RU2077885C1 - Antitumor agent for local treatment of malignant tumors - Google Patents

Abstract

FIELD: medicine, oncology. SUBSTANCE: biological antioxidants (retinol acetate and tocopherol acetate) were added to an aqueous-oily emulsion containing thioTEPA taken at the definite ratios. This provides additional prolongation of drug effect and enhances lymphotropicity. EFFECT: enhanced effectiveness of antitumor chemotherapy. 1 tbl

Description

 The invention relates to medicine, namely to oncology, to compositions used to increase the effectiveness of neoadjuvant chemotherapy for malignant tumors of various locations, as well as for palliative therapy of inoperable patients.

 The effectiveness of modern antitumor drugs in most malignant tumors is still not high enough (Blokhin N.N. Translatorova N.I. 1984). This is largely due to the lack of selectivity of the action of cytostatics on tumor cells. In addition, cytostatics in the required large doses has a toxic effect on normal cells and tissues, on the whole organism. Some of the cells of this tumor are resistant to the systemic use of existing chemotherapy drugs. Medicinal pathomorphism of the 3-4 degree of damage is noted only in 9% of all cases (Frank G.A. et al. 1989).

 A promising area of research to increase the effectiveness of drug therapy is the search for agents that can increase the effectiveness of chemotherapy drugs. One of the possible modulators of chemotherapy can be bioantioxidants (BAO), the biological mechanism of action of which is reduced to a shift in competitive free radical and enzymatic oxidation. An increased level of antioxidant activity of lipids was found in a number of experimental tumors during the period of their maximum growth rate (Zhuravlev L.I. 1968).

 The introduction of BAO in the form of thin emulsions, contributing to their more complete absorption, dramatically increases their effectiveness in the experiment. Evaluation of the therapeutic effect of BAO in an experiment using a transformation coefficient yielded a value of the order of 1.6-1.9 (Bobmassoco E. et al. 1976). It has been established that, with the combined action of BAO and chemical carcinogens, the duration of the latent period increases and the percentage of the occurrence of tumors decreases (A.I. Zhuravlev et al. 1958, 1959). However, the question of the possibility of using BAO in the treatment of malignant tumors remains open.

 An increase in the lymphatic transport of antitumor drugs was noted after intratumoral administration of cytostatics in emulsion forms. The increase in median survival in the experiment with the introduction of emulsions was 200% versus 146% in the case of using an aqueous solution of cytostatic (T.Kato, 1990, Kami, 1990). This composition was taken as a prototype.

The disadvantages of the proposed structure are:
the emulsion is unstable due to the use of sesame oil, because of its high specific gravity and viscosity, the emulsion is unstable, with a lifespan of only 6-8 hours, after which the complete separation of the emulsion occurs, which makes it unsuitable for administration;
the rapid exit of the cytostatic agent from the tumor zone and the possibility of complications (nephrosis, bleeding) when the emulsion is introduced into the tumor.

 In addition, there was no development of effective forms of emulsions for chemotherapy (depending on the physicochemical properties of the individual ingredients).

 The question of the possibility of increasing the antitumor effectiveness of cytostatics with the inclusion of BAO emulsion in them was not studied. The studies were only experimental in nature. There was no data on clinical testing of the composition.

 Previously, oxidants were used only separately with chemotherapy, which significantly reduces the effectiveness of chemotherapy. It is important to note that administration of antioxidants (BAO) per os or parenterally does not reach the target molecules (DNA, RNA, enzymes) in the tumor cell due to low selectivity.

 The purpose of the invention is to increase the effectiveness of antitumor chemotherapy. The goal is achieved by introducing into the composition of the drug a water-oil emulsion of immobilized cytostatics and biooxidants. The choice of thiotephe as an antitumor agent was due to its high efficiency in the treatment of malignant tumors of various localization (breast, ovarian, etc.). Sunflower oil was used as the oil phase. BAO (vitamin A, vitamin E) was added to the emulsion in the form of oil solutions. Emulsions were prepared in an ultrasonic disintegrator in three modes for 60 s each. For the stability of the emulsion, 0.5 ml of the TWIN-20 surfactant was added to it.

