of an effective amount of 9-oxoacridine - 10 - acetic acid, its pharmaceutically acceptable salt or ester to a patient in need thereof and (b)hormonotherapy aimed at decreasing androgen action.

A method of inducing the sensitivity of prostate cancer to hormonotherapy aimed at decreasing androgen action, comprising administration of an effective amount of a compound selected from the group including 9-oxoacridine — 10 — acetic acid, its pharmaceutically acceptable salt and ester.

A method of increasing the sensitivity of prostate cancer to hormonotherapy aimed at decreasing androgen action, comprising administration of an effective amount of a compound selected from the group including 9-oxoacridine - 10 - acetic acid, its pharmaceutical acceptable salt and its ester. According to present invention, preferred salts of 9-oxoacridine- 10-acetic acid are selected from the group including sodium, meglumine, eglumine salts and a salt with 3-O-(N,N-dimethylamino-rø-propyl)-l,2:5,6-di-O-isopropyliden-α,D- glucofuranose.

According to present invention, preferred esters of 9-oxoacridine- 10-acetic acid are selected from the group, including ethyl, propyl, butyl, isopropyl and amyl esters.

According to one embodiment of the invention, hormonotherapy aimed at decreasing androgen action is orchiectomy. In another embodiment of the invention, hormonotherapy aimed at decreasing androgen action includes administration of one or more agents for decreasing androgen action (further called "antiandrogen agents").

An anti-androgen agent is selected preferably from the group including non- steroidal or steroidal antiandrogens, steroid synthesis inhibitors, in particular, 5-alpha- reductase inhibitors, glucocorticoids, estrogens, agonists (analogues) of luteinizing hormone-releasing hormone (LHRH) and LHRH antagonists.

In some embodiment of the invention, hormonotherapy aimed at decreasing androgen action may represent maximal androgen blockade or discontinuous (intermittent) androgen blockade.

If appropriate, one or several chemotherapeutic agents are additionally administered to a patient.

In some further embodiments of the method according to the invention, 9- oxoacridine-10-acetic acid, its salt or ester can be administered as a treatment course prior to the hormonotherapy or as a treatment course concurrently with hormonotherapy. Alternatively, the administration of 9-oxoacridine-lO-acetic acid, its salt or ester is started prior to hormonotherapy and continued concurrently with hormonotherapy.

9-oxoacridine-10-acetic acid is a compound having the following structural formula

According to another nomenclature, the name of this compound is 10- (carboxymethyl)-9(10i/)acridone, CAS number is 38609-97-1, the international nonproprietary name is cridanimod.

Certain derivatives of 9-oxoacridine-10-acetic acid were proposed in 1971 by Hoffmann-La Roche Inc. researchers as potent antiviral agents (US patent 3,681,360).

Nowadays, medical preparations on the basis of 9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts are proposed for the treatment and prevention of a wide range of diseases. In particular, its immunomodulatory, interferonogenous, antibacterial, antipromotor and radioprotective properties are well known.

Surprisingly, the inventors of the present invention have found that the use of 9- oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters provide for the increase in efficacy of treatment of prostate cancer and rapidly prevent the progress of hormone refractoriness, which is the main reason of cancer hormonotherapy failure. Further, 9-oxoacridine-lO-acetic acid, its pharmaceutically acceptable salts and its esters provide for overcoming the primary or secondary hormone refractoriness.

Though it was reported before that 9-oxoacridine-10-acetic acid possesses no significant cytostatic activity, in the present invention it was established on animal models that the tumor growth inhibition by standard for such cases hormonotherapy is more effective in the presence of 9-oxoacridine-10-acetic acid and its salts, than in their absence.

It is known that 9-oxoacridine-10-acetic acid has interferon-inducting properties. However, the inventors of the present invention have established that in respect of tumor growth inhibition 9-oxoacridine-10-acetic acid continues to manifest dose- depending efficacy in doses exceeding the maximal interferon-inducing dose, in other words, the dose threshold of 9-oxoacridine-10-acetic acid, by exceeding which there is typically no further increase of tissue and serum interferon levels. Moreover, in situations when the system of interferon release is already exhausted (this is observed by repeated administration of any interferon inducer, including 9-oxoacridine-10-acetic acid), 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters continue to exert dose-dependent influence on prostate tumor growth inhibition in combination with hormonotherapy, preventing the progress of hormone resistance and overcoming the hormoneresistance that already exists.

Thus, the inventors of the present invention have found a novel mechanism of action of 9-oxoacridine-10-acetic acid, that provides for the new use of 9-oxoacridine- 10-acetic acid, its pharmaceutically acceptable salts and esters. In particular, the use of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and its esters allow to overcome or at least to inhibit the hormone resistance of prostate cancer to hormonotherapy.

Further, it was unexpectedly found that if 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters are administered prior to hormonotherapy, this sensitizes tumor to subsequent hormonotherapy, and the effect is retained even after withdrawal of 9-oxoacridine-lO-acetic acid or its derivatives from administration.

It shall be appreciated that as used in the present invention description, when the 9-oxoacridine-10-acetic acid is mentioned, its pharmaceutically acceptable salts and its esters are also meant. The term "pharmaceutically acceptable salt" as used herein, means those salts, which retain the above mentioned properties of 9-oxoacridine-10- acetic acid and which are not unacceptable biologically or unacceptable in some other way. The pharmaceutically acceptable salts derived from the salt forming bases could be obtained with inorganic or organic bases. The salts with inorganic bases include but are not limited to, sodium, potassium, lithium, ammonium, calcium and magnesium salts.

The salts with organic bases include, but are not limited to, salts of primary, secondary, tertiary and quaternary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines tri(cycloalkyl)amines, substituted cycloalkylamines, di(substituted cycloalkyl)amines, tri(substituted cycloalkyl)amines, cycloalkenylamines, di(substituted cycloalkenyl)amines, di(substituted cycloalkenyl)amines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclylamines, diheterocyclylamines, triheterocyclylamines, mixed di- and tri-amines, where at least one of the substitutes on amine differs and is selected from the group, including alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclyl, etc. Amines, in which two or three substitutes together with the nitrogen atom to which they are connected, form a heterocyclyl or a heteroaryl, also are included here.

