WO2005120638A1

WO2005120638A1 - Combination of radio waves and pharmacologically active substances

Info

Publication number: WO2005120638A1
Application number: PCT/DE2005/001028
Authority: WO
Inventors: Jochen Kalbe; Georg Ludwig
Original assignee: Jochen Kalbe; Georg Ludwig
Priority date: 2004-06-09
Filing date: 2005-06-09
Publication date: 2005-12-22
Also published as: JP2008537489A; CA2567477A1; EP1753507A1; WO2005120638A8

Abstract

The invention relates to a combination of radio waves and pharmacologically active substances selected from the group containing a) monoclonal antibodies and/or b) tyrosine-kinase inhibitors and/or c) angiogenesis inhibitors and/or d) farnesyl-transferase inhibitors and/or e) topoisomerase-I or topoisomerase-II inhibitors and/or f) cytokine and/or g) antisense oligonucleotides, optionally together with at least one chemotherapeutic agent. The invention also relates to the use of said combination for the prophylaxis and/or treatment of cancer, tumours and metastases.

Description

Combination of radio waves with pharmacologically active substances

description

The invention relates to a combination of radio waves with pharmacologically active substances. The combination according to the invention can further comprise chemotherapeutic agents and is preferably used for the prophylaxis and / or treatment of tumors and metastases.

The treatment of cancer with various radiation methods has long been known and is state of the art. These include radiation with X-rays, gamma radiation and less energy-intensive radiation such as microwaves.

In addition to radiation with high-energy X-rays or radioactive radiation, there are alternative techniques for treating tissue with electromagnetic radiation: 1. Microwave, frequency range 400 to 2500 MHz 2. Ultrasound, frequency range 0.5 to 5 MHz 3. Radio frequency, frequency range 3 to 300 MHz 4. "Hot source" - hyperthermia, hot water 5th laser

Irradiation with radio waves is particularly suitable for local treatment and is carried out in Europe according to the guidelines of the ESHO (European Society of Hyperthermie Oncology) (Hand, JW Quality Assurance Guidelines for ESHO protocols, Int. J. Hyperthermia 5, 1989, 421-428) ,

Combinations of different radiation therapies with hyperthermia, preferably generated by microwave treatment, are known and have been investigated (Hehr, T., Current and Potential Role of Thermoradiotherapy for Solid Tumors, Onkologie, 2003, 26, 295-302; Seegenschmiedt MH, radiotherapy and hyperthermia - a new one Path in interdisciplinary tumor therapy, Radiology Yearbook (Günther ed), Springer, 161-171, 1994). The synergies of this combination therapy are currently being investigated and have not yet been sufficiently documented (van der Zee J, point-counterpoint: what is the optimal trial design to test hyperthermia for carcinoma of the cervix? Point: addition of hyperthermia or cisplatin to radiotherapy for patients with cervical cancer; two promising combinations - no definite conclusions, International Journal of hyperthermia, 2002, Vol. 18 (1), 19-24).

The combination of hyperthermia with chemotherapeutic agents is also a therapy method already in use (WO 93/18751, Liposome encapsulated taxol and method of using the same; Kuwano H., Preoperative hyperthermia combined with chemotherapy and irradiation for the treatment of patients with esophageal carcinoma, Tumori, 1995, Vol. 81 (1), 18-22; Rietbroek RC, Hyperthermia in combination with chemotherapy in gynecological cancers, Nederlands tijdschrift voor geneeskunde, 2002, Vol. 143 (2), p: 85-8; Colombo R. , Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma, Journal of Clinical Oncology, 2003, Vol. 21 (23), 4270-6).

In principle, several additional effects are postulated for treatment with chemotherapy through additional treatment with hyperthermia: On the one hand, this is an improved bioavailability of the chemotherapeutic agents in the tumor through improved transport in and to the tumor and, on the other hand, a higher effectiveness in the thermally already stressed and thus weakened Tumor.

