RU2704020C1 - Combination of dehydroxymethyl epoxyquinomycin (dhmeq) and cytostatics for treating ovarian cancer - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: present invention refers to pharmaceutical industry, namely to a combination for intraperitoneal administration, for treatment and/or prevention of recurrent ovarian cancer. Combination for intraperitoneal administration for treating and/or preventing recurrent ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor, includes DHMEQ or a pharmaceutically acceptable salt thereof and at least one cytostatic or pharmaceutically acceptable salt thereof, cytostatic is cisplatin and/or paclitaxel taken in certain amounts. Pharmaceutical combination for intraperitoneal administration for treating and/or preventing recurrent ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor, includes a combination and one pharmaceutically acceptable excipient. A method of treating ovarian cancer involves intraperitoneal introduction of a combination.

EFFECT: disclosed combination is effective, non-toxic, stable and has high bioavailability.

9 cl, 4 dwg, 2 tbl

Description

Technical field

The invention relates to the field of medicine and pharmacology, and relates to the development and preparation of an effective drug combination comprising DHMEQ, which can be used to treat and / or prevent recurrence of ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor.

State of the art

Ovarian cancer (RV) is the most common cause of death among women among all gynecological oncological pathologies. Annually, about 140,000 women in the world die from OW [1]. One of the features of this tumor is late diagnosis, when there is already a lesion of the peritoneum, ascites, less often hematogenous metastases and tumor pleurisy. In the first year from the moment of diagnosis, the mortality rate is more than 35% [1, 2]. At the time of diagnosis, most patients have abdominal carcinomatosis. Surgical cytoreduction followed by intravenous chemotherapy with platinum and taxane compounds is a standard in the treatment of patients with advanced stages of ovarian cancer [3]. Although a partial and complete response is observed in 80% and 40-60% of cases, respectively, most patients develop relapse, and the median life expectancy is 18 months [4]. Over the past decades, 5-year survival has increased slightly with the use of more effective surgical methods and empirically selected combinations of cytostatics, but it still remains at an extremely low level and amounts to no more than 30% [2]. Such low results of standard treatment require the search for new approaches to drug treatment of patients with various stages of ovarian cancer. One of the alternative options for systemic treatment of ovarian cancer is the intraperitoneal administration of anticancer drugs or intraperitoneal chemotherapy [5]. An analysis of the results of intraperitoneal chemotherapy of ovarian cancer showed an increase in the effectiveness of treatment of patients compared with systemic intravenous [6]. One of the advantages of this therapy is the accumulation of the drug directly in the abdominal cavity, where this localization often metastasizes with the flow of intraperitoneal fluid, which, along with the large penetration of drugs into the tumor tissue, significantly increases the pharmacological effect. However, despite a number of advantages, this type of therapy does not find wide application in clinical practice [8], which is associated with the development of a number of complications during procedures, such as adhesions, the development of drug resistance and their low effectiveness, associated with high toxicity [ 7]. Only a limited number of drugs on the market are suitable for intraperitoneal chemotherapy. Therefore, along with the search for new methods of treatment, there is a need for new drugs with a more pronounced antitumor effect and less pronounced toxicity for their use by intraperitoneal administration for the treatment of OC. In addition, drugs combining low molecular weight, the ability to penetrate into tumor cells and a pronounced contact effect would be optimal for intraperitoneal therapy [6].

Disclosure of invention

The objective of the invention is to develop and obtain a new non-toxic effective drug combination based on DHEMQ, for the treatment and / or prevention of recurrence of ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor.

The technical result of this invention is the development and creation of a new effective non-toxic drug combination comprising DHMEQ and at least one cytostatic agent for the treatment and / or prevention of relapse of ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor, which has sufficient stability and high bioavailability. The combination according to the invention is characterized in that the action of one component of the combination potentiates the action of another and, as a result, a synergistic effect is manifested. The combinations of the invention also effectively reduce the growth and volume of an ovarian tumor compared to a monotherapy regimen.

The specified technical result is achieved by developing and creating a combination for intraperitoneal administration, intended for the treatment and / or prevention of recurrence of ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor, comprising a therapeutically effective amount of DHMEQ or its pharmaceutically acceptable salt and a therapeutically effective amount, according to at least one cytostatic agent or a pharmaceutically acceptable salt thereof.

In private embodiments, the therapeutically effective amount of DHMEQ is a daily dose of 1-15 mg / kg.