Specific examples of appropriate amines include, in particular, isoprpylamine, trimethylamine, diethylamine, tri(isopropyl)amin, tri(π-propyl)amine, ethanolamine, 2- dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylendiamine, glucosamine, N-alkylglucamine, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine etc.

An example of a salt of 9-oxoacridine-10-acetic acid with an alkali metal is the sodium salt:

An example of a salt with aminocompound is the salt with 1-deoxy-l- (methylamino)-D-glucitol (i.e. with meglumine, or, the same, with N- methylglucamine) :

H₂-CH₂-(CH₂OH)₄-CH₂OH

Other examples of salts with various complex quaternary ammonium bases include salts with amine-substituted carbohydrates, for example, with 2-deoxy-2- amino(or 2-alkylamino)-D-glucose, where R is H or a lower alkyl:

with 1 -deoxy- 1 -methylamino-D-glucose:

as well as salts with various esters of carbohydrates and aliphatic amino alcohols, for example

where R₁, R₂ are independently alkyl, aryl, heteryl

The examples of suitable cations include, in particular, cations of S-O-CNjN-dimethylamino-π-propy^-l^-.Sjό-di-O-isopropyliden-αjD-glucofuranose, 1-deoxy -l-(ethylamino)-D-glucitol (i.e. eglumine), 1- deoxy -l-(propylamino)-D- glucitol, 1- deoxy -l-(butylamino)-D- glucitol, 1- deoxy -l-(methylamino)-L- glucitol, 1- deoxy -l-(ethylamino)-L- glucitol, 1- deoxy -l-(propylamino)-L- glucitol, and 1- deoxy -l-(butylamino)-L- glucitol.

Suitable esters of 9-oxoacridine-lO-acetic acid include compounds obtained by hydrogen atom substitution in acid OH-group with an organic group R.

Examples of suitable esters include esters of 9-oxoacridine-10-acetic acid with lower alkyls (namely with (Q-C^alkyls, in particular ethyl, propyl, isopropyl, butyl and amyl esters), as well as with choline and other lypophilic alcohols. After rapid penetration through biological membranes in vivo, these compounds are easily hydrolyzed to free 9-oxoacridine-10-acetic acid.

According to the invention, 9-oxoacridine-10-acetic acid or its pharmaceutically acceptable salts and esters are proposed to enhance the efficacy of hormonotherapy that is intended for direct or mediated, complete or partial decrease of androgen action on tumor cells.

This therapy can represent hormonotherapy aimed at decreasing androgen action, in particular, orchiectomy, or include administration of one or more agents decreasing androgen action, further called "anti-androgenic agents". Hormonotherapy can also comprise several hormonotherapeutic methods.

The orchiectomy represents a surgical removal of testicles (castration) and is used as a method of classic ablative hormonotherapy, leading to an abrupt drop in endogenous androgens.

According to the invention, anti-androgenic agents can be selected from the group including nonsteroidal or steroidal antiandrogens, steroid synthesis inhibitors, in particular, androgen synthesis inhibitors, in particular, 5-alpha-reductase inhibitors, glucocorticoids or estrogens; agonists (analogues) of luteinizing hormone-releasing hormone (LHRH), and the LHRH antagonists.

Antiandrogens include steroidal and non-steroidal compounds that are able to inhibit endogenous androgen physiological activity. These compounds act to cause concurrent androgen receptors blockade in the target tissues; they do not interfere with biosynthesis and secretion of androgens. Cyproterone is an example of steroidal antiandrogens.

Examples of non-steroidal antiandrogens include flutamide, bicalutamide, nilutamide.

Antiandrogenic activity is inherent to a certain degree for a number of endogenous steroid compounds including progestins and estrogens. Their synthetic derivatives possess antiandrogenic activity, same as some of androgen derivatives.

Steroid synthesis inhibitors include compounds, which inhibit production of steroids, including androgens production, by altering the activity of steroidogenic enzymes; for example, aminoglutetimide and ketoconazole are steroid synthesis inhibitors. The compounds that inhibit 5α-reductase and therefore testosterone transformation into dihydrotestosterone possess a specific type of antiandrogenic activity. They do not bind to the androgen receptors, but they are also considered by pharmacologists as antiandrogenic agents .

5-alpha-reductase inhibitors include, in particular, finasteride (Proscar) and saw palmetto (Serenoa Repens) fruit extract (Permixon).

Glucocorticosteroid preparations (glucocorticoids) could, in particular, be selected from a group including hydrocortisone, prednisolone, dexamethasone.

Ethynilestradiol, diethylstilbestrol and hexestrol in particular belong to estrogens (estrogenic agents). Hypothalamic factors ("releasing-factors"), releasing pituitary hormones

(gonadorelin analogues), namely, luteinizing hormone-releasing hormone agonists, which inhibit androgen synthesis are represented, in particular, by triptorelin, buserelin, leuprolide (leuprorelin) and goserelin. As a luteinizing hormone-releasing hormone antagonist abarelix could be used.

A hormonotherapeutic action may be presented by administration of antiandrogens in combination with estrogens or luteinizing hormone-releasing hormone agonists (analogues).

One of the methods of hormonotherapy of prostate cancer is "maximal, or total, androgen blockade".

Prostate cancer hormonotherapy includes methods principally aiming at decreasing the amount of androgens or their ability to influence prostate cancer cells. Various means and methods are used that focus on different links of androgen synthesis, production or action; they typically include the following methods used in combination or separately: surgical or medical castration, administration of antiandrogens, 5-alpha- reductase inhibitors, estrogenic medications, agents that decrease androgen production and/or decrease the sensitivity of androgen receptors to androgenic signals.

Maximal androgen blockade (synonyms: total androgen blockade; combined androgen blockade) is a method of prostate cancer hormonotherapy, in which two or more means and methods of prostate cancer hormonotherapy are used, as a rule, with different mechanisms of antiandrogenic action.

The other known method is the intermittent (interrupted) androgen blockade. This method is used to prevent or delay the development of hormone refractoriness.