Depending on the tumor and chemotherapeutic agent, different effects can occur, which also show that the additional treatment with hyperthermia does not show any benefit (van Bree C, Local hyperthermie treatment does not enhance mitoxantrone effectiveness for responses of a rat solid tumor regrowing after irradiation, Journal of Cancer Research and Clinical Oncology, 1996, vol. 122 (3), 147-53).

The object of the present invention is to provide a combination of electromagnetic radiation and substances which is suitable for the prophylaxis and / or treatment of cancer, tumors and metastases.

This problem is solved by the technical teaching of the independent claims. Further advantageous refinements, aspects and details of the invention result from the dependent claims, the description and the examples. Surprisingly, it was found that a combination of radio waves and certain substances is very suitable for the prophylaxis and treatment of cancer, tumors and metastases.

The above-mentioned substances are preferably at least one pharmacologically active substance and more preferably pharmacologically active substances used in cancer therapy.

In particular, these substances are active substances selected from the group comprising: a) monoclonal antibodies and / or b) tyrosine kinase inhibitors and / or c) angiogenesis inhibitors and / or d) famesyl transferase inhibitors and / or e) topoisomerase I or II inhibitors and / or f) cytokines and / or g) antisense oligonucleotides.

Therapeutic antibodies to be used according to the invention are monoclonal antibodies against tumor cells and metastases. These include antibodies such as Cetuximab, Trastuzumab, Alemtuzumab, Rituximab, Bevacizumab, EMD7200, Rencarex, HeFi-1, Apolizumab, Tositumomab, ABX-EGF, HuMAx-EGFR, Labetuzumab, Pemtumomab, Triab, Mab17-1A (Panore , MDX-220, MDX-447, MDX-H210, gemtuzumab ozogamicin, radiolabeled antibodies such as indium-111 (In-111) ibritumomab tiuxetan, yttrium-90 (Y-90) ibritumomab tiuxetan, anti-CD80 mAb, WX-G250RIT ( 131 iodine).

Tyrosine kinase inhibitors are molecules that prevent the function of the tyrosine kinase. This can be done by blocking the Epidermal Growth Factor Receptor (EGFR) such as B. ErB-1, ErB-2 (Her2 / Neu), ErB-3, ErB-4, or other receptors of transmembrane factors such as vascular endothelium growth factor (VEGF), fibroplast growth factor (FGF), platelet derived growth factor (PDGF ), Insulin Like Growth Factor (IGF-I) or Hepacotyte Growth Factor (c-met). This can be both antibodies and “small act as molecules. Examples of “small molecules” to be used according to the invention include Gefitinib, Imatinib, PKI-166, CI-1033, SU-6668.

Angiogenesis inhibitors are substances that suppress the growth of the blood supply to the tumor. These include e.g. B. Cilengitide, Neovastat, IM862, SU5415, SU5416, SU6668 and Suramin.

Famesyl transferase inhibitors are e.g. B. BMS214662 and R115777 (Zarnesta tipifarnib).

Examples of cytokines as immunomodulators are aldesleukin, interleukin-2, interleukin-12, interferons such as interferon-alpha 2a, interferon-alpha 2b, interferon beta, interferon gamma and recombinant tumor necrosis factors such as tasonermin.

To the antisense oligonucleotides z. B. AP12009 counted.