In some particular embodiments, the therapeutically effective amount of DHMEQ is a daily dose of 7-15 mg / kg.

In some particular embodiments, the therapeutically effective amount of DHMEQ is a daily dose of 10-12 mg / kg.

In some particular embodiments, the therapeutically effective amount of DHMEQ is a daily dose of 14.2 mg / kg.

In particular embodiments, the cytostatic is cisplatin and / or paclitaxel.

In particular embodiments, the subject is a human.

In particular embodiments of the invention, DHMEQ or its pharmaceutical salt and cytostatic or its pharmaceutically acceptable salt are administered to the subject simultaneously, sequentially or separately.

The technical result is also achieved by developing and creating a pharmaceutical composition for intraperitoneal administration, intended for the treatment and / or prevention of recurrence of ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor, comprising a combination according to the invention and at least one pharmaceutically acceptable excipient .

In particular embodiments, the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent.

The technical result is also achieved through the implementation of a method for the treatment of ovarian cancer, characterized by intraperitoneal administration of a combination according to the invention.

In particular embodiments of the invention, the daily dose of DHMEQ in combination is 1-15 mg / kg.

In particular embodiments, the daily dose of DHMEQ in combination is 7-15 mg / kg.

In particular embodiments, the daily dose of DHMEQ in combination is 10-12 mg / kg.

In particular embodiments of the invention, the components of the combination are administered to the subject simultaneously, sequentially or separately.

In particular embodiments, the subject is a human.

Definition and terms

V / b - intraperitoneal;

DMSO - dimethyl sulfoxide;

MPD - maximum tolerated dose;

OA is an ovarian tumor;

RY - ovarian cancer;

SPG - average life expectancy;

UPZ - increase in life expectancy;

CP - cisplatin;

T / C% = (SPL _experience / SPL _control ) × 100;

T / C - Treatment (Control) / Control (control) - shows how many percent has changed the average life expectancy in groups relative to control groups;

SRW - inhibition of tumor growth;

DHMEQ - dehydroxymethylepoxyquinomycin, a specific low molecular weight inhibitor of NF-kB, characterized by the following structural formula:

.

.

For a better understanding of the present invention, the following are some of the terms used in the present description of the invention.

In the description of the present invention, the terms “includes” and “including” are interpreted as meaning “includes, inter alia,”. These terms are not intended to be construed as “consists of only”.

The terms “treatment” , “therapy” encompass the treatment of pathological conditions in a subject, preferably a person, and include: a) blocking (stopping) the course of the disease, b) alleviating the severity of the disease, i.e. induction of disease regression.

The term “subject” encompasses all types of mammals, preferably humans.

The term "cytostatic" in this document refers to platinum derivatives (in particular, Cisplatin, Carboplatin, Oxaliplatin) and taxanes (in particular, Docetaxel, Paclitaxel). The ranges of effective dosages of cytostatics may, in particular, be 30-150 mg / m ² for cisplatin and 135-175 mg / m ² for paclitaxel.

The term "prevention" , "prevention" covers the elimination of risk factors, as well as the prophylactic treatment of subclinical stages of the disease in a subject, preferably a person, aimed at reducing the likelihood of clinical stages of the disease. Subjects for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increase in the risk of clinical stages of the disease compared with the general population. Preventive therapy refers to a) primary prevention and b) secondary prevention. Primary prophylaxis is defined as prophylactic treatment in patients (subjects) whose clinical stage of the disease has not yet begun. Secondary prophylaxis is the prevention of the repeated onset of the same or similar clinical condition of the disease.

The term "risk reduction" covers therapy that reduces the incidence of the clinical stage of the disease. Examples of reducing the risk of disease are primary and secondary disease prevention.

The term " prevention of ascites state " means that after appropriate prophylactic treatment of the present invention, the formation of ascites fluid is completely eliminated or reduced, or, in another embodiment, that nevertheless, the resulting ascites fluid disappears or the degree of its formation is reduced.

The term " treatment of ascites condition " means that after appropriate treatment according to the present invention, ascites fluid present in a patient does not form or its degree of formation is reduced.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk. Examples include pharmaceutically acceptable alkali metal salts and / or alkoxides (e.g., potassium, sodium, lithium salts).