The essence of intermittent androgen blockade is to begin hormonotherapy from combined androgen blockade and to continue it until the tumor response to the therapy is reached (until the lowest steady state level of serum prostate-specific antigen (PSA) is achieved). Then the therapy is interrupted to permit the growth of new clones of androgen-sensitive prostate cancer cells, waiting until the PSA level returns to 10-20 ng/ml. Thereafter, the androgen blockade is started again. This method is based upon the fact that remaining tumor cells from androgen-dependent clones compete for nutrition and space with androgen-refractory cells, and later the tumor responds to restarted hormonotherapy. The use of the intermittent androgen blockade allows to delay the hormone refractory status development of prostate cancer cells and to improve survival in the patients. The combination of these methods with administration of 9-oxoacridine-10- acetic acid or its pharmaceutically acceptable salts or its esters provides for increasing in efficacy of these methods.

Under a maximal androgen blockade, the administration of 9-oxoacridine-lO- acetic acid or its pharmaceutically acceptable salts or its esters allows to reach a more rapid decrease of the prostate-specific antigen (PSA) level. At that, in an intermittent androgen blockade, accompanied with the administration of 9-oxoacridine-lO-acetic acid or its pharmaceutically acceptable salts or its esters, apart from a more rapid PSA level decrease, its more slow increase after antiandrogenic action interruption is observed. Besides, the use of the 9-oxoacridine-10-acetic acid or its pharmaceutically acceptable salts or its esters increases the number of an intermittent androgen blockade cycles, before the hormone refractoriness develops.

If appropriate, this treatment of prostate cancer may be completed by use of chemotherapeutical preparations, such as docetaxel, paclitaxel, mitoxantrone, doxorubicin, vinblastine and etoposide.

At that, the preferred combinations in chemo-hormonotherapeutic regimens are the combinations of mitoxantrone and its analogues with prednisolone, of docetaxel (or palitaxel) with glucocorticoids, for example, with prednisolone, of doxorubicin or platinum derivatives with glucocorticoids. Additionally, in hormonotherapeutic schemes, calcitriol and/or its analogues could be used, that bound to the vitamin D₃ receptors as those, for example, described in the application US 2003/011975 Al.

The experiments conducted by the inventors of the present invention in the development process have shown that the 9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts and its esters were able not only to increase the effect of hormone therapeutics , that aimed the decrease of androgen action onto androgen- dependent cells, including prostate cells and prostate cancer cells, but also, what is much more interesting, the 9-oxoacridine-10-acetic acid and its pharmaceutically acceptable salts and its esters were found to be able, just in combination with hormonal remedies, to enhance noticeably the cytostatic therapy effect in prostate cancer.

If chemotherapy was added on different stages to such combined hormonotherapy or was used after such combined exposure (hormonotherapy plus the 9-oxoacridine-10-acetic acid or its pharmaceutically acceptable salts and its esters), it exerted much more pronounced inhibiting influence on the tumor's growth. Such effect was observed in therapy of the hormone refractory variant of malignant prostate tumor as well.

In the course of work on the invention, it was also suddenly revealed that the combined exposure of prostate cancer cells to the 9-oxoacridine-lO-acetic acid or its pharmaceutically acceptable salts or its esters, and antiandrogenic agents in the presence of androgens not only increases the proliferation-inhibitory effect of the antiandrogenic therapeutics, but enhances dramatically the effect of cytostatics from different classes. Such sensitizing effect of the combined exposure of hormonotherapeutic preparations and the 9-oxoacridine-10-acetic acid or its derivatives in regard to cytostatic chemopreparations' action was not achieved when the tumor cells were exposured to 9- oxoacridine-10-acetic acid or to prostate cancer hormonotherapeutics used separately. Interesting, that the "sensitization" effect maintained even after the cessation of combined action of the 9-oxoacridine-10-acetic acid (or its pharmaceutically acceptable salts or its esters) and hormone preparations. No such effects were found when, for example, interferons were used.

The pharmaceutical salts of the 9-oxoacridine-10-acetic acid may be used at a single dose from 0.5 to 100 mg/kg body weight (calculated based on the 9-oxoacridine- 10-acetic acid), preferably from 4 to 20 mg/kg body weight. At that, the daily dose may vary from 2 to 1000 mg/kg, preferably from 2 to 200 mg/kg. A concrete dosage of the preparation could be determined by a specialist on the basis of the present invention description and of the examples below.

It is intended that the used quantities of 9-oxoacridine-10-acetic acid or its pharmaceutically acceptable salt or its ester, as well as of an antiandrogenic agent are synergistically effective. By the term "effective amount" of an agent as provided herein is meant a nontoxic but sufficient amount of the agent to provide the desired effect, such as androgenic effect. As will be pointed out below, the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, and the particular compound and its mode of administration, and the like. Thus, it is not possible to specify an exact "effective amount." However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.

By "pharmaceutically acceptable" is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected compound or agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

In general, all the compositions according to the invention can alternatively include, be composed of, or be principally composed of any matching components disclosed in the present description, and such remedies, including the composition, the kit, and the combination, according to the invention, may additionally or alternatively be prepared in such a way that from them is excluded a component, a material, an ingredient or an object, which was used in a remedy, known in the "prior art", or which is not necessary to reach the technical result of the present invention.

The same refers to the inventive methods, which alternatively may include, be composed of, or be principally composed of any matching stages disclosed in the present description, and such inventive methods may additionally or alternatively exclude some stage or object, which is used in a method, known in the "prior art", or which is not necessary to reach the technical result of the present invention.

Further, the invention is illustrated by concrete examples, not limiting the scope of the present invention.

To designate the 9-oxoacridine-lO-acetic acid further the abbreviation CMA will be used.

The commercial available preparations of CMA salts, for example sodium CMA salt (preparation Neovir, Pharmsynthez, Russia), meglumine CMA salt (preparation Cycloferon, NTFF Polysan, Russia), as well as commercially available CMA (Sigma, USA, cat. # 17927, catalogue of year 2005), among others, were used in the experiments and the clinical studies carried out by the present inventors.

The esters and some other CMA salts were synthesized by known, relatively simple methods (see for example: Inglot A.D. et al., Archivum Immunologiae et Therapiae Experimentalis, 1985, vol. 33, pp. 275-285; RU 2135474; RU 2036198; RU 2033413). In some cases, for example, suppositories, containing CMA or its pharmaceutically acceptable salt or its ester, on the basis of widely used for this purpose suppository masses, such as Witepsol (Witepsol W 35, E 75), were prepared in a manner illustrated by the presented examples for rectal administration at the clinic. EXAMPLE 1. Preparation of a medication for local use.

