JP2017124994A - Device for cancer treatment and cancer relapse prevention and porphyrin-containing formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide means that is applied over a wide range of cancer targets and has reduced side effect and burden on a subject.SOLUTION: A porphyrin-containing formulation is used for the purpose of irradiating a subject with microwaves after administering the porphyrin-containing formulation to the subject.SELECTED DRAWING: None

Description

  The present invention relates to a technique for noninvasive cancer treatment with few side effects.

  There are numerous methods for treating cancer, such as surgical resection, chemotherapy, radiation therapy, bone marrow transplantation, and the like. Surgical excision is an invasive method and the physical burden on the patient is very high. In many cases, it is used in combination with chemotherapy and radiation therapy. As anticancer agents, various types such as antimetabolites, plant alkaloids, anticancer antibiotics, molecular target drugs, antibiotics, hormone agents and alkylating agents are known. Many anti-cancer (tumor) agents are capable of damaging normal cells in addition to killing tumor cells. The side effects of these anticancer agents are typically nausea, vomiting, alopecia and bone marrow function suppression. These side effects are often accompanied by a significant reduction in the patient's QOL.

  Various studies have been conducted as treatments with few side effects. For example, PDT therapy using porphyrins is known. In PDT therapy, generally, when a porphyrin is administered to a patient as a photosensitizer and then irradiated with a strong laser red light beam, tumor cells can be more easily destroyed. This mechanism is considered to lead cancer cells to cell death (apoptosis) through singlet oxygen generated by energy transfer from photoexcited porphyrin molecules to oxygen molecules.

JP 2001-512433 A JP 62-53920 A JP 09-48733 A

  However, since the depth of transmission of red light is limited to only a few millimeters, the target of application of PDT therapy is limited to some skin cancers and brain tumors used in combination with craniotomy.

  Therefore, an object of the present invention is to provide means for applying a wide range of cancer subjects and reducing the side effects and burden on the subject.

  The inventors of the present invention have intensively studied to solve the above problems. As a result, it was found that the subject can be solved by irradiating the affected area with microwaves from at least two or more directions so as to satisfy specific conditions after administering a porphyrin-containing preparation to a patient. Was completed. That is, the present invention is as follows.

The present invention (1) is a porphyrin-containing preparation that is used for the purpose of irradiating the subject with a microwave after administering the porphyrin-containing preparation to the subject.
In the present invention (2), the irradiation is irradiation of microwaves from at least two or more directions with respect to the specific part of the subject, and the irradiation is performed at the specific part at the plural parts. This is a porphyrin-containing preparation according to the present invention (1), which is carried out under a condition in which microwaves from directions resonate.
The present invention (3) is the porphyrin-containing preparation according to the present invention (1) or (2), wherein the irradiation is pulsed irradiation with a frequency of 1.5 to 5.0 GHz.
The present invention (4) is the porphyrin-containing preparation according to the present invention (2) or (3), wherein the specific site is a deep part of 0.5 cm or more from the body surface.
In the present invention (5), the porphyrin is one or more selected from 5-aminolevulinic acid and derivatives thereof, protoporphyrin IX and derivatives thereof, hematoporphyrin derivatives, benzoporphyrin derivatives, talaporfin, and polymers thereof. It is a porphyrin-containing preparation according to any one of the present inventions (1) to (4).
The present invention (6) is the porphyrin-containing preparation according to any one of the present invention (2) to (5), wherein the specific site is a site where the subject's malignant tumor is present.
This invention (7) is a microwave irradiation apparatus, Comprising: It is a microwave irradiation apparatus used in the use which irradiates a microwave with respect to the subject who administered the porphyrin containing formulation.
As for this invention (8), the said microwave irradiation apparatus has two or more microwave irradiation site | parts,
The irradiation is irradiation of microwaves from at least two or more directions on a specific part of the subject, and the irradiation is performed between the microwaves from the plurality of directions at the specific part. The microwave irradiation apparatus according to the present invention (7), which is configured to be implemented under a resonating condition.
The present invention (9) is the microwave irradiation apparatus according to the present invention (7) or (8), wherein the irradiation is pulse irradiation performed at a frequency of 1.5 to 5.0 GHz for a plurality of times.

  ADVANTAGE OF THE INVENTION According to this invention, the object of the cancer applied is wide, and it becomes possible to provide a means with few side effects and a burden which a subject suffers.

FIG. 1 is a schematic front view showing an embodiment of a microwave irradiation apparatus. FIG. 2 is a schematic side view showing an embodiment of a microwave irradiation apparatus. FIG. 3 is a perspective view showing an embodiment of the microwave irradiation apparatus. FIG. 4 is a schematic diagram illustrating an example of a driving unit of the microwave irradiation apparatus. FIG. 5 is a schematic diagram showing an embodiment of a micro electromagnetic wave generator. FIG. 6 is a schematic view showing another embodiment of the micro electromagnetic wave generator. FIG. 7 is a schematic diagram of a synergistic action on DNA with a porphyrin-containing preparation and a microwave. FIG. 8 is a schematic diagram showing the addition of a porphyrin-containing preparation (5-ALA), the schedule of microwave irradiation, and the arrangement of microwave irradiation to the sample. FIG. 9 is a graph showing the influence on pancreatic cancer cell growth inhibition by the combined effect of a porphyrin-containing preparation (5-ALA) and microwave irradiation. FIG. 10 is a graph showing the influence of 5-ALA concentration on pancreatic cancer cell growth inhibition by a porphyrin-containing preparation (5-ALA) alone. FIG. 11 is a graph showing the influence of 5-ALA concentration on pancreatic cancer cell growth inhibition by the combined effect of a porphyrin-containing preparation (5-ALA) and microwave irradiation. FIG. 12 is a graph showing a comparison of pancreatic cancer cell growth inhibitory effects by the combined effect of a porphyrin-containing preparation (talaporfin) and microwave irradiation. FIG. 13 is a graph showing the influence of the concentration of talaporfin on pancreatic cancer cell growth inhibition by a porphyrin-containing preparation (talaporfin) alone. FIG. 14 is a graph showing the influence of the concentration of talaporfin on pancreatic cancer cell growth inhibition by the combined effect of a porphyrin-containing preparation (5-ALA) and microwave irradiation.