 The composition was tested in Moscow P.A. Herzen in an experiment on a PC-1 carcinoma model.

The experiments were performed on male Wistar rats with an initial weight of 200-220 g. Tumors were transplanted subcutaneously into the anterior abdominal wall by the administration of 0.4 mg of a 25% suspension of tumor tissue in a 0.9% sodium chloride solution. On the 14th day after inoculation, the tumors of the animals were divided into seven groups of 10 rats each;
1. A parathormous emulsion was introduced containing 10 mg of thiotepa and 3 parts of the oil phase (sunflower oil with BAO).

 2. Introduced the same dose of the drug. The emulsion contained 7 vol. including sunflower oil with BAO.

 3. An emulsion was introduced in a similar manner and at the same dose, in which sesame oil (3 parts by volume) was used as the oil phase.

 4. Introduced in a similar manner and at the same dose, an emulsion containing 7.0 vol. including sesame oil.

 5. Papatumorously injected in the same dose an aqueous solution of thiotepa.

 6. Intravenously injected a solution containing 10 mg of thiotepa.

 7. Control group (tumor inoculation).

 Data on the dynamics of tumors in animals of various groups are presented in the table.

 It can be seen that by 28 days of the experiment, the size of the tumors in animals of groups 1 and 2 was significantly smaller than in animals of groups 4–7. At all subsequent periods of the experiment, the size of the tumors in group 1 was significantly smaller than in all others. The size of the tumors in groups of animals that received an emulsion form with BAO was significantly different from the groups where emulsions without BAO were administered.

 In clinical conditions, the method was carried out as follows: used water-in-oil emulsions containing thiotepheum 60 mg retinol acetate in oil 25000 IU 1.0 ml of tocopherol acetate in oil 0.01-1.0 ml, sunflower oil 1.0 ml TWIN-20 and water for injection 7 ml.

 After mixing, the ingredients were processed in an ultrasonic disintegrator for 3 minutes. Then the emulsion was placed in a sterile vial and injected once parathormous.

 An example of a specific implementation. Patient Nechaeva V.N. 48 years old, and / b BA-284, was in the Department of General Oncology at the P. A. Herzen Scientific Research Institute of Scientific Research from 11.02 to 03.03.92.

 Clinical diagnosis: cancer of the right breast stage II A, T2NOMO. From the anamnesis: in the summer of 1989, a puncture of compaction was performed in the right mammary gland. The histological conclusion of the cyst. On 07.91, a new pea-sized seal appeared, which subsequently increased approximately 4 times. Turned to the Moscow Scientific Research Institute. P.A. Herzen. On admission, a 4 x 4 cm, mobile, tumor is palpated in the upper-outer quadrant. The patient was discussed at a clinical conference. Given the presence of prognostically unfavorable factors, rapid tumor growth, burdened by heredity (the mother died of cancer), on 02.02.92, 60 mg of thiotepha in emulsion form was introduced parathumously according to the method described above. No complications were observed. 02/20/92, a radical operation was performed resection of the right breast. The postoperative period was uneventful. Histology: E 52328-46, ductal cancer, drug pathomorphosis in different parts of the tumor is expressed differently, in general, III tbsp. The entire center of the tumor is necrotic; the area of the tumor in the injection zone is also necrotic. In l / at metastases are not revealed. The patient was re-discussed at the clinical conference of the department, she was given a course of radiation therapy. The patient continues to be observed in the clinic of Moscow P.A. Herzen.

 Thus, the introduction of the cytostatic tiotepa in the emulsion form of biological antioxidants (tocopherol and retinol) significantly increased efficiency by increasing the prolongation and lymphotropy of the antitumor drug.

Claims (1)

An antitumor agent for topical treatment of malignant tumors, including thiophosphamide, characterized in that it additionally contains retinol acetate, tocopherol acetate, components of a water-in-oil emulsion - sunflower oil, tween-20 and water in the following ratios of components in a single dose:
Thiophosphamide 60 mg
Retinol acetate in oil 25,000 IU in 1 ml
Tocopherol acetate 0.01 1 ml
Sunflower oil 1 ml
Tween-20 0.5 ml
Water for injection 7 million

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