Chemotherapeutic agents to be used according to the invention

Folic acid antagonists such as methotrexate, antagonists of purine and pyrimidine bases such as fluorouracil, capecitabine, gemcitabine, cytarabine, pentostatin, cytosine arabinoside, mercaptopurine, fludarabine, cladribine, thioguanine, paclitaxel, nitrosourea, mitopinocincinophenoncinolamine, etoposinopinone, etopinosine trinoconcinol, etopinosine trinocinate, platinum Gramicidin D, ethidium bromide, emetine, mitomycin, tenoposide, colchicine, mithramycin, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, streptozotocin, alkylating cytostatics such as cyclophosphamide, ifanfulfatin, carbosulfatin, melanoplatinum, melanoplatinum, carbohydrate, melamine, carbohydrate, melamine, carbohydrate Oxaliplatin, procarbazine, dacarbazine, temozolomide, etoposide, teniposide, mitotic inhibitors such as vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, trofosfamide, chlorambucil, treosulfan, estramustine, nimustin, dicustinostomycininocininotinostin, antibinininocinininokinininocininotin, antibininocininokininin, antibininocininokinininocininotin, antibininocininotin, antibininocininotin, antibininocytin Doxorubicin (Adriamycin), Doxorubicin lipo, idarubicin and epirubicin, bleomycin, mitomycine, mitoxantron, amsacrin, actinomycin D, hormones and hormone antagonists such as Buselerin, Goselerin, Leuprorelin, Triptorelin, anti-estrogens such as Tamoxifen, aromatase inhibitors such as Aminoglutethestan, Testrozolanolan, Exact Cytostatics such as miltefosine, hydroxyurea, tretinoin, topoisomerase inhibitors such as camptothecin derivatives such as irinotecan or Hycamtin, topotecan or other chemotherapeutic agents such as imatinib, amsacrine, pentostatin, bexarotene and asparaginase.

The aforementioned chemotherapeutic agents can optionally be used together with the combination according to the invention.

Surprisingly, it was also found that radio waves (3 to 300 MHz) significantly increase the effectiveness of certain substances for combating cancer, tumors and metastases. In many cases this happens with a simultaneous reduction in the side effects of these substances. As

Substances include the above-mentioned pharmacologically active substances and more preferably the pharmacologically active substances used in cancer therapy and the chemotherapeutic agents.

The present invention therefore also relates to the use of radio waves to increase the activity of the aforementioned substances and / or to reduce the side effects of the aforementioned substances.

While increasing the activity of the lowering of the IC is meant, for example o- ₅ value of a pharmacologically active substance. However, an increase in activity also means that almost the same result is achieved with less pharmacologically active substances.

The reduction in side effects preferably affects chemotherapeutic agents (cytostatics) or the side effects caused by these active ingredients. The side effects of chemotherapy drugs are well known to those skilled in the art and pose serious problems in tumor therapy.

By using the combination according to the invention, the prospect of successful therapy is significantly greater and the quality of life of the patients is also significantly improved. It is also essential that treatment with

Radio waves occur in a non-invasive form, ie the electro-hyperthermia uses electrodes which are placed at a short distance above the skin and at a minimal distance from the tumor without the need for surgery and which irradiate the tumor in a targeted manner through the skin. Thus, the electrodes do not need to be introduced to the tumor, for example, by using a catheter. This reduces treatment costs and is much more pleasant for the patient and associated with a significantly lower risk.

The combination according to the invention is used in particular in the following types of cancer or tumor and metastasis: breast carcinomas, in particular recurrences after radiation and chemotherapy, skin cancers, such as basaliomas, spinaliomas, melanomas, skin metastases, all malignant tumors which are close to the body surface, soft tissue tumors , Endometrial cancer, cervical cancer, ovarian cancer or ovarian cancer, testicular cancer or vulvar cancer, germ cell tumors, prostate cancer, thyroid cancer, liver cell cancer, liver metastasis, colon cancer or colorectal cancer and non-small cell cancer, rectal cancer, rectal cancer, non-rectal cancer, rectal cancer, rectal cancer, rectal cancer, rectal cancer, rectal cancer Hodgkin's lymphoma, pancreatic cancer or pancreatic carcinoma, connective tissue tumor or soft tissue sarcoma, adenocarcinomas such as gastric, pancreatic, biliary or esophageal carcinomas, other gastric carcinomas, osteolytic carcinomas, and the like. osteoplastic carcinomas, renal cell carcinomas, malignancies of the gastrointestinal tract, brain tumors such as glioblastoma, astrocytomas, tumors of the ear, nose and ear area, malignant neoplasm, neuroblastoma, choroidal melanoma, acute leukemia,