  In the present claims and the present specification, the “body surface” refers to skin and other tissues, and is not limited to a surface that can be visually recognized in a normal state, and refers to a surface portion in a body cavity such as a digestive tract or a respiratory organ. Shall be included. “Deep part” indicates the depth (distance) from the “body surface” of the end of the “specific part”. Furthermore, the “specific site” is a site where the presence of a tumor can be confirmed by a site where porphyrins accumulate, CT, PET examination, or other methods, and the effect of the present invention can be expected.

  Further, in the claims and the specification, “pulse irradiation” refers to an irradiation method in which microwave irradiation is intermittently performed (for example, irradiation → pause → irradiation → pause → irradiation).

The porphyrin derivative or microwave irradiation apparatus according to a preferred embodiment of the present invention will be described in the following order.
(1-1) Description of preparation containing porphyrin (1-2) Administration method of preparation containing porphyrin (2-1) Description of microwave irradiation device (2-2) Usage of microwave irradiation device (3) Mechanism of action concerning synergistic effect of preparation containing microwave and porphyrin (4) Use of the present invention

≪Porphyrin-containing preparation≫
The porphyrin-containing preparation according to this embodiment will be described in detail.

<Type>
The porphyrin-containing preparation that can be used in the present invention is not particularly limited. As long as the effect of the present invention is exhibited, it can be used. For example, as PDT, already covered porfimer sodium {Photophilin (registered trademark)} (hematoporphyrin derivative), talaporfin sodium {resaphyrin (registered trademark)}, and 5-aminolevulinic acid hydrochloride {Araglio (registered) Trademark)), Hexaminolevulinate {Hexvix (registered trademark)}, methyl aminolevulinate {Metvix (registered trademark)}, hexylaminolevulinate {Cevira (registered trademark)} Verteporfin {Visudyne (registered trademark)}, and Temoporfin {Foscan (registered trademark) } Etc. are mentioned.

  The porphyrins of the present invention include porphyrins, derivatives thereof, complexes thereof, polymers thereof and salts thereof, and precursors thereof, in the case where the effects of the present invention are exhibited, the porphine skeleton Including those having Specific examples include porphyrins contained in the above porphyrin-containing preparation. Among them, protoporphyrin IX or a derivative thereof, 5-aminolevulinic acid or a derivative thereof as a precursor, hematoporphyrin derivative, a benzoporphyrin derivative, or talaporfin, which is a porphyrin derived from plant chlorophyll, or a polymer thereof is preferable. Furthermore, porfimers, talaporfin or 5-aminolevulinic acid or derivatives thereof are particularly suitable. These may be used singly or may be used in plural.

(Combination therapy including porphyrins)
As described above, insurance is applied as a treatment method using the action of laser light and a photosensitive substance. The subject is also used for identifying a tumor site in early lung cancer, early esophageal cancer, gastric cancer, and brain tumor craniotomy. This utilizes the property that porphyrins 1) accumulate specifically in a tumor, and 2) can effectively produce singlet oxygen by light irradiation.

  However, the laser beam has a depth of about 5 to 10 mm, and must be used in combination with skin cancer on the skin surface or invasive means such as surgery. Furthermore, its application is limited depending on the degree of cancer invasion, such as the degree of cancer invasion, tumor size, and metastasis. The present invention is considered to be very useful as a non-invasive means that can be applied to deeper cancers and that has less side effects and less burden on the patient.

<Manufacturing method>
A method for producing these porphyrin-containing preparations is not particularly limited. It can be produced by a known method. In addition, these porphyrin-containing preparations can also be obtained by purchasing commercially available products.

<Possible forms of porphyrin-containing preparations>
The porphyrin-containing preparation according to this embodiment includes a case where a pharmacologically acceptable salt is formed with an acid or a base. Moreover, those solvates and optical isomers are also included. Further, in the present embodiment, the porphyrin-containing preparation according to the present embodiment may be crystalline or non-crystalline, and if a crystalline polymorph exists, it is a single product of any of those crystalline forms. Or a mixture.

  Further, in this embodiment, the porphyrin-containing preparation containing the porphyrin-containing complex undergoes metabolism such as oxidation, reduction, hydrolysis, etc. in vivo to produce the antitumor porphyrin-containing complex according to this embodiment. Also includes compounds.

<Side effects>
Here, a side effect means an action that is unnecessary for treatment seen at the time of administration or an action that can cause a clinical disorder. Specific examples of side effects of the porphyrin-containing preparation according to this embodiment include photosensitivity, dyspnea, liver dysfunction, digestive disorders (including nausea, vomiting, diarrhea) and hematopoietic disorders. The administration of a porphyrin-containing preparation alone is considered to have no serious side effects that reduce the patient's QOL.

  On the other hand, cytotoxic anticancer drugs are not only effective for cancer cells but also for normal cells that are actively engaged in cell division. Yes. In the porphyrins-containing preparation administered to the subject to be irradiated with the microwave according to the present embodiment, (1) the porphyrins have a property of accumulating in cancer cells, and (2) the porphyrins are irradiated with electromagnetic waves. (3) Since the microwave irradiation apparatus according to this embodiment can perform strong irradiation only at the cancer site, it can be said that it is particularly effective in reducing side effects. .

<Administration method>
When using the porphyrin-containing preparation according to this embodiment, the administration route is not particularly limited. Although it can be administered orally or parenterally, it is usually intravenous (intravenous infusion). The dose is not particularly limited as long as the effects of the present invention are exhibited. The dosage of a normal porphyrin-containing preparation is the type of the porphyrin-containing preparation, the degree of symptoms, the patient's age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, properties of the pharmaceutical preparation, formulation and type. Depends on the type of active ingredient. For example, as an injection, 40 mg / m ² as talaporfin sodium and 2 mg / kg as porfimer sodium can be intravenously injected once. For example, as an internal preparation, 20 mg / kg can be orally administered as aminolevulinic acid hydrochloride. If the patient experiences excessive toxicity, a dose reduction is necessary. The dosage and dosing schedule may be altered if one or more additional chemotherapeutic agents are used in addition to the combination therapy of the present invention.

