RU2376999C2 - Antitumorigenesis method - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely oncology, and can be used in treatment of malignant tumours. The method consists in intravenous introduction of metallocomplex that is substratum oxidation catalyst f, and ascorbic acid that is an oxidation substratum. Then tumour tissue is heated by radiation of wavelength at least 0.800 mcm to temperature 41°C and more during at least 5 minutes.

EFFECT: method provides high therapeutic effectiveness, including owing to selection of specific radiation for hyperthermia.

13 ex, 1 tbl

Description

The present invention relates to medicine, namely to oncology, and can be used in the treatment of malignant tumors.

A known method of suppressing tumor growth by using a binary catalytic system, which consists in the sequential administration to animals with tumors of a metal complex (substrate oxidation catalyst) and ascorbic acid (oxidation substrate). The catalyst accumulating in the tumor tissue leads to catalytic oxidation of the substrate, resulting in the formation of highly reactive oxygen species, including free radicals with high cytotoxic potential. As the catalyst, salts of octa-4,5-carboxylic acid cobalt phthalocyanine (Terafthal) are used [RF patent 2106146, A61K 31/40, 03/10/98] or its esters (Ether) [RF patent 2172319, C07F 15/06, 08/20/2001], as well as the corrin derivative - hydroxycobalamin (a derivative of vitamin B ₁₂ ). This method allows to achieve inhibition of the proliferation of human tumor cells in vitro, as well as inhibition of tumor growth and increased life expectancy in animals with tumors.

Closest to the proposed solution is a method of suppressing tumor growth in an experiment on animals (mice and rats) by the sequential intravenous administration of 2 drugs - an oxidation substrate catalyst - sodium salt of octa-4,5-carboxyphthalocyanine cobalt (Teraftal, TF) and ascorbic acids (Ak) (Russian Chemical Journal, 1998, Volume XLP No. 5, pp. 144-144).

The disadvantage of this method is the insufficiently high (average) antitumor activity of these binary catalytic systems in animals with transplantable tumors.

The objective of the invention is to develop such a method of suppressing tumor growth, which would provide a more pronounced and persistent inhibition of tumor growth in animals.

To solve this problem, a method of suppressing tumor growth, combining the use of binary catalytic systems (BCS) "Metal Complex + Ascorbic Acid" and hyperthermia, is proposed.

The problem is solved as follows:

BCS components are intravenously administered to the animal: metal complex (substrate oxidation catalyst) - ascorbic acid (oxidation substrate), followed by heating the tumor tissue to a temperature of at least 41 ° C for at least 5 minutes.

The upper temperature limit and the duration of its maintenance are determined in each case taking into account the geometry of the tumor and the method of its heating, as well as the presence of important organs and tissues near it, damage to which is unacceptable when heated.

The method is as follows.

In mice with transplantable malignant tumors (sarcoma and carcinoma), the metal complex (substrate oxidation catalyst) is administered intravenously in doses from MTD (maximum tolerated dose) and lower. Then, ascorbic acid (oxidation substrate) is administered intravenously in doses corresponding to a molar ratio of the metal complex: Ak equal to 1: 5-1: 30.

As a catalyst, use:

Terafthal (TF) - sodium salt of octa-4,5-carboxylic acid cobalt phthalocyanine;

Ether-adduct of the complex of tetra methylpent (hexa) ethylene glycol ether of phthalocyanine-2,3,9,10,16,17,23,24-octacarboxylic acid with cobalt (II) and poly-O- (1-hydroxy-2-propyl) cycloheptadextrin

Oxycobalamin (Ok) -Coα- [α- (5,6-dimethylbenzimidazatyl)] - Coβ-hydroxycobamide hydrochloride.

The tumor is heated after the introduction of BCS components to a temperature of at least 41 ° C for a period of at least 5 minutes.

Tumor heating is carried out immediately after the introduction of the oxidation substrate using laser radiation with a wavelength of 0.8000 microns. The temperature in the tumor is controlled by a needle thermocouple and maintained at a predetermined level for a certain time.

The effectiveness of the method is evaluated using the criterion generally accepted in experimental oncology - “Tumor growth inhibition” (TPO,%), as well as an additional criterion - “Therapeutic gain” (TV,%), which shows how much the therapeutic effectiveness of each treatment method is increased individually with their combined use. TV is calculated by the formula:

TV _by SRW = [(RO _control- RO _experience ) / PO _control ] × 100, where

RO _control - the average tumor volume in animals in the control group, which were treated only with hyperthermia or BCS;

RO _experience - the average tumor volume in animals in the experimental group who received combined treatment - haperthermia + BCS.

Examples of specific performance of the method.

Examples characterizing the antitumor effectiveness of the combined use of BCS based on terataphthale, epheter, oxycobalamin and hyperthermia are presented in the table.

Examples 1-3.

As a tumor model, an Ehrlich tumor is used. Terafthal is administered intravenously in doses from 4 mg / kg to 40 mg / kg. Ascorbic acid is used in doses corresponding to the painting ratio Tf: Ak from 1: 5-1: 30. The tumor is heated using laser radiation with a wavelength of 1.06 μm to a temperature of 41 ° C-43 ° C. The set temperature is maintained for 10-30 minutes. As can be seen from the data presented in the table, the combined use of BCS "TF + Ak" and hyperthermia leads to persistent (within 16-26 days after treatment) inhibition of tumor growth by 82% -51% (increasing the effectiveness of monotherapy using only hyperthermia on 72% -63%).