The invention also relates to pharmaceutical compositions that contain combinations according to the invention and one or more pharmaceutically acceptable carriers, solvents and / or excipients, such as can be introduced into the body of the subject together with the combination that is the essence of the present invention, and which do not destroy the pharmacological activity components of the combination according to the invention, and are non-toxic when administered in doses sufficient to deliver a therapeutic amount of the components of the combination.

The pharmaceutical compositions of this invention comprise combinations of the invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, lubricants, etc. .d suitable for a particular dosage form. Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; and phosphate buffers. Also in the composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, excipients, preservatives and antioxidants.

As used herein, a “therapeutically effective amount” refers to that amount of a compound that is necessary for detectably killing cancer cells or inhibiting their growth or propagation speed throughout the body, the size or number of tumors, or other characteristics of the cancer. The exact amount required may vary from subject to subject, depending on the type, age and general condition of the patient, the severity of the disease, the characteristics of the anticancer agent, etc.

The term "dose" in this document refers to the amount of active (active) substance that is administered to a patient in need of appropriate treatment to obtain a therapeutic effect.

Combinations for the treatment and / or prevention of recurrence of ovarian cancer in a subject characterized by a malignant tumor or malignant metastases of the invention are intended for simultaneous, separate administration or administration after a certain period of time. The term "simultaneous" or "simultaneously" , if it refers to therapeutic use, means that in the treatment are administered two or more active ingredients in the same way and at the same time, that is, together. Co-administration involves, in particular, co-delivery, for example, in a single dosage form, in particular in a single injection.

The term "separate" or "separate" , if it refers to therapeutic use, means that during treatment, two or more active ingredients are administered at approximately the same time in at least two different ways. Administration “after a certain period of time” means that two or more ingredients are administered at different times, and especially when the administration of one active ingredient is complete before the administration of the other or other active ingredients. Thus, one of the active ingredients can be administered for several months before the introduction of the other active ingredient or ingredients. In this case, simultaneous administration is excluded. Introducing “after a certain period of time” also includes cases where the ingredients are administered at different time periods (for example, when one ingredient is administered once a day and another ingredient is administered once a week).

By " ovarian cancer (tumor) " in this document is meant any malignant ovarian neoplasms, such as, for example, serous, endometriotic, mucinous, light-cell, serous-mucinous, undifferentiated or mixed epithelial carcinomas, but not limited to them.

Brief Description of the Drawings

Figure 1. Survival curves of rats with ovarian tumor in the control groups and groups with combinations according to the invention, where DHMEQ at a dose of 14.2 mg / kg

Figure 2. The effect of the test substances and combinations according to the invention on the change in body weight of animals.

Figure 3. The effect of the studied substances and combinations according to the invention on the tumor growth of the SKOV-3 cell line in the xenograft model (* - p <0.05 compared to the Control group).

Figure 4. Inhibition of tumor growth (TPO) on the 18th day of the study of the growth of tumor cells of the SKOV-3 line in a xenograft model (* - p <0.05 compared to the Control group).

Detailed Disclosure of Invention

The possibility of an objective manifestation of a technical result when using the invention is confirmed by reliable data given in the examples containing experimental information. It should be understood that these and all examples cited in the application materials are not limiting and are provided merely to illustrate the present invention.

As a result of the experiments, unexpectedly obtained data demonstrating a potentiating antitumor effect (the combination effect is greater than the total effect of the combinants) of DHMEQ in combination with cytostatics, in particular with cisplatin and / or paclitaxel. Datain vivoshow that DHMEQ, an inhibitor of NF-kB, in combination with a cytostatic agent, in particular cisplatin or paclitaxel, is highly effective in several models of ovarian cancerin vivo, the effect becomes unexpectedly stronger and longer than the sum of the effects of individual drugs, which indicates that the combinations are characterized by significantly improved indicators of effectiveness for the treatment of ovarian cancer. Thus, the combinations according to the invention, namely DHMEQ in combination with cytostatics, in particular cisplatin and / or paclitaxel, are promising for use as an effective drug for the treatment and / or prevention of recurrence of ovarian cancer in a subject characterized by a malignant tumor or metastases malignant tumors, including ascites, associated with ovarian cancer.