Acoustic neuroma, ampoule carcinoma, anal carcinoma, bladder cancer, breast cancer, Burkitt's lymphoma, corpus carcinoma, CUP syndrome,

Small intestine cancer, small intestine tumors, ependymoma, epithelial cancers, ewing tumors, gastrointestinal tumors, gallbladder cancer, uterine cancer, cervical cancer, gynecological tumors, haematological neoplasia, hairy cell leukemia, urethral cancer, skin cancer, brain metastasis, brain metastasis

Pituitary tumor, carcinoids, Kaposi's sarcoma, larynx cancer, bone cancer, colon carcinoma, craniopharyngioma, mouth and lip cancer, leukemia, eyelid tumor, lymphoma, rectal cancer, medulloblastoma, melanoma, meningioma, Hodgkin's disease, neuroma, nasal cancer, fungus Oligodendroglioma, esophageal carcinoma, osteosarcoma, penile cancer, plasmacytoma, pharynx cancer, retinoblastoma, vaginal cancer, Schneeberger disease, T-cell lymphoma (mycosis fungoides), thymoma, tube carcinoma, eye tumors, urethral cancer, urological cancer and urinary cancer, urothelial cancer, urothelial cancer, urothelial cancer.

In the combination according to the invention, the radio waves are in a frequency range from 3 to 30 MHz, preferably 5 to 20 MHz and particularly preferably 10 to 15 MHz. A frequency of 13.56 MHz is particularly preferred. Furthermore, the radio waves are preferably generated by capacitive coupling.

Furthermore, the present invention relates to a method for the prophylaxis and / or treatment of cancer, tumors and / or metastases by using the combination according to the invention. The tumors are preferably cancerous and benign tumors.

In this method for the prophylaxis and / or treatment of cancer, tumors and / or metastases, radio waves in combination with at least one active substance are selected from the group a) monoclonal antibodies and / or b) tyrosine kinase inhibitors and / or c) angiogenesis Inhibitors and / or d) farnesyl transferase inhibitors and / or e) topoisomerase I or II inhibitors and / or f) cytokines and / or g) antisense oligonucleotides

used. The radio wave field is preferably applied extratumorally.

As already mentioned, one or more chemotherapeutic agents can be administered in addition to the administration of one or more of the active ingredients mentioned under ^a ) ~ 9).

The chemotherapy drugs are preferably selected from the group listed above. In the case of the active substances mentioned under a) - g), the abovementioned ones are also suitable.

The radio wave field is preferably generated by capacitive coupling and is also preferably applied extratumorally. Treatment with radio waves is carried out with devices that generate the radio wave field through a capacitive coupling. In the case of capacitive coupling, the tissue is located between two electrodes, which are fed via an AC voltage source and as Capacitor plates serve. The electromagnetic field builds up between these electrodes in the form of a medium-wave radio wave.

The radio wave field is preferably applied extratumorally, particularly preferably extratumorally and extracorporeally. This means that, as a rule, no invasive interventions for treatment with radio waves are necessary, although electrodes that are difficult to access can also be brought near the tumor in the case of invasive electrodes. The method according to the invention for the treatment of cancer, tumors and / or metastases thus uses an external source for radio waves, which is combined with the administration of at least one of the antitumor agents mentioned herein. Thus, the present invention discloses the use of at least one preferably extratumoral and extracorporeal source for radio waves together with at least one of the anti-cancer agents mentioned herein for generating a combination which is suitable for the treatment of cancer, tumors and / or metastases. The at least one antitumor agent is usually administered, for example, by inhalation or intravenously, intraperitoneally, intramuscularly, subcutaneously, mucocutaneously, orally, rectally, transdermally, topically, buccally, intradermally, intravaginally, intragastricly, intracutaneously, intranasally, intrabuccally, percutaneously or sublingually.