250 g of finely crystalline 9-oxoacridine-lO-acetic acid were mixed during heating to 60 degrees Celsius with a suppository mass, consisting from a widely used basis for suppositories Witepsol W 35 and Tween 80 emulsifier, the mixture was homogenized in a mixer, and a suppository mass with total weight 1.5 kg was obtained; 970 suppositories were molded, each weighing 1.5 g and having the following composition: 9-oxoacridine-10-acetic acid - 0.250 g; twin 80 - 0.45 g; Witepsol W 35 - 1.2 g. The yield was 97%.

EXAMPLE 2. Enhancement of the hormonotherapy effect on the model of a prostate adenocarcinoma hormone refractory variant in rats

Male Copenhagen rats weighing 200-230 g were used. To model tumor process, under ketamine anesthesia, the 5 mm volume pieces of androgen-sensitive refractory (AT-variant) of Dunning R3327 rat prostatic adenocarcinoma were transplanted subcutaneously into the right thigh. Hormone therapy was started 2.5 months after transplantation when the tumor volume reached 0.5- 1.5 CM³. CMA (as sodium salt) (NaCMA) treatment or interferon beta- Ia treatment were realized as preliminary sensitization regimen (i.e. "pre-sensitization") or as therapy regimen (synchronously with hormone therapy). In the first variant, treatment (regimen I) was started 2-2¹A weeks before hormone therapy commencement and was finished at the day before hormone therapy commencement. In the second variant, treatment (regimen II) was started synchronously with hormone therapy commencement and was continued to the end of the experiment. Also, in one of experiment series prior to hormone therapy commencement the animals were started to receive NaCMA or interferon beta Ia, correspondingly, and then the animals were continued to be treated with above preparations during the hormone therapy course (regimen III). Under all treatment regimen (I, II or III) CMA (as sodium salt) was given every day at dose 10 mg per kg of animal weight, and interferon beta - Ia was given every day at dose 1 x 10⁵ UI per kg of animal weight.

Immediately before hormone therapy and then once per week, size of the tumor was measured and tumor volume was calculated. Treatment efficacy was evaluated with Tumor Growth Inhibition index (TGI). TGI was determined as the ratio of the difference between average tumor volume from treated animals and average tumor volume from negative control animals, divided by average tumor volume from negative control animals. TGI was evaluated in percentage points.

Avg.tumor vol.in the neg. cntrl group-Avg.tumor vol.in the , _nno/GI (%)= group ^{Xi υ(J /0}

Average tumor vol. in the neg. cntrl group

In the experiments, the antiandrogen bicatulamide (3 mg/kg/d), that was administered orally in a starch gel 15 mg/kg daily.

The LHRH analogue goserelin (Zoladex, AstraZeneca) was also used (in a dose of 0.1 mg/kg once every 4 weeks) in combination with calcitriol (Sicor Pharmaceuticals, Inc., USA), that was administered subcutaneously 1 mkg per animal 3 times a week.

Estramustine (Estracyt, Pharmacia & Upjohn, USA) was injected intraperitoneally 50 mg/kg 3 times a week during 4 weeks in combination with paclitaxel (Taxol, Bristol Myers Squibb Co.), that was injected intravenously 2 mg/kg once a week for 4 weeks.

The castration was one more variant of hormonotherapy.

Additionally, in the experiment a group of animals was introduced, that received a topoisomerase II inhibitor mitoxantrone and a glucocorticoid prednisolone.

Mitoxantrone (Novantrone, Lederle Laboratory, UK) was injected intravenously at a dose 0.25 mg/kg once every 3 weeks, and prednisolone (Simplex Pharma, India) - as intramuscular injections at a dose 30 mg/kg daily.

The variants of hormone treatment and therapeutic regimens, as well as experiments' results are illustrated by Table 1.

Table 1.

Enhancement of the hormonotherapy effect on the model of a prostate adenocarcinoma hormone refractory variant in rats

* See explanation in the text of the description

The higher the TGI is, the more effective the used combination is. In all the experiments, the index for the combination including NaCMA is higher, than that in the experiment without NaCMA use or for a combination with interferon β.

From the presented data, it is obvious that NaCMA induces the sensitivity of the hormone refractory prostate cancer to the hormonotherapy much more effectively, than interferon. By that, Na CMA in distinction from the interferon βla, has proved to be able to "presensitize" the tumor to further hormone (or chemo-hormone) treatment (regimen I).

Besides, for the hormonotherapy of hormone refractory cancer other combinations of hormone and chemo-hormone treatment were used, including antiandrogens, as non-steroidal, so steroidal; androgen synthesis inhibitors, including 5- alpha reductase inhibitors, glucocorticoids, antifungal steroids; estrogens; LHRH agonists (analogues); LH-RH antagonists, as well as their different combinations, including those with chemotherapeutics. Among chemotherapeutics, taxanes (for example, paclitaxel), topoisomerase II inhibitors (for example, mitoxantrone); vinca alcaloids (for example, vinblastine); antitumor antibiotics (for example, doxorubicin); platinum preparations (for example, cisplatin), as well as different combinations of those groups preparations between them, for example, paclitaxel or docetaxel with estamustine; estramustine with vinblastine or etoposide, were used.

As derivatives of the 9-oxoacridine-10-acetic acid, pharmaceutically acceptable salts and its esters, in particular, ethyl ester, were used.

In all the cases, the 9-oxoacridine-lO-acetic acid derivative showed much more pronounced effect in the sensitivity increase or sensitivity induction (that is overcoming the hormone refractoriness), than interferon βla. The maximal effect was observed in the variant of administration regimen, when 9-oxoacridine-10-acetic acid or its pharmaceutically acceptable salts and its esters were administrated prior to commencement of the hormone (chemo-hormone) treatment, and the administration was continued further under the ongoing hormonotherapy or chemo-hormonotherapy.

EXAMPLE 3. Prevention of hormone refractoriness development in human prostate cancer by constant, as well as by discontinuous (intermittent) antiandrogenic treatment.