Characterization of the biological activity of the combination according to the invention

The study of the antitumor activity of the drug DHMEQ during monotherapy and the combination according to the invention on transplantable ovarian tumor in female rats

To assess the antitumor activity of DHMEQ during monotherapy and the combination according to the invention, in particular a combination comprising DHMEQ and cisplatin, 300 Wistar female rats weighing 160-200 g were used, which were inoculated with an ovarian tumor strain (OA), which was obtained from the Russian Scientific Research Center . N.N. Blokhina RAMS. Although xenographic models are not ideal, they are widely used to evaluate the potential efficacy of drugs against OC in preclinical studies. In this study, we used an experimental model of disseminated OC in rats [2], obtained by intraperitoneal inoculation of ascitic OA, which is reproducible and adequate for studying the efficacy and safety of drugs with intravenous administration. The OC used in this experiment is a low-grade epithelial OC. The tumor was vaccinated in 100% of cases. In its morphology and course (the nature of metastasis, accumulation of ascites), OA is very close to the corresponding human tumors. This tumor is characterized by metastasis to the paratracheal lymph nodes, the formation of numerous tumor nodes in the abdominal cavity, abundant ascites, and the absence of a large solid tumor. According to the literature, it is known that OA is more aggressive than xenograft models, the average duration of animals after inoculation is 14 ± 2 days.

To evaluate the combined effect with DHMEQ and as a comparison drug, cisplatin was used in this study, which kills cells at different stages of the cell cycle, forms DNA-protein and DNA-DNA cross-links, and also interacts with their nucleophilic groups. The low molecular weight of cisplatin compared with other cytostatics contributes to its more rapid penetration into tumor tissue, which increases its effectiveness with intraperitoneal administration. The cisplatin AUC is significantly lower than paclitaxel, however, the latter has a higher molecular weight and showed slightly lower efficiency in other studies on the selected model of OC, but higher activity in combination with DHMEQ than in paclitaxel monotherapy (Fig. 4).

As a result of the studies of the life expectancy of animals after the introduction of the combination according to the invention, the data presented in table 1.

Table 1. The results of the study of the life expectancy of animals with the introduction of Cisplatin, DHMEQ, a combination of DHMEQ with Cisplatin according to the invention.

Group Life expectancy, day T / S,% UPZH,% Average Median Maximum Comparison group OA + solvent OA (control) 17.4 ± 1.7 19 21 137 37 OA + Cisplatin (4 mg / kg) 32.3 ± 2.5 34 40 254 154 OA + NaCl solution 0.9%,
single administration 17 ± 2,3 19 23 134 34 OA + DHMEQ (14.2 mg / kg) 25.5 ± 7.4 fifteen 73 201 101 OA + DHMEQ (14.2 mg / kg) + Cisplatin (4 mg / kg) 61.8 ± 8.2 73 73 487 387 OA + solvent (DMSO) 12.7 ± 1.5 13.5 21 - -

As follows from the data presented, a significant increase in life expectancy was obtained using a combination of DHMEQ (14.2 mg / kg) with Cisplatin (4 mg / kg) and amounted to 387% (p = 0.005, log-rank test) compared to the control group (figure 1). The combination of DHMEQ / Cisplatin also increased the life expectancy of rats by 91% compared with the group of animals that were given just Cisplatin (p = 0.003, log-rank test). The combination of DHMEQ and Cisplatin unexpectedly showed a potentiating (synergistic) effect on the effectiveness of ovarian cancer therapy (16 rats in each group).

More than 50% of the animals in the DHMEQ + Cisplatin combination group remained alive on the 73th day of the experiment. In this case, not a single animal remained in the group with Cisplatin, and only one rat remained alive in the group with DHMEQ. The results in the combination group would be higher if not forcibly stopping the experiment. Therefore, in clinical pharmacology, the indicator "median life expectancy" or "median survival", which identifies the life expectancy of 50% of the participants in the study, is also often used. During the study, the group with the combination of DHMEQ + Cisplatin, it is maximum and is 73 days and characterizes the potentiating effect of the combination.

The combination of DHMEQ / Cisplatin also statistically significantly reduced the formation of tumor pleurisy compared to control groups.

Thus, the use of a combination of DHMEQ with a cytostatic, in particular, in the form of pharmaceutical compositions for injection therapy of intraperitoneally disseminated ovarian cancer in oncology, is promising.

The study of the antitumor activity of DHMEQ with monotherapy and in combination with Cisplastin and Paclitaxel in a SKOV-3 ovarian cancer xenograft model.

To evaluate the antitumor activity of the combinations of the invention, in particular DHMEQ / cisplatin and DHMEQ / paclitaxel combinations based on tumor size and not life span, SKOV-3 human ovarian cancer xenograft models were used.