The frequencies of the radio waves or the radio wave field are in the range from 3 to 30 MHz, preferably from 5 to 20 MHz, particularly preferably from 10 to 15 MHz and particularly preferably at 13.56 MHz, i.e. at the frequency released in Europe for such applications.

In the described method, the radiation with radio waves and the application of the active ingredient can take place simultaneously or with a time delay, with 72 hours, preferably 48 hours and particularly preferably less than 24 hours lying between the administration of the active ingredient and the treatment with radio waves.

Depending on the indication, it is preferred to carry out the radiation with radio waves at the same time as the administration of the active ingredient or with a time delay. The preferred periods for the delayed application of radiation and application of the active ingredient are 12, 24, 36, 48, 60 and 72 hours, with 24, 48 and 72 hours being particularly preferred. For those skilled in the art, only a few attempts are required to determine the optimal sequence of radiation and administration of the to find out at least one active ingredient together with at least one chemotherapeutic agent.

Furthermore, the at least one active ingredient mentioned under a) to g) can also be administered at the same time or with a delay with the at least one chemotherapeutic agent. The time difference can range from a fraction of an hour to a few days. However, simultaneous administration is preferred.

The active ingredients and chemotherapeutic agents are applied in customary formulations and preferably systemically.

Description of the figures: FIG. 1 shows the course of treatment within 90 days of treatment of colon carcinomas with cetuximab and with cetuximab in combination with electrohyperthermia (EHT), (CEA and CA 19-9 are tumor markers)

FIG. 2 shows the course of treatment over several months of therapy for pancreatic carcinoma with liver metastases using a combination of Gemzar and cetuximab and local electrohyperthermia (EHT).

Examples

Example 1 :

Electro hyperthermia:

Hyperthermia for the treatment of cancer means the targeted heating of the carcinogenic tissue in order to kill the cancer cells. The treatment temperature is an important parameter. However, the cells protect themselves from thermal destruction with so-called heat shock proteins (HSP). In electrohyperthermia, the target tissue is heated by means of electricity, which results in less heat shock protein synthesis in the cells than in the conventional hyperthermia process, and tumor cells can thus be destroyed more effectively.

For electrohyperthermia, a device with a precisely set working frequency of 13.56 MHz of the following specification was used: Working principle: application of capacitively coupled radio frequencies

Method: electrohyperthermia or loco-regional electrohyperthermia

Radiated power in the range of 30 - 150 W transmitter: water-bolus

Control parameters of treatment: equivalent temperature

A possible principle of operation of electrohyperthermia:

An external electrical field can maintain temperature gradients of 1 K / m and thus generate a permanent heat flow of 1500 nW / m ² , which is significantly higher than the natural heat flow (20nW / m ² ) through the target cell membranes. This gradient and the resulting heat flow can cause currents of 150 pA / m ² through the membrane, primarily by the flow of Na ⁺ into the cell; these currents are significantly stronger than the typical sodium current of 123 pA / m ² from the cell. As a result, the membrane is depolarized and thus destabilized and the Na ⁺ / K ⁺ pump is strengthened. ATP is required for this, which further increases the heat generation on the membrane. The membrane is far more permeable to water than to ions, so water is the largest component transported in thermodynamic coupling. A thermal flow of 0.001 K / nm can therefore build up a pressure of up to 1.32 MPa. Because malignant cells are usually due to the higher

Phospholipid concentrations have relatively rigid membranes destroyed increased pressure selectively the malignant cells before it affects the healthy cells. This principle of action has not yet been scientifically verified and should therefore be regarded as a hypothesis.