The experiments were carried out using hormone-sensitive human prostate cancer cell LNCaP (ATCC, CRL -1740) inoculated subcutaneously at a dose 1 x 10⁶ cells in the flank to athymic BALB/c "nude" mice, 6-8 weeks of age. When the tumor reached the size of about 1.0 cm in diameter, the mice were subjects to hormone ablation (castration) under ketamine anesthesia. Then the animals were randomly distributed into several equal groups. In all the animals, two times before castration and twice a week after castration the total serum prostate-specific antigen (PSA) level, as an inoculated tumor growth marker was measured with an ELISA-method (AlkorBio, Russia).

The first group of animals (group 1, N = 30) received testosterone enanthate as a compensation of the androgen ablation (Testosterone depot, Jenapharm, Germany) at a dose 30 mg/kg once a week, beginning from the 2 week after castration for 2 weeks. Then a three-week break followed, signifying the restoration of androgen deprivation, and then again a 2 week cycle of testosterone enanthate administration was repeated. The cycles ("deprivation - testosterone") were continued until the moment, when the serum PSA level exceeded the pre-castration serum PSA level, what served as a marker of the progression of the tumor to an androgen-independent state. In contrast to the first group of animals, the second group of animals (group 2, N

= 30) did not receive testosterone, and thus, was subject to constant androgen deprivation.

Each group was divided into three equal subgroups A, B, C.

The A subgroups (i.e. IA and 2A, correspondingly) received 9-oxoacridine-10- acetic acid (CMA) (at a dose 15 mg/kg weight subcutaneously, every other day during the whole hormonotherapy course,).

The B subgroups (i.e. IB and 2B, correspondingly) received interferon beta- Ia (IF) in a dose 1 x 10⁵ IU/kg daily.

The C subgroups (1C and 2C) served as a control: they did receive neither the inventive medication, nor interferon beta- 1 a (IF) .

As the moment of the tumor transition into hormone refractory state served the moment, when the serum PSA level exceeded the pre-castration serum PSA level in an individual animal. The average time for the group (in days) from the castration moment up to the hormone refractoriness development (T_R) was estimated, as well as the ratio of the PSA level at the 15 week of the therapy course to the pre-castration PSA level (PSA₀/PSA₁₅). The study data are presented in Table 2.

Table 2. Prevention of the hormone refractoriness development in human prostate cancer

From the presented data it is evident, that CMA in all the androgen deprivation regimens prevents the hormone refractoriness development in human prostate tumor much more effectively, than IF.

EXAMPLE 4. Overcoming of developed human prostate cancer hormone refractoriness.

The experimental model described in the previous example, was used, but androgen deprivation was induced not by castration, but by administration of a LHRH analogue buserelin in combination with the antiandrogen flutamide: when the tumor reached the size of about 1.0 cm in diameter, flutamide (Flucinom, Schering-Plough, USA) was administered to the mouse at a dose 10 mg/kg daily orally in starch gel and buserelin (Buserelin-depot, Pharm-synthes, Russia) intramuscularly at a dose 0.15 mg/kg once every 4 weeks. Two times prior to the hormonotherapy commencement and then twice a week after the hormonotherapy commencement the total serum prostate- specific antigen (PSA) level was measured with an ELISA-method (AlkorBio, Russia), as an inoculated tumor growth marker.

As the moment of the tumor transition into hormone refractory state served the moment, when the serum PSA level exceeded the pre-castration serum PSA level in an individual animal. (As a rule, it took place at the 4-5 week from the hormonotherapy commencement). Next day after the establishment of this fact, the animal randomly distributed in one of the 3 following groups.

The animals from the first group began to receive CMA in a dose 25 mg/kg body weight daily intraperitoneally. The animals from the second group began to receive interferon beta-1 (IF) in a dose 2.OxIO⁶ IU subcutaneously. The animals from the third group served as negative control and received, accordingly, physiological solution injections.

CMA, IF or placebo (physiological solution) were injected according to this regimen up to the experiment's end. The regimen and doses of the combined antiandrogenic treatment (buserelin plus flutamide) did not change during the whole experiment.

As a case of developed hormone refractoriness overcoming was considered the fact of the PSA decrease lower than the pre-castration value during a period no less than 2 weeks. In each group, the percentage of animals was estimated, in whom the tumor hormone sensitivity restored. The results of the experiments are presented in Table 3.

Table 3. Overcoming of the developed hormone refractoriness in human prostate cancer.

From the presented data it is evident that CMA is much more effective, than IF, restores the lost hormone sensitivity in human prostate cancer.

EXAMPLE 5. Overcoming the acquired hormone refractoriness of locally advanced prostate cancer by the inventive method.

On examination examination 6 years ago, patient P., 67 years old was found to have increased PSA level (8ng/ml). After digital rectal examination, stage T₂C prostate cancer was diagnosed and verified by biopsy (Gleason score 7 (3+4)). In some months after radical prostatectomy, at which stage T3b was established, Gleason score 7, PSA level increased from 0.10 to 0.80 ng/ml. Pelvic computed tomography revealed mesenteric lymph nodes' lesions. Among the treatment options offered to patient, his chose high-dose bicalutamide monotherapy, 150 mg once a day, with irradiation of the breasts to prevent tenderness and gynecomastia.

PSA decreased to undetectable level after 4 months of the therapy commencement. But in 6 months after bicatulamide treatment beginning, PSA increased again up to 4.6 ng/ml, and liver functional impairment was observed (the patient suffered from chronic hepatitis). The patient received leuprolide (once in 4 weeks subcutaneously), in combination with vitamin D₃ and calcium preparations, for 3 years, but then PSA level increased again from 0.1 up to 1.4 ng/ml during 6 months, and testosterone level was lower than 50 ng/ml. As far as further treatment options provided the administration of the next line hormone agents or/and cytostatics, after the patient's consent has been obtained, it was decided to treat him by the inventive method.

For this purpose together with the preparations taken by the patient (leuprolide and vitamin D₃), the dosage of which was not changed, the patient began to receive the CMA as a sodium salt (2 ml 12.5% solution for injections = 250 mg, Neovir,

Pharmsynth.es, Russia) intramuscularly 2 times a week as 4 week courses with 1 week break.

2 months after the combined therapy was commenced, the analysis of prostate- specific antigen (PSA) showed that its level diminished twice. PSA level gained undetectable values within the next two months. Computed tomography was performed and it revealed no any progression of peritoneal lymphatic nodes affection, and no new lesions in other parts of the body were found. Thus, the inventive method is effective to overcome developed hormone refractoriness and to treat advanced prostate cancer.