(Dosage form to be administered)
The dosage form of the porphyrin-containing preparation of this embodiment when administered is not limited. For example, injection solutions, freeze-dried preparations, tablets and the like can be mentioned. Also, commercially available dosage forms can be used.

≪Microwave irradiation device≫
A microwave irradiation device (cancer treatment / recurrence prevention device) suitably used in the present embodiment will be described in detail with reference to the drawings.

  According to the microwave irradiation apparatus according to the present embodiment, there is provided a method for operating the microwave irradiation apparatus that further improves the therapeutic effect, reduces side effects and burden on the patient, and can be automatically operated.

  According to the microwave irradiation apparatus according to the present embodiment, the physical and mental burden of the treatment target is small and a high therapeutic effect can be obtained as compared with the conventional technique. In addition, treatment is possible even with a stent or metal tooth embedded, which is highly convenient. It can be said that the risk at the time of combined use with the porphyrin-containing preparation according to this embodiment is less.

  Hereinafter, an example of a microwave irradiation apparatus suitably used in the present embodiment will be described with reference to the drawings. In the description of the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. In addition, the drawings are exaggerated for easy understanding, and the dimensional ratios do not necessarily match those described. In addition, as long as the effects of the present invention are exhibited, a commercially available microwave irradiation device may be used, or a plurality of devices may be used.

  As shown in FIG. 1 and the like, the microwave irradiation apparatus 100 includes a pair of opposed magnetrons 65 (consisting of a magnetron head 61 and a magnetron body 60), a cylindrical housing 10 having a magnetron 65 therein, and a treatment target. Temperature measuring means 75 capable of acquiring temperature data of the skin surface 5, distance measuring means 70 capable of acquiring distance data between the magnetron 65 and the treatment object 5, and the magnetron 65 along the inner wall surface of the housing 10. And a micro electromagnetic wave generator having a distance adjusting means 80 that can be moved. The micro electromagnetic wave generator is attached to the holder 90 so that a pair of magnetrons 65 are arranged opposite to each other.

  The microwave irradiation apparatus 100 further includes a support base 20 on which the treatment target 5 can be placed, and a first drive composed of a ball screw that can move the support base 20 in the short direction of the support base 20. Means and a ball screw arranged substantially parallel to the longitudinal direction of the support base 20 and capable of moving the holder 90 to which the micro electromagnetic wave generator is attached substantially parallel to the longitudinal direction of the support base 20. 2 drive means. By providing the first driving means, the support base 20 is moved in the short direction of the support base 20 (the direction represented by the trajectory B in FIG. 2) while the treatment target 5 is placed on the support base 20. It becomes possible to make it.

  The microwave irradiation apparatus further includes distance measuring means capable of acquiring distance data between the magnetron and the treatment target, and distance adjusting means capable of moving the magnetron along the inner wall surface of the casing. You may have.

<Drive means>
The second driving means in the microwave irradiation apparatus 100 includes a guide bar 30, a ball screw 40, a motor 50, and a moving unit 35 attached to the holder 90. A ball screw 40 is disposed in parallel with the guide bar 30, and the ball screw 40 is connected to a motor 50. As the motor 50 rotates, the moving unit 35 can move along the guide bar 30 and the ball screw 40. Accordingly, the holder 90 and the micro electromagnetic wave generator attached to the holder 90 move substantially parallel to the longitudinal direction of the support base 20. By controlling the rotation speed of the motor 50, the moving distance can be controlled.

  The rotational motion of the motor 50 is converted into a linear motion by the ball screw 40, and the moving unit 35 moves. The motor 50 is preferably a pulse motor because accurate positioning control can be realized. By combining the pulse motor and the ball screw, the moving unit 35 can be positioned with high accuracy and high reproducibility.

  The first driving means in the microwave irradiation apparatus 100 has the same configuration as the second driving means, and includes a guide bar, a ball screw, and a motor. The motor is preferably a pulse motor. As the motor rotates, the support base 20 can move along the guide bar and the ball screw. Accordingly, the support base 20 moves in the short direction of the support base 20. The movement distance of the support base 20 can be controlled by controlling the number of rotations of the motor.

  Note that the microwave irradiation apparatus may be one in which a driving means is attached to a support base and the support base is moved in the longitudinal direction of the support base, or both the support base and the holder are moved. . The microwave irradiation apparatus 100 according to the present embodiment, which moves the holder 90, is preferable from the viewpoint of avoiding a reduction in the therapeutic effect due to the movement of the treatment target and a small installation space.

<Micro electromagnetic wave generator>
The micro electromagnetic wave generation unit has at least a pair of magnetrons housed in a cylindrical casing, and is arranged so that the pair of magnetrons face each other. The treatment target is disposed between the pair of magnetrons facing each other. The micro electromagnetic wave generator also has a temperature measuring means. The micro electromagnetic wave generator may further include a distance measuring unit and a distance adjusting unit.

  Two or more pairs of magnetrons may be arranged. In this case, the paired magnetrons are arranged to face each other. Alternatively, they may be arranged at a right angle such as 90 degrees. Two or more microwave irradiation apparatuses can also be used.

  FIG. 5 is a schematic diagram showing an embodiment of a micro electromagnetic wave generator. The micro electromagnetic wave generation unit 200 includes a cylindrical casing 10, a magnetron 65, a temperature measurement unit (not shown), a distance measurement unit (not shown), and a distance adjustment unit 80. The magnetron 65 can be moved along the irradiation axis of the micro electromagnetic wave by the distance adjusting means 80.

  FIG. 6 is a schematic view showing another embodiment of the micro electromagnetic wave generator. The micro electromagnetic wave generation unit 210 includes a cylindrical casing (not shown), a magnetron 65, a temperature measurement unit 75, a distance measurement unit 70, and a distance adjustment unit 80. The magnetron 65 can be moved along the irradiation axis of the micro electromagnetic wave by the distance adjusting means 80. In this example, the motor shaft and the magnetron 65 are connected by a wire. Thereby, when the motor rotates and winds the wire, the magnetron 65 can be moved to the motor side. Conversely, when the motor rotates and stretches the wire, the magnetron 65 can be moved away from the motor.

