Method of induction of hyperthermia in the experiment

 

The invention relates to medicine. Method of induction of hyperthermia in the experiment, including regional introduction of the magnetically controlled drug in the area of tumor localization with its subsequent concentration, fixation in a constant magnetic field and heat in an alternating magnetic field through the layer of water having a constant temperature. 6 table.

The invention relates to experimental medicine and can be used in Oncology for the treatment of tumors of different localization in the experiment.

There is a method of induction of hyperthermia malignant tumors of animals in an alternating magnetic field: after intratumoral injection magnetospirillum particle animal induction heated mouse can withstand a 3-minute treatment, after the 7-minute treatments they die [1].

There is a method of induction of hyperthermia malignant tumors of animals in an alternating magnetic field: after intratumoral injection magnetospirillum particle animal, covered with electrically insulating material, an induction heated mouse can withstand a 9-minute treatment, after a 15-minute treatments they die. The surviving animal: the electric field induces electric charges on the skin of experimental animals. Electric charges generate electric spark discharges, which have high toxicity and maim experimental animals. Animals suffer from toxicity caused by electric spark discharge and overheating.

Closest to the proposed method of induction of hyperthermia (prototype) [3] is a technique in which mice after intratumoral injection of magnetic fluid is placed in a bolus (cuvette with two leaves), bolus mouse feature between the poles of the core (frequency 500 kHz induction from 1 to 10 kA/m) and induction heated. The temperature of the environment of the animal is maintained at +35oTemperatures tumor 42-45oC.

The prototype has the same drawbacks as analogs: and concentrated flow in the tumor (diffuse in the body) the state of the magnetically controlled drug, which is concentrated in the liver from 12 to 14%, in the spleen, kidneys and other organs of the reticuloendothelial system, leading to toxicity and decrease therapeutic effect, after a week of remission relapse occurs.

The invention aims to remedy these disadvantages, the safety and therapeutic effect. Ukazayvat placed in an inhomogeneous static magnetic field so to the product were concentrated and were recorded in the tumor along the power lines, then the animal is oriented so that the tumor was located in the space of maximum intensity alternating magnetic field passing through the layer of water with a constant temperature, and incubated for a specified time, followed by repetition of the procedure from 3 to 12 sessions of 3-6-day intervals, depending on the malignancy and tumor volume. The length of the break depends on the physical condition of the animal, which determine the appearance and mobility: looks better than the animal, the shorter the break.

By passing an alternating electromagnetic field through the layer of water of thickness 1.2-21 mm, with a constant temperature, absorbed the energy of the electric field and restored the constant temperature of the environment of the animal, there is electrochemotherapy animal.

The method is as follows: 6th-9th day after inoculation, when the tumor volume reaches 21-30 mm3injected into the center of the tumor 300 μl of a solution of the magnetically controlled anticancer drug (table of contents-Fe2About336 mg), Orient the heterogeneous tumor in the pits inhomogeneous static magnetic field and stand 3-9 min, next, the tumor is oriented in an alternating magnetic field (frequency 50 - 1000 kHz, induction of 7.2 kA/m - 12 kA/m, the thickness of 0.15-15 kW), missed through a water layer thickness of 1.2-21 mm with a constant temperature (electrochemotherapy) introduced the drug induction heated and through 3-15 minutes the temperature of the tumor is increased to(+42) - (+45)oWith, withstand 6: 45 a.m. minutes (depending on capacity). Immediately after heating measure the temperature in the rectum (not to exceed +37oC). Every 3-6 days procedure hyperthermia again, only from 3 to 12 times. The results of treatment are presented in the examples.

All procedures are conducted in accordance with the recommendations [4]. All the data is processed statistically according to the recommended criteria for reliable accept differences when<0,05 [4]. The temperature is determined using alcohol and electric thermometers. In preliminary in vitro experiments to determine the optimal parameters of the DC and AC magnetic fields at a concentration of fixation and induction heating of the magnetically controlled anticancer drug in the phantom of the tumor and in vivo in experimental animals: mice, rats, rabbits, dogs.