During treatment, an automatic adjustment (standing wave ratio, SWR <1.1) guarantees a standing electrical effect. As a consequence of the relatively low field strength (max. 500 V / m), which is applied between the electrodes and the capacitor (applicator for coupling to the body area to be treated), there is a reduced penetration (approx. 10 ⁶ V / m) into the membrane-protected cell interior.

The equipment developed for electro-hyperthermia includes an applicator in which the patient forms the dielectric in the capacitor and thus becomes part of the precisely adapted electrical resonance circuit, which enables the standing wave ratio to be set with high precision.

The electrohyperthermal device carries out the exact adjustment and adjustment as well as all fine adjustments that normally have to be carried out by people, and continuously measures the electrical parameters in order to always control the process. In order to measure the temperature of the treated tissue, the measured absorbed energy as well as the impedance is used. The applicator is adjusted and adjusted based on electrodynamic calculations. A relatively minor one

Total energy can be used for the treatment due to the good selectivity and the precisely aligned heat absorption.

Furthermore, the surface of the capacitor, which is used for capacitive coupling with the patient, is well cooled in order to avoid burns to the skin and to enable the use of a higher treatment energy without a simultaneous risk of overheating. Usually, the thermal energy is not sufficient to heat the skin to more than 40 ° C.

Patients are treated by placing the electrode (s) as close as possible to the surface of the skin while keeping the minimal distance from the tumor. The duration of treatment is one hour for three days a week. It is essential that no side effects were observed during or after treatment. Example 2:

Treatment of colon cancer with cetuximab and with cetuximab in combination with electrohyperthermia.

Four patients with metastatic colorectal cancer (mCRC) in a comparable stage (CEA ~ 6000 ng / ml) were divided into two groups.

Each group was treated with the monoclonal antibody cetixumab (400 mg / m ² initial dose, 250 mg / m ² weekly dose) and 2 of the 4 patients additionally with local electro-hyperthermia three days a week (Monday, Wednesday and Friday) for one hour each treated. Treatment was continued for 10 weeks.

FIG. 1 clearly shows that the CEA after 60 days was significantly lower in the patients with additional electrohyperthermal treatment than in the patients who had only received the antibody cetuximab.

Example 3:

Therapy of pancreatic carcinoma with liver metastases using a combination of Gemzar and cetuximab and local electro-hyperthermia.

A patient with metastatic pancreatic cancer was treated with a combination of Gemzar (1000 mg / m ² ) and cetuximab (400 mg / m ² initial dose, 250 mg / m ² weekly dose) for 7 months. During this treatment, the tumor markers CEA and CA 19-9 rose continuously. In the eighth month there was also one

Electro hyperthermia treatment performed. The additional treatment with electrohyperthermia was given three days a week for one hour each. The dose of Gemzar and cetuximab administered remained unchanged during this time.

Figure 2 clearly shows that the values of both tumor markers decreased significantly from the time of the additional treatment with local electrohyperthermia. Further examples:

Experiments according to Example 2 are currently being carried out on the following tumors:

Cervical tumor, non-Hodgkin carcinoma, melanoma, rectal carcinoma, neck and neck tumor, soft tissue sarcoma, lung cancer, bladder cancer, breast cancer, recurrent breast cancer, small cell lung cancer, glioblastoma, gastric cancer and esophageal cancer.

The following substances are used as active ingredients, which are administered in addition to electrohyperthermia:

Vincristine, doxorubicin, epirubicin, imatinib, rencarex, cilengitide, neovastat, interferon gamma, dacarbazine, cyclophosphamide, daunorubicin and interleukin.

First results show comparable positive results with FIG. 1.

It is pointed out that electrohyperthermia is used as a non-invasive treatment method and the electrical field is applied from the outside, so that the treatment is simple and gentle for the patient.

Claims

claims

1. Combination of radio waves with at least one active ingredient selected from the group a) monoclonal antibodies and / or b) tyrosine kinase inhibitors and / or c) angiogenesis inhibitors and / or d) farnesyl transferase inhibitors and / or e) Topoisomerase I or II inhibitors and / or f) cytokines and / or g) antisense oligonucleotides.