Example 4

As a tumor model, sarcoma S-37 is used. Doses of BCS components, as well as the regimen of hyperthermia, are similar to those indicated in example 3.

As can be seen from the table, the combined use of BCS "TF + Ak" and hyperthermia in mice with S-37 leads to biologically significant inhibition of tumor growth at the level of 60% -53% (maintaining the effect for more than 14 days, increasing the effectiveness of monotherapy using only hyperthermia 55%).

Examples 5-6.

As a tumor model, an Ehrlich tumor is used. The etheter is administered intravenously at a dose of 125 mg / kg. Ascorbic acid is used in a dose corresponding to a molar ratio of Epiter: Ak equal to 1:30. The tumor is heated using laser radiation with a wavelength equal to 0.800 microns to a temperature of 41 ° C-43 ° C. The set temperature is maintained for 10-30 minutes.

As can be seen from the data presented in the table, the combined use of BCS "Efiter + Ak" in hyperthermia leads to persistent (within 14-18 days after treatment) inhibition of tumor growth by 72% -53% (increasing the effectiveness of monotherapy using only hyperthermia on 69% -48%).

Examples 7-8.

As a tumor model, sarcoma S-37 is used. The ethereal is administered intravenously at doses of 625 mg / kg and 1250 mg / kg. Ascorbic acid is used in a dose corresponding to a molar ratio of Epiter: Ak of 1:30. The regimen of hyperthermia is similar and is indicated in example 6.

As can be seen from the table, the combined use of BCS "Efiter + Ak" and hyperthermia in mice with S-37 leads to biologically significant inhibition of tumor growth at the level of 71% -51% (maintaining the effect for more than 18 days, increasing the effectiveness of monotherapy using only hyperthermia 72% -64%).

Examples 9-11.

As a tumor model, an Ehrlich tumor is used.

Oxycobalamin is administered intravenously at doses of 85 mg / kg and 170 mg / kg. Ascorbic acid is used in a dose corresponding to a molar ratio of Oak: Ak equal to 1:10. The tumor is heated using laser radiation with a wavelength equal to 0.800 microns to a temperature of 43 ° C-45 ° C. The set temperature is maintained for 10-30 minutes.

As can be seen from the data presented in the table, the combined use of BCS "Oxycobalamin + Ak" and hyperthermia leads to inhibition of tumor growth by 72% -53% (maintaining the effect from 11 to 20 days, increasing the effectiveness of monotherapy using only hyperthermia by 73% - 65%).

Examples 12-13.

As a tumor model, sarcoma S-37 is used.

Oxycobalamin is administered intravenously at the doses indicated in Examples 9 and 11. Ascorbic acid is used in a dose corresponding to a molar ratio of Oc: Ak equal to 1:10 and 1:20. The hyperterm mode is similar and is indicated in example 9.

As can be seen from the table, the combined use of BCS "Oxycobalamin + Ak" and hyperthermia in mice with S-37 leads to biologically significant inhibition of tumor growth at the level of 70% -55% (maintaining the effect for more than 13 days, increasing the effectiveness of monotherapy using only hyperthermia 85% -82%).

Thus, the proposed method allows to increase the therapeutic efficacy of monotherapy of malignant tumors using BCS "Metallocomplex + Ascorbic acid" or hyperthermia by 86-63%; (therapeutic gain) and 85-48% (therapeutic gain), respectively.

The application of the proposed method is not limited to the mentioned types of tumors, while other doses of the binary catalyst system components and the temperature of heating the tumor can be applied.

Table 1 The antitumor efficacy of the combined use of BCS based on Terafthal, Epheter, Oxycobalamin and hyperthermia in mice with transplantable malignant tumors. Example No. Tumor model Catalyst dose The molar ratio of catalyst: Ak Hyperthermia Antitumor efficacy Therapeutic gain,% t ° C duration min SRW,% duration of biologically significant effect, days in relation to the effectiveness of hyperthermia in relation to the effectiveness of BCS BCS "Terafthal + Ak" → hyperthermia one AOE 1/10 MTD 1:30 41 thirty 70-55 twenty 68 70 2 1/5 MTD 1: 5 41 twenty 62-51 16 72 71 3 MTD 1:10 43 10 82-77 > 26 63 71 four S-37 MTD 1:10 43 10 60-53 > 14 55 68 BCS "Efiter + Ak" → hyperthermia 5 AOE 1/10 MTD 1:30 41 thirty 72-54 eighteen 69 65 6 1/10 MTD 1:30 43 10 64-53 fourteen 48 63 7 S-37 _^1/2 MTD 1:30 43 10 68-65 fourteen 64 71 8 MTD 1:30 43 10 71-51 > 18 72 79 BCS “Oxycobalamin + Ak” → hyperthermia 9 AOE _^1/2 MTD 1:10 43 10 69-50 eleven 73 81 10 _^1/2 MTD 1:10 45 5 77-59 > 13 65 80 eleven MTD 1:10 45 5 86-66 twenty 68 84 12 S-37 _^1/2 MTD 1:20 43 10 70-65 > 13 85 72 13 MTD 1:10 43 10 63-55 > 13 82 86

Claims (1)

A method of suppressing tumor growth by intravenous administration of a metal complex — a catalyst for oxidizing a substrate and then ascorbic acid — an oxidizing substrate, characterized in that after the administration of ascorbic acid, the tumor tissue is heated by radiation with a wavelength of at least 0.800 microns to a temperature of at least 41 ° C for not less than 5 minutes