Pre the STW electrochemotherapy. 18 male mice divided into 3 equal groups. Mice measure the temperature in the rectum. Each mouse was placed for 5 minutes in a constant magnetic field induction of 0.2 T, the gradient of 0.015 T/see After that mice group 1 incubated 45 min in an alternating electromagnetic field; mice 2 groups incubated 45 min in an alternating electromagnetic field with partial protection against electric field; mice 3 groups incubated 45 min in an alternating electromagnetic field, missed through a water layer thickness of 1.2-21 mm with a constant temperature (full protection against electric fields and overheating, electrochemotherapy), at frequency (f) 0,88 MHz, induction (H) 7,2 kA/m, the power of 0.15 kW. Immediately after treatment the effects of constant and alternating magnetic fields from each mouse measures the temperature on the skin surface and in the rectum. 1 and 2 groups, with no complete protection against electrical surges and overheating (without electrochemotherapy) animals charged (in contact with the body of the animal is observed glow neon indicator, this indicates an electrical charge on its surface), the temperature in the rectum of mice +36,5oWith, on the surface of the skin- (+37) - (+42)oWith, in addition to overheating, they are exposed spark electric is actionsee discharge point burns the skin with a diameter up to 3 mm and a depth of 1.5 mm In places electrical lesions appear multiple bleeding wounds, in the future, the tail becomes inflamed and loses flexibility. After that, most of the test animals survive, but 30-60% of mice spontaneously anotherwise part or the whole tail, animals do not breed. In group 3, the temperature in the rectum and on the skin surface +36,5oAnd absolutely no signs of electrical damage, animals feel normal. Protective effect of electrochemotherapy is because when the transmission of the electromagnetic field through the layer of water absorbed energy of the electric field and the excess heat, the animal is unloaded (when in contact with the body of the animal glow neon indicator is not observed, it indicates the absence of an electric charge on its surface), skin temperature +35oC.

T. O., electrochemotherapy fully protects experimental animals from toxicity caused by electric spark discharge and overheating. This is the advantage of the inventive method compared to known.

Example 2. Concentration and fixation of the magnetically controlled anticancer drug inhomogeneous static magnetic field in the tumor tissues. Ostiguy 21-30 mm3injected into the center of the tumor each shot mouse 300 μl of a solution of the magnetically controlled anticancer drug (table of contents-Fe2About336 mg). Mice are divided into 3 equal groups. Mice of group 1 is placed in an inhomogeneous static magnetic field induction of 0.2 T, the gradient of 0.015 T/cm so that the tumor was a coaxial magnet, and incubated for 5 minutes When this happens: the growth and orientation of the magnetic particles anticancer drug is parallel to the force lines of the field, their concentration and fixation in tumor tissues, with subsequent induction heating denominated answers tumors receive after 28 days; in group 2 without magnetic concentration and fixation (magnetically directed drug is administered, but the tumor is not placed in a constant magnetic field) get low antitumor effect. Mice of group 1 in tumors removed after concentration and fixation of the magnetically controlled anticancer drug inhomogeneous static magnetic field, find from 63 to 75% (weight. ) Fe from introduced as part of the magnetically controlled anticancer drug. In 2 and 3 groups, without concentration and fixation of the magnetic antitumor Separate.

T. O. , inhomogeneous static magnetic field concentrates and fixes the magnetic antitumor drug in the tumor. This explains the high antitumor effect and confirms the advantage of the inventive method compared to known.