(Magnetron)
The magnetron 65 includes a magnetron main body 60 and a magnetron head 61, and emits a micro electromagnetic wave generated by the micro electromagnetic wave oscillation unit 62 existing in the magnetron main body 60 from the magnetron head 61. The frequency of the micro electromagnetic wave is preferably 1.00 to 5.00 GHz, more preferably 2.00 to 3.00 GHz, and even more preferably 2.45 GHz. The electromagnetic energy of the micro electromagnetic wave is preferably about 500 to 1000 W.

  The micro electromagnetic wave generator of the microwave irradiation apparatus according to the present embodiment has a magnetron 65 housed in a cylindrical housing 10, and the micro electromagnetic waves are emitted from the magnetron head 61 and emitted from the opening of the housing 10. It is the composition which becomes. Surprisingly, the micro electromagnetic wave generation unit of the present embodiment can realize a higher therapeutic effect by adopting such a configuration.

(Temperature measuring means)
Although it does not restrict | limit especially as the temperature measurement means 75, The thing which can measure the temperature data of the skin surface of a treatment object in sufficient accuracy in real time without contact is preferable. An example of such temperature measuring means is a radiation thermometer. An example of the radiation thermometer is an infrared radiation thermometer.

(Distance measuring means)
The distance measuring means 70 is not particularly limited. For example, the distance measuring means 70 emits ultrasonic waves, lasers, infrared rays, etc., and measures the distance from the time it takes to receive the reflected wave, and uses a camera and image processing. Can be used, for example, a laser length meter.

(Distance adjustment means)
Although it does not restrict | limit especially as the distance adjustment means 80, For example, the combination of a hydraulic jack, a motor, a ball screw, and a motor is mentioned. The distance adjusting unit 80 may include, for example, a guide bar, a ball screw, and a pulse motor, similarly to the first driving unit and the second driving unit described above.

<Rotating means>
The microwave irradiation device 100 of this embodiment has a rotating plate 32. As shown in FIGS. 2 and 3, when the rotating plate 32 rotates, the holder 90 rotates along a circular orbit A having the center point C as the center. Thereby, the magnetron 65 which opposes can be rotated in the plane substantially perpendicular | vertical to the longitudinal direction of the support stand 20. FIG.

  Various modifications can be made to the microwave irradiation apparatus 100 without departing from the scope of the present invention.

≪How to use microwave irradiation device≫
As a method of using the microwave irradiation apparatus of the present embodiment, for example, a temperature data acquisition step in which the temperature measurement means acquires the temperature data of the skin surface to be treated, an irradiation step in which the magnetron irradiates the micro electromagnetic wave, A first moving step in which the driving means moves the support base in the short direction; a second moving step in which the second driving means moves the micro electromagnetic wave generator along the longitudinal direction of the support base; The temperature data acquisition step, the irradiation step, the first movement step, and the second movement step are executed until the micro electromagnetic wave generation unit reaches a preset position. When the temperature data value acquired in step 1 exceeds the first set value, the irradiation of the micro electromagnetic wave is interrupted, and when the temperature data value falls below the second set value, It is intended to operate to resume the elevation.

  The operation method of the microwave irradiation apparatus includes a distance data acquisition step in which the distance measurement means acquires distance data between the magnetron and the treatment object, and a distance adjustment means that determines whether the magnetron and the treatment object are based on the distance data. There may be further provided a distance adjusting step of moving the magnetron so that the distance between them becomes a preset distance.

<In case of solid cancer>
For example, when the treatment target has a tumor (solid cancer) in the abdomen, the starting point from which the micro electromagnetic wave generation unit starts the irradiation of the micro electromagnetic wave is set in the chest of the treatment target, and the above-mentioned “preset position” is set in the lower abdomen Set. The irradiation target region set in this way is divided into nine, for example, and these regions are sequentially irradiated with micro electromagnetic waves.

  More specifically, first, the first generation step and the second movement step move the micro electromagnetic wave generation unit to a position where one of the nine divided regions can be irradiated with the micro electromagnetic wave. Subsequently, the micro electromagnetic wave generator irradiates the micro electromagnetic wave. For example, with respect to one region, irradiation with micro electromagnetic waves is performed for 1 to 10 seconds, more preferably 3 to 8 seconds, particularly preferably 7 seconds, and this is repeated three times or more. The interval between irradiation is, for example, 3 seconds. In this way, when the irradiation of the micro electromagnetic wave to one of the nine divided regions is finished, the micro electromagnetic wave generating unit is again formed in the nine divided regions by the first moving step and the second moving step. Of these, it is moved to one of the unirradiated areas. Subsequently, as described above, the micro electromagnetic wave generator irradiates the micro electromagnetic wave. The above process is performed for all of the nine divided areas.

During this time, the temperature data acquisition process monitors the temperature data of the skin surface to be treated in real time, and if the acquired temperature data value exceeds the first set value, the irradiation of the micro electromagnetic wave is interrupted and the temperature When the data value falls below the second set value, the irradiation of the micro electromagnetic wave is resumed. The first set value is preferably 40 to 43 ° C, and particularly preferably 41.5 ° C. When the temperature of the skin surface of the treatment target reaches this temperature, the treatment target cannot withstand the heat. And when the value of the acquired temperature data falls below the 2nd setting value, irradiation of micro electromagnetic waves is restarted. The second set value is preferably set to the temperature of the skin surface to be treated immediately before the start of the irradiation of the micro electromagnetic wave. When the irradiation of the micro electromagnetic wave is resumed after the interruption of the irradiation of the micro electromagnetic wave due to the temperature data of the skin surface to be treated exceeding the first set value during the irradiation of the micro electromagnetic wave, It is good to irradiate electromagnetic waves.

  By the above operating method, it is possible to irradiate the micro electromagnetic wave over a wide range not only in the tumor forming part (abdomen) but also in the far part (chest to lower abdomen) away from the tumor.

(Focus irradiation)
In addition, the microwave irradiation apparatus used in the present embodiment irradiates electromagnetic waves from two or more directions using one or more electromagnetic wave oscillators and focusing means, and in a plurality of directions at a specific part. Microwave waves from each other can create a resonance point, and the affected area can be heated by focusing more on the cancer site.

  Here, porphyrins are known to accumulate at cancer sites. In such a microwave irradiation apparatus, when the porphyrins or porphyrin metabolites of the present invention accumulate at the cancer site in the irradiation after administration of the porphyrin-containing preparation, the cancer site is focused and irradiated. be able to. Therefore, the influence on other normal cells can be suppressed to a minimum, and efficient treatment becomes possible.