EXAMPLE 6. The treatment of recurrence of hormone refractory prostate cancer with the inventive method

A 58-year-old male patient underwent radical prostatectomy for localized prostate cancer 5 years ago (preoperative PSA level reached 6.4 ng/ml), Gleason score 6 (3+3), T2NXM0. The patient received no hormonotherapy. Further follow-up of the patient showed that the PSA was on the undetectable level. But due to relocation, the patient was not followed during next three years, and then he consulted his doctor with a complaint on stranguria and pains in his lumbar spine. On examination, a recurrence of prostate cancer was found with regional spread and spinal metastases (T3NlMlb); the serum PSA level reached 1110 ng/ml.

The depot-preparation of the LH-RH agonist buserelin was administered. To prevent the "flash - syndrome" phenomenon, 1 week before the start of treatment with buserelin-depot the patient began to receive an antiandrogen flutamide. Despite the fact that the testosterone level to the end of the second month decreased to the post- castration values, pains slightly increased, the computed tomography showed the increase of the primary site and of the affection of regional lymphatic nodes. The serum PSA level was 1560 ng/ml.

Against this background, the treatment with the inventive method was prescribed to the patient: the CMA eglumine salt was injected intravenously as a sterile solution for injections at a dose 500 mg once every 3 days, buserelin-depot and flutamide were continued at the same doses and regimen. Within next 2 months of the therapy with the inventive method (androgen blockade and CMA eglumine salt), pains diminished. The stranguria complaints diminished as well. The instrumental methods revealed the decrease of the primary tumor lesion and bone metastases. There were no new lesions found. The PSA level was 120 ng/ml. Thus, the inventive method is effective in hormone refractory prostate cancer recurrence treatment.

EXAMPLE 7. The prevention of the hormone refractoriness appearance (development) in treatment of advanced prostate cancer with the inventive method.

In a patient, 59 years old, on digital prostate exam a malignant prostate tumor was found, the biopsy gave Gleason score 7 (3+4). At the computed tomography revealed the tumor, expanding on the pelvis walls, the iliac lymph nodes involvement, as well as 2 liver metastases (T₄N₁M₁). The serum PSA level was 310 ng/ml. LH-RH agonist leuprolide (Lucrin-depot) 3.75 mg once every 4 weeks and bicatulamide

(Casodex) 50 mg per day were prescribed. One month after the treatment started, the serum PSA level was 1.2 ng/ml, and after next 2 months it was 0.2 ng/ml. At a control exam after 4 months, a partial regression of primary and secondary lesions was found, there were no new lesions revealed, the serum PSA level was 0.2 ng/ml.

Against this background, the treatment with the inventive method was prescribed to the patient: in addition to hormonotherapy preparations (leuprolide and bicatulamide) the patient began to receive orally the N-methylglucamine CMA as enteric coated tablets, 4 tablets (0.15 g each) at once daily (=600 mg/d) every day, 3 month courses with 2 week intervals.

12 months after the hormonotherapy commencement, the PSA remained at the 0.2 ng/ml level. During the following 4 years, the patient was examined with respect to the dimensions of existing lesions, a possible appearance of new lesions, and the PSA level. In spite of the fact that in such patients even at combined maximal androgen blockade further progression occurs no later than in 24-36 months (i.e. the hormone refractoriness appears), in this patient the hormone refractory form of prostate cancer did not occur during those 4 years. Thus, the prostate cancer treatment with the inventive method delays the hormone refractoriness development.

EXAMPLE 8. The prevention of prostate cancer relapse with the inventive method.

In a patient P., 69 years old, 5 years ago a prostate cancer was diagnosed (based on digital prostate exam, biopsy and pelvic tomography). The Gleason score was 8, the PSA before surgery was 45 ng/ml, distant and regional metastases were no found, the prostate volume was 45 cm³. A radical prostatectomy was performed with pelvic lymph nodes dissection. Histological examination of surgical material found lymph nodes involvement. The PSA level after surgery was 0.1 ng/ml. After surgery, to diminish the prostate cancer recurrence risk, the prophylaxis of prostate cancer recurrence with the inventive method was performed: the antiandrogen flutamide (750 mg daily orally, divided into 3 doses), and the sodium CMA salt (4 ml of 12.5% sterile solution for injections twice a week) were administered.

The serum PSA level remained on the indefinable level and there are no signs of tumor recurrence during the follow-up period of 5 years. Thus, the claimed method is highly effective for prostate cancer recurrence prophylaxis.

EXAMPLE 9. The increase of prostate cancer sensitivity to the hormonotherapy.

In a 53 years old patient, a rise of serum PSA up to 5.5 ng/ml was found, although 2 years before the PSA level was 2.0 ng/ml. The rectal examination showed a tumor of T₁C stage, the biopsy revealed Gleason score 7 (3+4). A radical retro-pubic prostatectomy was performed. Morphological examination of the surgical material found a Gleason score 8, the tumor expansion outward the gland capsule, without funicles or lymph nodes involvement in the process. After surgery, the PSA level decreased to 0.1 ng/ml. But in 21 months after surgery, the PSA level increased up to 0.2 ng/ml, and that was confirmed by PSA analysis one month later. Any other symptoms or signs of local relapse, or other organ involvement no were found. An LH-RH agonist leuprolide (3.25 mg once every 4 weeks) was administered, and two months later the PSA level decreased to undetectable values, but side effects appeared, namely vomiting and hot flushes. Besides, the bone densitometry revealed the signs of osteoporosis. For that matter, the patient was shifted to the intermittent androgen blockade regimen (leuprolide 7.5 mg once every 4 weeks and cyproterone acetate 200 mg/d) with additional vitamin D₃ and calcium preparation administration. The hot flushes decreased, the PSA level did not increase. To the 60 year of life, in spite of the therapy, the PSA level began to increase from 0.1 ng/ml to 0.5 ng/ml during 6 months. The serum testosterone stayed in the post-castration level range (less than 50 ng/ml). The computed tomography of the skeletal bones, of the abdomen, of the lungs, of the large and small pelvis did not reveal any metastases. 2 months later, the PSA level reached 2.5 ng/ml. The cessation of antiandrogenic therapy did not lead to the PSA decrease.