Example 3. The security of the claimed method. 12 mice males divided into 2 equal groups, experimental and control. 12 mice females divided into 2 equal groups, experimental and control. Mice measure the temperature in the rectum. Each mouse in the experimental group in the capsule is placed for 5 minutes in a constant magnetic field induction of 0.2 T, the gradient of 0.015 T/see Of a constant magnetic field electrostimulation mouse move in an alternating magnetic field, the frequency 0,88 MHz, induction of 7.2 kA/m, the thickness of 0.15 kW and maintain h min with an interval of 3 days. Immediately after the procedure is complete, measure the temperature on the skin surface and in the rectum. Skin temperature and rectal +36,5oC. After treatment the effects of constant and alternating magnetic fields of each of the male experimental group implanted into the cell to the female experimental group that received the same treatments. The average number of pups in litters of the experimental group is 5.6. The average number of pups in litters pin is dnaa the lifespan of mice in the control group is 49 months.

These results confirmed the safety of the claimed method in the treatment of cancer.

Example 4. Determining the dependence of the antitumor effect of skin temperature on the surface of the tumor and the duration of the session hyperthermia. 36 mice subcutaneously injected with a suspension of 106cell sarcoma S180, divided mice into 4 equal groups: 1, 2, 3 and 4. When the average tumor diameter up to 6 mm (about 6 days), mice 2, 3 and 4 groups in the tumor injected from 0.06% to 0,09 ml of 30% solution of the magnetically controlled anticancer drug. Mice 1, 2, 3 and 4 groups are placed for 5 minutes in a constant magnetic field induction of 0.2 T, the gradient of 0.015 T/cm, each mouse electrotermometry and placed in an alternating magnetic field. The temperature in the rectum and on the surface of tumors in mice of group 1 (without the magnetic anticancer drug) remains between(+36) - (+37)oC. the Temperature of the tumor in mice 2, 3 and 4 groups under the action of alternating magnetic fields for 24 min rises above +42oC. Histologically confirmed by the formation of necrotic tumor tissue in the center of the tumor, in addition, the tumors are detected clusters of living cells. In group 2, the tumor is heated for another 6 clusters of live tumor cells. In group 3 tumors heated 45 minutes, the temperature rises to(+44) - (+45)oWith, on the periphery of the tumor remain single living tumor cells. In group 4, the tumor is heated to 60 minutes, the temperature rises to(+45) - (+46)oWith live tumor cells are not detected, but the symptoms as a result of extensive skin burns, so further heating of tumors limit of 45 minutes (table. 1).

So it is preferable induction hyperthermia of the tumor at +45oC for 45 minutes

Example 5. Determining the dependence of the antitumor effect of the claimed method from the number of sessions induction heating of the tumor. 54 mice subcutaneously injected with a suspension of 106cell sarcoma S180, divided mice into 6 equal groups: 1, 2, 3, 4, 5 and 6. When the average tumor diameter up to 6 mm (about 6 days), mice 2, 3, 4 5 and 6 groups in the tumor injected from 0.06% to 0,09 ml of 30% solution of the magnetically controlled anticancer drug. Mice 1, 2, 3, 4, 5 and 6 groups placed for 5 minutes in a constant magnetic field induction of 0.2 T, the gradient of 0.015 T/cm, each mouse electrotermometry and placed in an alternating magnetic field. The temperature of the tumor in mice 2, 3, 4, 5 and 6 groups under the action of alternating magnetic fields for 24 min rises above pwholesale preparation) remains between the (+36) - (+37)oC. mice 2, 3, 4, 5 and 6, the temperature of the tumor continues to rise, and after 45 min reaches +45oC. the Procedure of heating of tumors in mice 2 groups meet 1 time, 3 groups of 2 times 4 - 6 times, 5 groups 9 times, 6 groups 12 times with an interval of 4 days (table. 2).