DHMEQ was dissolved in 100% DMSO. Stock solutions of DHMEQ in 100% DMSO were stored for no more than 2 weeks at + 4 ° C in a dark place outside of direct sunlight.

With the introduction of cisplatin and paclitaxel, the volume of administration was 8 ml / kg. All drugs were administered intraperitoneally.

Cultivation medium RPMI-1640 (PanEco; C330p) contains 10% FBS (HyClone; SV30160.03), 2 mM glutamine sodium (PanEco; Ф032), 1xSodium pyruvate (PanEco; Ф023), 1x Essential amino acids (PanEco; Ф115 / 50) , 1x Penicillin-streptomycin (PanEco; A065).

SKOV-3 human ovarian cancer cells were thawed in medium and cultured in T175 vials for attached cultures. As they reached 100% confluency, the cells were reseeded: on average once every 3-4 days. With detachment, the culture fluid was removed, washed in phosphate-buffered saline and a trypsin-EDTA 0.25% solution with Hanks salts (PanEco; P041) was added. Incubated for 5 minutes at 37 ° C, the medium was added and unscrewed. Next, the bottles were dispersed into T175.

On the day of implantation into mice, SKOV-3 cells were washed in serum-MEM medium (PanEco; C180p) without serum; they were counted and unscrewed at a speed of 900 rpm (R rotor 20.4 cm). It was unscrewed again at a speed of 900 rpm and resuspended in α-MEM medium with a temperature of less than 10 ° С until the cell density in the final suspension was 50 ml / ml. A volume of Matrigel equal to the volume of the cell suspension was added with a pre-cooled pipette and mixed smoothly. Thus, the final cell concentration was 25 million / ml.

A suspension of cells was injected into mice subcutaneously along the spine (in the region of the right scapula) in a volume of 0.2 ml (5 million cells) per mouse. Before implantation of the cells, the corresponding area of the mouse skin was shaved and treated with AHD-2000 disinfectant solution.

Table 2. Groups of animals in the experiment.

Group number A drug Number of animals The dose of active substances, mg / kg The volume of introduction, ml / kg number of introductions one Control / Solvent (DMSO) 6 0 5 fourteen 2 Cisplatin / Solvent (DMSO) 7 four 8/5 once / 14 3 Paclitaxel / Solvent (DMSO) 6 5 8/5 once / 14 four Paclitaxel / DHMEQ * 7 5/14 8/5 once / 14 5 Cisplatin / DHMEQ * 7 4/14 8/5 once / 14 * The introduction of the components of the combination was administered sequentially

Measurement of subcutaneous implanted tumors was performed 2 times a week. Tumor volume was determined by the formula:

π / 6 x L x W ² = mm ³ ,

where L - corresponds to the largest diameter of the tumor, W - to the smallest. Measurements were performed using a caliper.

The antitumor activity of the studied drugs, as well as the combinations according to the invention was determined by slowing the growth of the tumor relative to the tumors in the control group receiving the solvent. For this, the values of inhibition of tumor growth were calculated:

SRW = (С-Т) х100 / С,%

where C is the average tumor size in the control group treated with the solvent,

T is the size of the tumor in the experimental group.

SRW was determined on the 14th day of the study (after the last administration of the study drug and combinations according to the invention) and 4 days after that.

We also monitored the health and behavior of animals, recorded the number of deaths. The animals were examined at the time of administration of the compounds, and then twice a day (morning and evening) to register mortality and general condition.

Measurement of the weight of animals was carried out 2 times a week.

The average tumor sizes at the end of the study were used to statistically compare tumor growth inhibition. For the intergroup statistical comparison, the two-sided Mann-Whitney test (GraphPadPrizm) was used. Differences were determined at a statistical significance level ≤ 0.05.

The study showed that the introduction of the test substances does not affect the change in body weight of animals (Fig. 2).

The results of a study of the effect of the test substances and combinations according to the invention on tumor growth are shown in figure 3.

These results show that in animals in the Control group, the tumor size uniformly and constantly increased. Tumors of animals treated with paclitaxel once at a dose of 5 mg / kg, as well as once with cisplastin at a dose of 4 mg / kg, also increased with time. The increase does not differ from the “Control” group. Combinations of DHMEQ and Paclitaxel at doses of 14 mg / kg and 5 mg / kg, as well as DHMEQ and Cisplastine at doses of 14 mg / kg and 4 mg / kg, significantly slowed the growth of tumors. The effect persisted four days after completion of the drug.