  When this microwave is focused and irradiated, the affected area of the cancer is a combination of microwave irradiation described later and generation of active oxygen caused by porphyrins described later, promotion of DNA destruction via PARP, and cell death due to microwaves. This is because the action becomes remarkable.

  Further, in the above operation method, the distance measuring unit acquires the distance data between the magnetron and the treatment target, and the distance adjustment unit is configured to detect the distance between the magnetron and the treatment target based on the distance data. A distance adjustment step of moving the magnetron so that the distance between them becomes a preset distance may be performed.

<For liquid cancer>
When the treatment target has liquid cancer, the start point is set at the top of the head, and the “preset position” is set at the tip of the foot. As a result, it is possible to irradiate the whole body with micro electromagnetic waves, and a high therapeutic effect can be obtained for liquid cancer without using an anticancer agent or the like.

  Microwaves are sequentially irradiated over the entire irradiation target region set in this way. More specifically, first, the micro electromagnetic wave generator is moved to the starting point by the first moving step and the second moving step. Subsequently, the micro electromagnetic wave generator irradiates the micro electromagnetic wave. In this case, the micro electromagnetic wave generation unit may continue to irradiate the micro electromagnetic wave, and during this time, the first moving step and the second moving step may continuously move the irradiation target portion to be treated. Moreover, you may further combine the rotation process mentioned later with a 1st movement process and a 2nd movement process. The time required for irradiating the whole body of the treatment object with the micro electromagnetic wave is about 5 minutes.

  While performing the above process, the temperature data of the skin surface to be treated is monitored in real time by the temperature data acquisition process. And when the value of the acquired temperature data exceeds a 1st setting value, irradiation of a micro electromagnetic wave, a 1st movement process, and a 2nd movement process are interrupted. Here, when the rotation process is performed, the rotation process is also interrupted. And when the value of temperature data falls below the 2nd setting value, irradiation of a micro electromagnetic wave, the 1st movement process, and the 2nd movement process are restarted. Here, when the rotation process is performed, the rotation process is also restarted. The first set value and the second set value are the same as in the case of the solid cancer described above.

  Hereinafter, each process will be described.

<Temperature data acquisition process>
In the temperature data acquisition step, the temperature measurement means 75 acquires temperature data of the skin surface of the treatment target 5. As described above, in one embodiment, the temperature measuring means 75 is a radiation thermometer.

<Distance data acquisition process>
In the distance data acquisition step, the distance measurement means 70 acquires distance data between the magnetron 65 or the magnetron head 61 and the treatment target 5. As described above, in one embodiment, the distance measuring means 70 is a laser length measuring device. The laser length measuring device has a laser emitter and a laser receiver. The laser length measuring device emits a laser from a laser projector. Subsequently, the laser receiver receives the laser. Based on this result, distance data between the magnetron 65 or the magnetron head 61 and the treatment target 5 is acquired.

<Distance adjustment process>
In the distance adjustment step, the distance adjustment unit 80 moves the magnetron based on the distance data obtained in the distance data acquisition step so that the distance between the magnetron 65 and the treatment target 5 becomes a preset distance.

If the distance between the magnetron 65 and the treatment target 5 is too far, the effect of irradiating the micro electromagnetic wave tends to be difficult to obtain. Further, if the distance between the magnetron 65 and the treatment target 5 is too short, there may be a problem that the treatment target 5 cannot withstand heat. The distance between the magnetron 65 and the treatment target 5 is preferably any of the following (1) to (3). Thereby, a therapeutic effect improves notably.
(1) The distance between the magnetron and the affected area (cancer) to be treated is 20 to 30 cm.
(2) The distance between the magnetron and the skin surface to be treated is 20 to 30 cm.
(3) The distance between a pair of opposing magnetrons is 40-60 cm

  More precisely, the distance between the magnetron (1) and the affected area (cancer) to be treated is the distance between the micro-electromagnetic oscillation part of the magnetron and the affected area (cancer) to be treated. The distance between the magnetron head and the affected area (cancer) to be treated is 10 to 30 cm. In this case, the distance from the surface of the skin to be treated to the affected area (cancer) is obtained in advance based on the CT image, PET image or MRI image, and the distance between the magnetron head and the affected area (cancer) to be treated is Adjust to 10-30 cm.

  The distance between the magnetron (2) and the skin surface to be treated is more precisely the distance between the magnetron micro-electromagnetic wave oscillating portion and the skin surface to be treated. The distance between the magnetron head and the surface of the skin to be treated is 10 to 30 cm.

  The distance between the pair of magnetrons facing each other in (3) above is more precisely the distance between the micro electromagnetic wave oscillation parts of the pair of magnetrons facing each other. The distance between the pair of magnetron heads facing each other is 20 to 60 cm.

  When setting the distance between the magnetron and the treatment target to (1) or (2) above, the distance between the magnetron and the treatment target by the distance adjustment step based on the distance data obtained in the distance data acquisition step Is adjusted. Further, when the distance between the magnetron and the treatment target is set to (3) above, the magnetron is kept fixed at a predetermined position of the cylindrical casing.

  Of the above (1) to (3), the most therapeutic effect can be expected in the case of (1). However, in the case of the above (1), it may be difficult to determine how to set the distance between the magnetron and the treatment target in a remote part away from the affected part (cancer). In addition, it is necessary to know in advance where the affected area (cancer) exists in the body to be treated. In such a case, it is easy to set the distance between the magnetron and the treatment target to (2) above, and even in this case, although it does not reach (1) above, a certain degree of therapeutic effect is obtained. I can expect. Although the therapeutic effect does not reach (1) and (2), it may be set to (3) according to the situation.

<Irradiation process>
In the irradiation process, the magnetron 65 irradiates the micro electromagnetic wave for a certain time. Since the micro electromagnetic wave generators are arranged so that the paired magnetrons 65 are opposed to each other, the micro electromagnetic waves irradiated from the paired magnetrons interfere with each other, and stronger electromagnetic energy is obtained. In addition, the microwave irradiation is not particularly limited as long as the angle formed by the micro electromagnetic waves irradiated from the paired magnetrons resonates at the porphyrin accumulation site (tumor site). For example, the angle is preferably 30 to 180 degrees, more preferably 90 to 180 degrees, although it varies depending on the depth of the affected area, the intensity of the irradiated microwave, and the distance of the irradiation apparatus.