The "second-line" hormonotherapy was administered - ketoconazole and hydrocortisone. The PSA level slightly decreased (from 100 ng/ml to 80 ng/ml during 6 months), and began to rise again (up to 220 ng/ml in 2 months of therapy).

To the patient, a systemic chemotherapy was proposed, including docetaxel, that the patient refused. By the patient's consent, the treatment with the inventive method was prescribed. For this purpose, the ketoconazole and hydrocortisone regimen was continued in same doses with intravenous injections of 10% CMA eglumine salt sterile solution for injections - 250 mg every second day during 1 month with further oral administration of fine crystalline CMA in capsules ( 600 mg twice a week).

Under this therapy the PSA level decreased to 10 ng/ml within next 4 months. The following examinations conducted with a 4 months intervals showed further decrease of the PSA level. Thus, the inventive method efficiently increases the sensitivity of prostate cancer to the "second-line" hormonotherapy.

EXAMPLE 10. The treatment of advanced metastatic prostate cancer with the inventive method.

There were 10 patients with a disseminated metastatic prostate cancer (mostly bone metastases) with exhausted hormonotherapy methods, including "second-line" hormonotherapy. The patients were randomly distributed into two groups. All the patients were treated with 21 -day chemo-hormonotherapy course (three cycles, 7 days each).

Each weekly cycle comprised: intravenous administration of docetaxel (Taxoter, Aventis Pharma) at a dose of 70 mg/kg body weight on the second day of the cycle; orally estramustine (Estracyt, Pharmacia & Upjohn) 10 mg/kg/d (280 mg capsules) every day the first five days of the cycle, intravenously hydrocortisone (Hydrocortisone, Gedeon Richter) 20 mg twice a day during the whole cycle, and orally dexamethasone (KRKA, Slovenia) 7.5 mg twice a day during the first day of the cycle.

One half of the patients (1^st group) received additionally intravenous injections of 2 ml 12.5% CMA sodium salt (250 mg) as sterile solution once a day. The second half of the patients received, besides chemo-hormonotherapy, interferon beta- Ia (Avonex, Biogen B.V., the Netherlands) at a dose of 3 mln IU daily subcutaneously.

After the chemo-hormonotherapy course was completed, the progression was not found in any of the 1 group patients (0%), and in the group 2 the progression was diagnosed in 2 patients (40%); the stabilization was noted in 1 patient of the group 1

(20%) and in 2 patients of the group 2 (40%); the partial regression was noted in 4 patients of the 1-st group (80%) and in 1 patient (20%) from the 2-nd group.

The PSA decrease to more than 50% from the baseline level, was observed in 4 patients of the group 1 (80%) and in 2 patients of the group 2. Moreover, in one half of the patients of the group 2 side effects developed, related to interferon: fever, rash. Such effects were not observed in the group of patients receiving the inventive medication. Thus, the CMA sodium salt is highly effective at chemo-hormonotherapy of advanced prostate cancer, at that, it is more effective than interferon beta- Ia and has less side effects.

EXAMPLE I l

Enhancement of the efficacy of hormonotherapy in rat model of hormonerefractory prostate adenocarcinoma

The experiments were carried out similarly to the ones in Example 2, however the sodium salt was substituted by other CMA salts, and other CMA esters were used. In particular, the following CMA salts: a salt with 2-desohydroxy-2-amino-D-glucose (DAGCMA); lithium salt (obtained as described in RU 2202547 (LiCMA)); salts with l-desoxy-l-(methylarnino)-D-glucitole (MethylCMA.), with l-desoxy-l-(ethylamino)- D-glucitol (EthylCMA). Further, ethyl ester (EthylEtCMA) and isopropyl ester of CMA (PropylEtCMA) were used, obtained as described in RU 2033413. (When preparing PropylEtCMA, respectively, isopropylchlorine acetate was used). Further, (N₅N - dimethyl amino)ethyl ester of CMA (DMCMA) was used (see, Szulc et al. Szulc, B et al., Antiviral Research, v. 7 (1987), pp. 109-117, (DMCMA)). DMCMA was prepares as described in Archivum Immunologiae et Therapiae experimentalis, 1985, vol.33, pp. 275-285. Further, CMA salt with 3-O-(N,N-dimethyl amino -n- propyl)- 1,2:5, 6-di-O- isopropylidene - α, D - glucofuranose was used obtained as described in RU 2118532 (PropylCMA). All the compounds were administered in equmolar amounts, i.e. 4,3 x 10 ^'2 mmol/kg. CMA esters due to their poor solubility were administered in the form of fine suspension on physiological solution.

Table N° 4. Enhancement of the efficacy of hormonotherapy in rat model of hormonerefractory prostate adenocarcinoma

Group number Treatment Hormone TPO , %

/Hormone therapy therapy 2 weeks since 12^th week since regimen* the beginning of the beginning hormone of hormone therapy therapy

1 2 3 4 5 6

1 NO (=negative - - - - control)

2 - - 47 26

EthylEtCMA 55 42

I

Interferon βla 50 31

Bicalutamide DAGCMA 60 64

II

Interferon βla 55 47

LiCMA 73 80

III

Interferon βla 53 49 Continuation of Table 4.

* see explanations in example 11. The higher is the TPO index, the higher is the efficacy of the used combination. In all the examples, TPO index for the combination comprising different CMA salts or esters, was higher than in the experiments in the absence of CMA salts/esters, or in the experiments with the use of a combination of hormone therapy with interferon lβ. The obtained data clearly show that the studied CMA salts and esters induce/ enhance the sensitivity of prostate cancer to hormone therapy in much more greater extent than Interferon. It shall be also noted that different CMA salts and esters, contrary to Interferon βla, are capable of "presensitizing" the tumor for subsequent hormone or chemo-hormone treatment (Regimen I).

Claims

1. Use of 9-oxoacridine-lO-acetic acid, its pharmaceutically acceptable salts and esters, in combination with antiandrogenic hormonetherapy, for the treatment, prophylaxis or relapse prevention of prostate cancer.

2. Use of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters for inducing or increasing the sensitivity of prostate cancer to hormone therapy.