When studying the size of tumors and inhibition of tumor growth (SRW) on the 14th day of the study and on the 18th day, in particular, it was shown that daily administration of DHMEQ at a dose of 14 mg / kg after a single injection of Cisplastine at a dose of 4 mg / kg and Paclitaxel at a dose of 5 mg / kg leads to a significant decrease in the size of the tumors and an increase in TPO (Fig. 4). On the 18th day of the study (the fourth day after cessation of drug administration), the results are the same as on the 14th day.

Thus, it was shown for the first time that daily intraperitoneal administration of a combination according to the invention, in particular a combination comprising DHMEQ at a dose of 14 mg / kg after a single intraperitoneal administration of cisplastine and / or paclitaxel, leads to a decrease in the growth rate of a SKOV-3 cell line tumor in a xenograft model .

Although the invention has been described with reference to the disclosed embodiments, it should be apparent to those skilled in the art that the specific experiments described in detail are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. It should be understood that various modifications are possible without departing from the gist of the present invention.

List of literature, which is included in the present description of the invention by reference:

[1] Siegel R., Ma J., Zou Z., Jemal A. .. Cancer statistics, 2014 // CA: A Cancer Journal for Clinicians. - V. 64. - P. 9–29.

[2] Bast R.C. Jr, Hennessy B., Mills G. B. The biology of ovarian cancer: new opportunities for translation // Nat Rev Cancer. - 2009 .-- V. 9 (6). - P. 415-28

[3] Marcus C.S., Maxwell G. L., Darcy K.M. et al. Current approaches and challenges in managing and monitoring treatment response in ovarian cancer // J. Cancer. - 2014 .-- Vol. 5. - P. 25-30.

[4] Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet. - 2009. - V.374. - P 1371-82.

[5] Chua, T.C. Intraoperative hyperthermic intraperitoneal chemotherapy after cytoreductive surgery in ovarian cancer peritoneal carcinomatosis: systematic review of current results / T.C. Chua, G. Robertson, W. Liauw et al. // J. Cancer Res. Clin. Oncol. - 2009. - Vol. 135. - P. 1637-1645.

[6] Eskander R.N., Cripe J., Bristow R.E. Intraperitoneal chemotherapy from Armstrong to HIPEC: challenges and promise // Curr. Treat. Options Oncol. - 2014 .-- Vol. 15. - P. 27–40.

[7] Eskander R.N., Cripe J., Bristow R.E. Intraperitoneal chemotherapy from Armstrong to HIPEC: challenges and promise // Curr. Treat. Options Oncol. - 2014 .-- Vol. 15. - P. 27–40.

[8] Bowles E.J., Wernli K.J., Gray H.J. et al. Diffusion of intraperitoneal chemotherapy in women with advanced ovarian cancer in community settings 2003–2008: the effect of the NCI clinical recommendation // Front. Oncol. - 2014. - V. 10. - P 4-43.

Claims (9)

1. The combination for intraperitoneal administration, intended for the treatment and / or prevention of recurrence of ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor, comprising DHMEQ in an amount of 14-14.2 mg / kg or its pharmaceutically acceptable salt and at least one cytostatic or a pharmaceutically acceptable salt thereof, wherein the cytostatic is cisplatin in an amount of 4 mg / kg and / or paclitaxel in an amount of 5 mg / kg. 2. The combination according to claim 1, characterized in that the indicated number of components of the combination is a daily dose. 3. The combination according to claim 1, characterized in that the subject is a human. 4. The combination according to claim 1, characterized in that DHMEQ or its pharmaceutically acceptable salt and cytostatic or its pharmaceutically acceptable salt are administered to the subject simultaneously, sequentially or separately. 5. A pharmaceutical composition for intraperitoneal administration intended for the treatment and / or prevention of recurrence of ovarian cancer in a subject characterized by a malignant tumor or metastases of a malignant tumor, comprising the combination according to claim 1 and at least one pharmaceutically acceptable excipient. 6. The pharmaceutical composition according to claim 5, characterized in that the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent. 7. A method of treating ovarian cancer, including the intraperitoneal administration of a combination according to claim 1. 8. The method according to claim 7, characterized in that the components of the combination are administered to the subject simultaneously, sequentially or separately. 9. The method according to claim 7, characterized in that the subject is a human.

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