(Pulse irradiation)
As the microwave irradiation method according to the present invention, pulse irradiation is suitable. As an irradiation condition of this pulse irradiation, the frequency of the micro electromagnetic wave irradiated by the magnetron 65 is preferably 1.5 to 5.0 GHz, and more preferably 2.00 to 3.00 GHz.

  The irradiation cycle of this pulse irradiation can be changed depending on the type of cancer, the site, and the like. It is preferable to repeat this cycle about 3 to 10 times.

  The irradiation time of the micro electromagnetic wave also varies depending on the distance between the magnetron 65 and the treatment target 5. More specifically, when the distance between the magnetron 65 and the treatment target 5 is any one of (1) to (3) described above, it is preferably 1 to 10 seconds, and 2 to 8 seconds. It is more preferable. If the irradiation time is within the upper range, the treatment subject will feel less “hot”, and a high therapeutic effect can be obtained. In addition, the expression of HSP (heat shock protein) is suppressed, and repeated treatment in a short period of time. It is also possible to do this. For example, treatment may be performed twice a day.

  In addition, the resting period between irradiation is not particularly limited as long as it is a period in which damage to normal cells other than the heat shock protein production and focus site can be suppressed, for example, 1 to 10 seconds is preferable, More preferably, it is 3 to 5 seconds.

(Focus irradiation and pulse irradiation)
In this way, by using resonance action (focus irradiation) and pulse irradiation, it is possible to concentrate and irradiate a microwave with stronger energy on the affected area. Therefore, an efficient effect can be produced in a shorter time. That is, it is possible to induce a synergistic apoptosis by the porphyrin and microwave described later at the porphyrin accumulation site (tumor site), and at the same time, to suppress undesirable effects such as cytotoxicity other than the porphyrin accumulation site.

  The depth (depth) considered to be able to exert a high irradiation effect by resonating the microwave wave according to the present embodiment by the combination of focus irradiation and pulse irradiation is 2 to 15.0 cm from the body surface. It is considered to be a degree.

<Transfer process>
In the first moving step, the first driving means moves the support base 20 in the short direction. Further, in the second moving step, the second driving unit moves the micro electromagnetic wave generation unit along the longitudinal direction of the support base 20.

<Rotation process>
In one embodiment, the method of operating the microwave irradiation apparatus may further include a rotation process. In the rotating step, the rotating means (the rotating plate 32) rotates the micro electromagnetic wave generating portion by a predetermined angle within a plane substantially perpendicular to the longitudinal direction of the support base 20. Thereby, it becomes possible to irradiate the treatment object 5 with the micro electromagnetic waves from different angles, and the treatment effect can be further enhanced.

  In the operation method of the microwave irradiation apparatus of the present embodiment, the temperature data acquisition process, the irradiation process, the first movement process, the second movement process, and the case until the micro electromagnetic wave generation unit reaches a preset position. The distance data acquisition process, the distance adjustment process, and the rotation process are executed.

  The temperature data acquisition process may be performed continuously during the operation of the microwave irradiation apparatus, or may be performed only while the irradiation process is being performed (including the period during which the irradiation of the micro electromagnetic wave is interrupted). . In addition, the irradiation process, the first movement process, the second movement process, and the distance data acquisition process, the distance adjustment process, and the rotation process, if present, are executed in any order as long as the effect of the present invention is obtained. May be.

  Further, the irradiation process, the temperature data acquisition process, the first movement process and the second movement process, and the distance data acquisition process, the distance adjustment process and the rotation process, if present, are continuously performed during the operation of the microwave irradiation apparatus. It may be executed.

<Automatic operation>
The microwave irradiation apparatus can be operated by automatic operation by programming a treatment routine according to each treatment object.

<Irradiation start time>
In this embodiment, after administration of the porphyrin-containing preparation, the timing for starting microwave irradiation varies depending on the porphyrin-containing preparation used together. For example, during administration of porphyrins or 0.5 to 10 hours after administration is preferable, and 1 to 8 hours after is more preferable. This is because microwave irradiation is more effective after the porphyrins are accumulated at the cancer site, and it is desirable from the viewpoint of avoiding side effects on normal cells.

≪Action mechanism regarding synergistic effect of microwave and porphyrin-containing preparation≫
The action mechanism of the porphyrin-containing preparation of the present embodiment will be described in detail below mainly with respect to the synergistic effect with the microwave.

<Action mechanism of porphyrin-containing preparation>
The mechanism of action of the porphyrin-containing preparation is based on the binding of the porphyrin-containing preparation in the cell to the N-7 position of guanine and adenine, which are constituent bases of DNA such as cancer. When heavy atoms such as porphyrins are bonded to two DNA strands, a bridge is formed and DNA replication is inhibited. Moreover, since apoptosis is induced, it is considered that anticancer activity is expressed.

<Mechanism of cancer cell killing effect of microwave>
As described above, since microwaves raise the temperature intermittently for a short time, HSP (heat shock protein) is difficult to produce and kills cancer cells. In normal hyperthermia, since it warms slowly, HSP which acquires heat tolerance tends to increase. Therefore, since HSP cannot be performed, cancer cells cannot have heat resistance, and cell death due to heat is promoted. Furthermore, the action mechanism of microwave irradiation includes not only direct DNA damage, but also inhibition of AKT-mTOR protein, translation of mRNA via phosphorylation of 4E-BP1 and p70S6 kinase, suppression of autophagy, It suppresses the biosynthesis of ribosomes and the transcriptional activation that leads to mitochondrial metabolism and adipogenesis, causing apoptosis.

<Principle of synergism between microwave and porphyrin-containing preparation>
The synergistic action of the microwave and the porphyrin-containing preparation will be described in detail below.