3. Use of 9-oxoacridine-10-acetic acid, its pharmaceutically acceptable salts and esters for manufacture of a medical preparation for inducing or increasing the prostate cancer sensitivity to hormonotherapy or for overcoming hormone refractoriness of prostate cancer.

4. Use according to any one of claims 1 to 3, wherein said salt of 9-oxoacridine- 10- acetic acid is selected from the group including sodium, meglumine, eglumine salts and the salt with 3-O-(N,N-dimethylamino-«-propyl)-l,2:5,6-di- O-isopropyliden-α,D-glucofuranose.

5. Use according to any one of claims 1 to3, wherein said ester is ethyl ester.

6. A pharmaceutical composition for inducing or increasing the sensitivity of prostate cancer to hormone therapy, comprising an effective amount of 9- oxoacridine-10-acetic acid, its pharmaceutical acceptable salt or ester and a pharmaceutically acceptable carrier or excipient.

7. A pharmaceutical composition of claim 6, wherein said salt of 9-oxoacridine-l 0- acetic acid is selected from the group including sodium, meglumine, eglumine salts and the salt with 3-O-(N,N-dimethylamino-«-propyl)-l,2:5,6-di-O- isopropyliden-α,D-glucofuranose.

8. A pharmaceutical composition of claim 6, wherein said ester of 9-oxoacridine- 10- acetic acid is ethyl ester.

9. A pharmaceutical composition for the treatment, prophylaxis or relapse prevention of prostate cancer, comprising (a) 9-oxoacridine-lO-acetic acid, its pharmaceutical acceptable salt or ester, and (b) at least one antiandrogenic agent, in amounts that together are efficient for the said treatment, prophylaxis or relapse prevention, and (c) a pharmaceutically acceptable carrier or excipient.

10. A pharmaceutical composition of claim 9, wherein said salt of 9-oxoacridine- 10-acetic acid is selected from the group including sodium, meglumine, eglumine salts and the salt with 3-0-(N,N-dimethylamino-π-propyl)-l,2:5,6-di- O-isopropyliden-α,D-glucofuranose.

11. A pharmaceutical composition of claim 9, wherein said ester is ethyl ester.

12. A pharmaceutical composition of claim 9, wherein said antiandrogenic agent is selected from the group including non-steroidal and steroidal antiandrogens, steroid synthesis inhibitors, 5-alpha-reductase inhibitors, glucocorticoids, estrogens, luteinizing hormone-releasing hormone (LHRH) agonists (analogues) and LHRH agonists.

13. A method of prostate cancer treatment or prophylaxis, comprising the steps of: (a) administration of an effective amount of 9-oxoacridine-10-acetic acid, its pharmaceutical acceptable salt or ester to a patient in need thereof, and (b) hormonotherapy aimed at decreasing androgen action.

14. A method of claim 13, wherein said salt of 9-oxoacridine-10-acetic acid is selected from the group including meglumine, eglumine salts and the salt with 3- O-(N,N-dimethylamino-«-propyl)-l,2:5,6-di-O-isopropyliden-α,D- glucofuranose.

15. A method of claim 13, wherein said ester of 9-oxoacridine-10-acetic acid is ethyl ester.

16. A method of claim 13, wherein the hormonotherapy aimed at decreasing androgen action is orchectomy.

17. A method of claim 13, wherein said hormonotherapy includes administration of one or more agents selected from the groups including non-steroidal and steroidal antiandrogens, steroid synthesis inhibitors, 5-alpha-reductase inhibitors, glucocorticoids, estrogens, luteinizing hormone-releasing hormone (LHRH) agonists (analogs) and LHRH agonists.

18. A method of claim 17, wherein said 5-alpha-reductase inhibitor is finasteride or saw palmetto (Serenoa Repens) fruit extract.

19. A method of claim 13, wherein said hormonotherapy is selected from total androgen blockade and intermittent androgen blockade.

20. A method of claim 13, further comprising administration of one or more chemotherapeutic agents to the patient.

21. A method of claim 13, wherein 9-oxoacridine-lO-acetic acid, its pharmaceutical acceptable salt or ester is administered prior to hormonotherapy.

22. A method of claim 13, wherein 9-oxoacridine-10-acetic acid, its pharmaceutical acceptable salt or ester is administered concurrently with hormonotherapy.

23. A method of claim 13, wherein the step of administration of 9-oxoacridine-10- acetic acid, its pharmaceutical acceptable salt or ester is started prior to hormonotherapy and continued concurrently with hormonotherapy.

24. A method of prostate cancer relapse prevention, comprising the steps of (a) administration of an effective amount of 9-oxoacridine-10-acetic acid, its pharmaceutical acceptable salt or ester to a patient in need thereof and (b) hormonotherapy aimed at decreasing androgen action.

25. A method of claim 24, wherein said salt of 9-oxoacridine-10-acetic acid is selected from the group including meglumine, eglumine salts and the salt with 3- O-(N,N-dimethylamino-«-propyi)- 1 ,2 : 5,6-di-O-isopropyliden-α,D- glucofuranose.

26. A method of claim 24, wherein said ester of 9-oxoacridine-10-acetic acid is ethyl ester.

27. A method of claim 24, wherein said hormonotherapy aimed at decreasing androgen action includes the administration of one or more of agents selected form the group including non-steroidal and steroidal antiandrogens, steroid synthesis inhibitors, 5-alpha-reductase inhibitors, glucocorticoids, estrogens, luteinizing hormone-releasing hormone (LHRH) agonists (analogs) and LHRH agonists.

28. A method of claim 27 wherein said 5-alpha-reductase inhibitor is finasteride or saw palmetto (Serenoa Repens) fruit extract.

29. A method of inducing or increasing the sensitivity of prostate cancer to hormone therapy aimed at decreasing androgen action, comprising administration of an effective amount of a compound selected from the group including 9- oxoacridine - 10 - acetic acid, its pharmaceutical acceptable salt or ester.

30. A method of claim 29 wherein said salt of 9-oxoacridine-lO-acetic acid is selected from the group including meglumine, eglumine salts and the salt with 3-O-(N,N-dimethylamino-π-propyl)-l,2:5,6-di-O-isopropyliden-α,D- glucofuranose.

31. A method of claim 29 wherein said ester of 9-oxoacridine-l 0-acetic acid is ethyl ester.