Get: 1 group of mice tumor volume for each mouse steadily increasing with no signs of regression in the second group, the average volume of tumors decreases slowly, the increase in life expectancy 117%: - in the third group, the average volume of tumors is significantly reduced, complete tumor regression was observed in one of the 9 mice, the increase in life expectancy of mice 140%; - in the fourth group, the average volume of tumors in the majority of cases continues to increase until the twelfth day, after which begins the reduction of tumors and, finally, their symptoms are not evident within 3 months complete regression of tumors was observed in 4 out of 9 mice, the increase in life expectancy of mice 160%; - in the fifth group after 9 therapeutic effects slightly increased the lifespan of mice 163%; - in the sixth group after 12 therapeutic effects of a decrease in life span of mice up to 140%; the p 6. The increase in the average life expectancy of mice after intratumoral induction of hyperthermia sarcoma S180. 20 mice subcutaneously injected with a suspension of 106cell sarcoma S180 and divide them into 2 equal groups. When the average tumor diameter up to 6 mm (about 5 days), mice (groups 1 and 2 measure the temperature in the rectum, tumor injected from 0.06% to 0,09 ml of 30% solution of the magnetically controlled anticancer drug imisa placed for 5 minutes in a constant magnetic field induction of 0.2 T, the gradient of 0.015 T/see Mice 2 groups electrotermometry and induction heated tumors (frequency 0,88 MHz, induction of 7.2 kA/m 0,15 kW) h min at(+44) - (+45)oWith repeat treatments after 4 days. Immediately after heating is discontinued measure the temperature on the surface of a tumor in the rectum mouse elektrotermometria. After nine times, with an interval of 4 days of re-heating, tumors in mice modifitsiruyutsya and rejected over the next 3 weeks. Out of 10 mice survived 6 (60%). On the spot otorgada tumors formed baldness that after 6 to 9 months overgrown hair. Induction heating sarcoma S180 leads to full regress tumors in 4 animals and to increase the average length W is abolitionniste life of mice in the treatment of dense forms of sarcoma S180 (PL. 3). The results indicate the superiority of the claimed method over known.

Example 7. Determining the number of procedures and distant antitumor effect of induction of hyperthermia of the tumor. Pieces of tumor tissue (solid Ehrlich carcinoma), containing magnetically directed drug implanted 45 mice under the skin of the right side; the mice are divided into 5 equal groups. In group 1 mice do not carry out the procedure of induction heating, in group 2 performed 2 times, 3 group - 4 times, 4 group 12 times in 5 group - 18 times with an interval of 4 days (table. 4). Get: 1 group of mice tumor volume for each mouse steadily increasing; in the second group, the average volume of tumors is slightly reduced and in mice develops short-term remission;
in the third group, the average volume of tumors is significantly reduced, UPI mice increases to 110%;
- in the fourth group, the average volume of tumors in the majority of cases continues to increase until the twelfth day, after which begins the reduction of tumors and, finally, their symptoms are not evident within 3 months, complete regression of tumors was observed in 1 out of 9 mice, the increase in life expectancy of mice 120%. Histological confirmation is, however, immediately after the third heat on the periphery of the tumor still find viable tumor cells. Complete regression of the tumor occurs within 4 weeks after the twelfth heat treatments. The results show a higher antitumor effect when repeating the procedures of induction heating in the 2, 3 and 4 groups of mice, 5 group shows the mortality of animals from metastases associated with the characteristics of the course of Ehrlich carcinoma (table. 4).

So acting, to achieve complete regression of tumors and manifestations of distant antitumor effect should be repeated heating. The results indicate the superiority of the claimed method over known.