  As described above, the microwave alone has a cancer cell killing rate of about 28%, and even 5-ALA and talaporfin used suitably in the present embodiment have been observed to inhibit cancer cells. As the mechanism of action, apoptosis of the AKT-mTOR system has been observed in the action of microwave alone (Motomura, T., et al. (2010), Evaluation of systemic external microwave hyperthermia for treatment of pleural metastasis in orthotopi lung cancer model. Oncology Reports 24: 591-598.). On the other hand, porphyrins are substances with strong cancer cell accumulation (Taraporfin interview form and aminolevulinic acid interview form). In addition, it is known that protoporphyrin is activated by microwave irradiation, and active oxygen ROS such as singlet active oxygen is produced, causing apoptosis of cancer cells (Susumu Nakajima et al., Et al. (1982) , generation of superoxide by microwave wave and cancer cell destruction effect, medical progress 122, 256-260).

  Furthermore, microwave irradiation promotes uptake by chelating heavy metals such as Zn and Cu existing in cells into porphyrins (Pineiro, M., (2014), Microwave-Assisted Synthesis and Reactivity of Porphyrins., Current Organic Synthesis, 11, 89-109.), They inhibit Capase-3, Caspase-8, etc. (Signe B., et al. (2005), Metalloporphyrins inactivate caspase-3 and -8., FASEB J. , 19, 1272-1279.). Caspases 3 and 8 have a function of activating PARP, which is an enzyme that repairs DNA. Therefore, microwave irradiation also contributes to inhibition of DNA repair of PARP by inhibiting the action of Caspases 3 and 8 through porphyrins (Weaver AN, (2013), Beyond DNA-repair : additonal functions of PARP1 in cancer., Frontiers in Oncology, 3, 1-11., Murai J., et al. (2012), Trapping of PARP1 and PARP2 by Clinical PARP inhibitors, Cancer Research 72, 5588-5599. And Tuli R., et al., (2014), Radiosensitization of Pancreatic Cancer Cells In vitro and In vivo through Poly (ADP-ribose) Polymerase Inhibition with ABT 888., Translational Oncology, 7, 439-445.

  That is, microwave irradiation is (1) direct apoptosis of tumor cells, (2) direct DNA damage with active oxygen as a synergistic effect on porphyrins, and (3) repair DNA damage. As a whole, it is considered that an extremely large synergistic effect with porphyrins is recognized by exerting the effect of inhibiting the activity of PARP.

<Applicable tumor site depth>
According to the present invention, the present invention can be applied to a deeper cancer than conventional PDT therapy. The depth of the microwave varies depending on the fat content of the tissue, but may be, for example, 0.5 cm or more from the body surface, and may be 1.0 cm or more. That is, the effect can be expected even when the distance from the body surface to the end of the tumor site is 0.5 cm or more, more specifically 1.0 cm or more.

<Application>
The target cancer is not particularly limited, but it should be a target even if it is a cancer or sarcoma that is not applicable in PDT therapy because of the above-mentioned depth of penetration and low damage to normal cells in the vicinity. Can do. For example, head and neck cancer, stomach cancer, colon cancer, rectal cancer, colon cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, bladder cancer, prostate cancer, uterine cancer, pharyngeal cancer, esophageal cancer, renal cancer, Examples include ovarian cancer, testicular cancer, and liposarcoma. In particular, high effects can be expected for colon cancer, rectal cancer, breast cancer, esophageal cancer, stomach cancer, head and neck cancer, and liposarcoma.

  Next, the present embodiment will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to these examples.

  In order to investigate the effect of microwave irradiation after administration of a porphyrin-containing preparation, an in vitro test was carried out on cell growth inhibition for MIAPaCa-2 pancreatic cancer cells. The following materials and equipment were used for this test.

<< Test Example 1 >>
Preparation used: Preparation containing porphyrin (Product name: 5-aminolevulinic acid (5-ALA) 1.5 g / vial, manufactured by Nobel Pharma)
cell:
(1) Cell line (MIAPaCa-2 pancreatic cancer cell (ATCC (registered trademark) CRL-1420 ^™ )
(2) Origin / Origin: Human pancreatic cancer-derived cell line (3) Source: ATCC (American Type Culture Collection)
Culture plate: Cell culture plate (12 holes) (model number: 353043, manufactured by Falcon)
Equipment used: Name (Microwave treatment device, manufactured by Technolink Co., Ltd.)

<Example 1>
In 12 wells of the culture plate, a cell line (5 × 10 ⁴ cells / mL) is seeded in Dulbecco's Modified Eagle's Medium (DMEM) medium (1.0 mL), and 18 hours later (hereinafter, time after cell seeding) And a test solution with a 5-ALA concentration of 1.0 μmol / mL was added to each 1.0 mL. After 24 hours (that is, 4 hours after 5-ALA administration), MW (microwave at a frequency of 2.45 GHz was obtained by the arrangement of the equipment as shown in FIG. 8 (distance between the center of the plate and the magnetron head was 30 cm). ) For the first irradiation. Thereafter, irradiation with MW for the second to third times was performed 48 hours and 72 hours later. Each MW irradiation was performed once for 7 seconds, 2 seconds, 7 seconds, 2 seconds, and 7 seconds (FIG. 8). Thereafter, after 74 hours, staining measurement was performed.

<Example 2>
The test was performed in the same manner as in Example 1 except that the concentration of 5-ALA to be added was 5.0 μmol / mL.

<Comparative Example 1>
Cell lines were seeded in McCoy's 5a medium and allowed to pass for 74 hours (control).

<Comparative example 2>
The test was performed in the same manner as in Example 1 (that is, only MW irradiation) except that 5-ALA was not added.

<Comparative Example 3>
The test was performed in the same manner as in Example 1 except that MW irradiation was not performed.

<Comparative Example 4>
The test was performed in the same manner as in Example 2 except that MW irradiation was not performed.

  Table 1 summarizes the above-described conditions.

  The test results are shown in Table 2 and FIG. The MIAPaCa-2 pancreatic cancer cell viability by microwave irradiation at the center of the plate (NO6, 7) was 72.09% when MW alone was irradiated when control (MW non-irradiated group) was 100%, 28% The survival rate was reduced. Assuming that the case where only 5-ALA 1 μmol / mL was added was 100%, the MW irradiation was reduced to half by 47.48%. In addition, even with 5-ALA of 5 μmol / mL, the survival rate was reduced to 51.37% by MW irradiation, and the interaction was clearly recognized.

Further, when IC ₅₀ was calculated, IC ₅₀ was 7.078 μmol / mL in the case of 5-ALA alone (FIG. 10). However, by MW irradiation, IC _{50 of} 5-ALA was 0.678 μmol / mL. Yes (FIG. 11), there is a difference of 10 times or more compared to non-irradiation with MW, and a synergistic effect was also observed from the IC ₅₀ aspect. The results are shown in FIGS. Note that the method of calculating the _{IC 50,} relative to the concentration of 5-ALA, taking the natural logarithm of MIAPaCa-2 pancreatic cancer cell viability was calculated by subtracting a regression line.

<< Test Example 2 >>
Preparation used: Preparation containing porphyrins (Product name: Rezaphyrin (Talaporfin sodium) 40 mg / mL, manufactured by Meiji Seika Pharma Co., Ltd.)
cell:
(1) Cell line (MIAPaCa-2 pancreatic cancer cell (ATCC (registered trademark) CRL-1420 ^™ )
(2) Origin / Origin: Human pancreatic cancer-derived cell line (3) Source: ATCC (American Type Culture Collection)
Equipment used: Name (Microwave treatment device, manufactured by Technolink Co., Ltd.)

<Example 3>
The test was conducted in the same manner as in Example 1, except that the porphyrin-containing preparation to be used was talaporfin and a test solution in which the concentration of added talaporfin was 30 μg / mL was added.

<Example 4>
The test was performed in the same manner as in Example 3 except that the concentration of talaporfin to be added was 100 μg / mL.

<Comparative Example 5>
The test was performed in the same manner as in Example 3 except that MW irradiation was not performed.

<Comparative Example 6>
The test was performed in the same manner as in Example 4 except that MW irradiation was not performed.

  Table 4 summarizes the conditions described above.

  The test results are shown in Table 5 and FIG. The MIAPaCa-2 pancreatic cancer cell viability (average value) by microwave irradiation at the center of the plate (NO.6, 7) is 100% when only 30 μg / mL of talaporfin is added. In this case, it was halved to 49.60%. In addition, the survival rate (average value) of cancer cells was 26.02% by MW irradiation at 100 μg / mL of talaporfin, and the survival rate decreased to ¼, and a synergistic effect was clearly observed.

Further comparison, calculation of _{IC 50,} when the talaporfin only, _{IC 50} is was 44.457μg / mL, the MW irradiation, _{IC 50} of talaporfin is a 15.162μg / mL, and MW unirradiated There was a difference of about 3 times, and a synergistic effect was recognized. The results are shown in FIGS. Note that the method of calculating the _{IC 50,} relative to the concentration of talaporfin take the natural logarithm of MIAPaCa-2 pancreatic cancer cell viability was calculated by subtracting the regression line.

<< Test Example 3 >>
In order to confirm the synergistic action with the porphyrin preparation by the focus irradiation of the microwave wave, the pancreatic cancer cell viability of MIAPaCa-2 other than the plate holes 6 and 7 of the 12-well plate shown in FIG. Calculation was performed under the conditions shown (calculated as the average value of the numerical values in the plate holes 1 to 5 and 8 to 12). The measurement was performed under the same conditions as in the examples and comparative examples shown in parentheses in Table 7 except for the position deviated from the center of the plate (plate holes 6 and 7). Table 7 shows the results of MIAPaCa-2 pancreatic cancer cell viability and its standard deviation.

  As shown in Table 7, the synergistic action with the porphyrin preparation by the microwave wave could not be confirmed at the site outside the resonance point of the microwave wave. From this, it was found that cell damage due to microwave irradiation was minimized outside the focus irradiation site (that is, corresponding to the normal site to be irradiated). Furthermore, from these results, it was presumed that the remarkable synergistic effect of the present invention is exhibited only at the site where the microwave wave resonates, for example, at the deep part of the irradiation target.

5 ... treatment target, 10 ... housing, 20 ... support base, 30 ... guide bar, 32 ... rotating plate, 35 ... moving part, 40 ... ball screw, 50・ ・ ・ Motor, 60 ... magnetron main body, 61 ... magnetron head, 62 ... micro electromagnetic wave oscillating unit, 65 ... magnetron, 70 ... distance measuring means, 75 ... temperature measuring means , 80 ... Distance adjusting means, 90 ... Holder, 100 ... Microwave irradiation device, 200, 210 ... Micro electromagnetic wave generation part, A, B ... Orbit, C ... Center point.

Claims (9)

  A porphyrin-containing preparation, which is a porphyrin-containing preparation used for irradiating the subject with a microwave after administering the porphyrin-containing preparation to a subject.   The irradiation is irradiation of microwaves from at least two or more directions on a specific part of the subject, and the irradiation is performed between the microwaves from the plurality of directions at the specific part. The porphyrin-containing preparation according to claim 1, which is carried out under a resonating condition.   The porphyrins-containing preparation according to claim 1 or 2, wherein the irradiation is pulsed irradiation with irradiation at a frequency of 1.5 to 5.0 GHz a plurality of times.   The porphyrin-containing preparation according to claim 2 or 3, wherein the specific site is a deep part of 0.5 cm or more from the body surface.   The porphyrin is at least one selected from 5-aminolevulinic acid and derivatives thereof, protoporphyrin IX and derivatives thereof, hematoporphyrin derivatives, benzoporphyrin derivatives, and talaporfin, and polymers thereof. 5. The porphyrin-containing preparation according to any one of 4 above.   The porphyrin-containing preparation according to any one of claims 2 to 5, wherein the specific site is a site where the malignant tumor of the subject exists.   A microwave irradiation apparatus, which is a microwave irradiation apparatus used for irradiating a subject to which a porphyrin-containing preparation has been administered. The microwave irradiation apparatus has two or more microwave irradiation portions;
The irradiation is irradiation of microwaves from at least two or more directions on a specific part of the subject, and the irradiation is performed between the microwaves from the plurality of directions at the specific part. The microwave irradiation apparatus according to claim 7, wherein the microwave irradiation apparatus is configured to be executed under a resonating condition.   The microwave irradiation apparatus according to claim 7 or 8, wherein the irradiation is pulsed irradiation with a frequency of 1.5 to 5.0 GHz.

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