Example 8. The increase in the average life expectancy of mice after intratumoral induction of hyperthermia sarcoma MH. 40 mice divided into 4 equal groups: group 1 control, 2, 3, 4 - experienced. All mice subcutaneously injected with a suspension of 106cell sarcoma MX11. When the average tumor diameter up to 6 mm (about 5 days), mice measure the temperature in the rectum, tumor injected from 0.06% to 0,09 ml of 30% solution of the magnetically controlled drug and placed for 5 minutes in a constant magnetic field induction of 0.2 T, the gradient of 0.015 T/cm, mice 2, 3, 4 groups electrotermometry and maintain the tumor in an alternating magnetic field (h is in 4 days: 2 group 4 times in group 3 to 8 times, in group 4, 12 times. In group 4, after eight times, with an interval of 4 days, repeat the procedure for treating tumors in mice modifitsiruyutsya and rejected over the next 3 weeks. Out of 10 mice survived 4 (40%). On the spot otorgada tumors formed baldness that in 6-9 months overgrown hair. 5 group after 12 times, with an interval of 4 days, repeat the procedure for treating tumors in mice modifitsiruyutsya and rejected over the next 3 weeks. Out of 10 mice survived 3 (30%). In the control group, after subcutaneous injection of 106cell sarcoma MH, all 10 mice develop tumors from which they die within 3 months. Induction heating sarcoma MX11 leads to an increase in life expectancy experienced mice to 150% (table. 5) compared to control.

So it is with hyperthermia sarcoma MX11 best results are 8-fold repetition of hyperthermia.

Example 9. Potentiation of antitumor immunity. In the control group And 6 mice injected pieces tumor MH under the skin of the right and left sides. In group B pieces of tumor tissue (sarcoma MG) containing magnetically directed drug implanted 9 mice under the skin of the right side, dopolnitelnye all mice induction heated h min with an interval of 4 days. In the treatment of these mice heating at +45oWith observed only in group B in tumors located on the right side. In table. 6 presents the values of the regression of the tumors on the right and left side on the 28th day after h min with an interval of 4 days procedures induction heating. In group a tumors detected in all mice on the right and left side. In group B full regression on the left side is observed in three out of nine mice, remote anti-tumor effect observed in each of these mice. Complete regression was not observed in 6 of the nine mice in group B, these mice is not observed distance effect (table. 6). T. O., an advantage of the claimed method over known is that induction heating causes potentiation of antitumor immunity.

These data confirmed the advantage of the inventive method increases the life expectancy of mice with induction heating of a solid form of sarcoma MH.

Example 10 Determination of the distant antitumor effect. Pieces of tumor tissue (sarcoma S180), containing magnetically directed drug 27 implanted mice under the skin of the right and left sides; mice divided into 3 equal groups. Mice of the first group on repeat. For groups 1 and 2 mice carry out induction heating 445 min with an interval of 4 days. In the treatment of these mice heating at +45oWith observed only in tumors located on the right side. Mice (groups 1 and 2 the growth rate of the tumors decreased in 2 times after repeated procedures of heating compared with 9 control mice, which procedure do not apply heat. After 28 days of the completion of induction heating in 2 mice group 1 observed complete regression of tumors, as on the right, the hook and on the left side.

So acting . induction heating of tumors leads to a rapid decrease in the volume of the tumors and the manifestation of distant antitumor effect. This is the advantage of the inventive method over known.

Thus, the claimed method is superior in efficacy and safety actions known methods of chemotherapy of sarcomas: S180, MH and Ehrlich carcinoma.

Sources of information
1. Medal B. S., W. Shorey, Gilchrist R. K., W. Barker, R. Hanselman Archives of surgery 79, (1959), pp. 427-431.

2. The Brusentsov N. A., Porubov, M., Eveli Y. K., Shumakov L. I., stockings, A. C. , kilimnik I. C., Razumovsky C. A. 4th all-Union Conf. on the application of magnetic fluids in biology and medicine the um Press, N. Y., (1997), pp. 569 - 595.

4. L. F. Larionov. Chemotherapy of malignant tumors. The honey.lit., M., 1962.


Claims

Method of induction of hyperthermia in the experiment, including regional introduction of the magnetically controlled drug in the area of tumor localization with its subsequent concentration, fixation and heating, the concentration and fixation of the drug is carried out in a constant magnetic field, and heat in an alternating magnetic field, missed through the layer of oxen, with a constant temperature.

 

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