2. The combination of claim 1, further comprising at least one chemotherapy agent.

3. Combination according to claim 2, wherein the at least one chemotherapeutic agent is folic acid antagonists, methotrexate, antagonists of purine and pyrimidine bases, fluorouracil, capecitabine, gemcitabine, cytarabine, pentostatin, cytosine arabinoside, mercaptopurine, fludarabine, cladribine and tioguanine Cytostatics, cyclophosphamide, ifosfamide, melphalan, thiotepa, busulfan, cisplatin, carboplatin, oxaliplatin, procarbazine, dacarbazin, temozolomide, etoposide, teniposide, mitotic inhibitors, vinblastine, vincristine, vindesin, vinorelucin, docfilinstramosilaxinamidosulfonametaxanilamidaxamidylamidylamidilamidylamidaxamidilamidylamidilamidolamidylamidilamidolamidylamidolamidylamidolamidylamidylamidylamidolamidylamidylamidylamidylamidylamidylamidylamidylamidylamidylamidylamidylamidylamidylamidylamidylamylamidylamylamidylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamate Nimustine, Carmustin, Lomustin, cytostatic antibiotics such as dactinomycin, anthracycline, daunorubicin, doxorubicin (adriamycin), doxorubicin lipo, idarubicin, epirubicin, bleomycin, mitomycine, mitoxantrone, amsacrormininininininone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone, actinone hormone , Anti-estrogens, tamoxifen, aromatase inhibitors, amino glutethimide, anastrozole, letrozole, exemestane, formestane, testolactone, glucocorticoids, miltefosine, hydroxyurea, tretinoin, topoisomerase inhibitors, camptothecin derivatives, irinotecan, hycamtin, topotecan, imatinib and amsacrinarine pentane.

4. Combination according to one of claims 1-3, wherein the radio waves are in the frequency range from 3 to 30 MHz, preferably 5 to 20 MHz and particularly preferably 10 to 15 MHz.

5. Combination according to one of claims 1-4, wherein the radio wave field formed by the radio waves is generated by capacitive coupling.

6. Combination according to any one of claims 1-5, wherein the monoclonal antibodies, tyrosine kinase inhibitors, angiogenesis inhibitors, farnesyl transferase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, cytokines and / or antisense oligonucleotides are selected from the group comprising cetuximab, trastuzumab, alemtuzumab, rituximab, bevacizumab, EMD7200, Rencarex, HeFi-1, apolizumab, tositumomab, ABX-EGF, HuMAx-EGFR, labetuzumab, pemtumomab, triab, Mab17-1A (PanX -210, MDX-220, MDX-447, MDX-H210, gemtuzumab, ozogamicin, radiolabeled antibodies, indium-111 (In-111) ibritumomab tiuxetan, yttrium-90 (Y-90) ibritumomab tiuxetan, anti-CD80 mAb, WX -G250RIT (131 iodine), Gefitinib, Imatinib, PKI-166, CI-1033, SU- 6668, Cilengitide, Neovastat, IM862, SU5415, SU5416, Suramin, BMS214662, R115777 (Zarnesta tipifarnib), Aldesleukin, Interleukteruk-2 -12, interferons, interferon-alpha 2a, interferon-alpha 2b, interferon beta, interferon gamma, Tasonermin, AP12009.

7. Use of the combination according to one of claims 1-6 for the prophylaxis and / or treatment of cancer, cancerous and / or benign tumors and metastases.

8. Use according to claim 7, wherein the cancer, the tumors and metastases are breast cancers, in particular recurrences after radiation and chemotherapy, skin cancers, such as basaliomas, spinaliomas, melanomas, skin metastases, all malignant tumors which are close to the body surface , Soft tissue tumors, endometrial cancer, cervical cancer, ovarian cancer or ovarian cancer, testicular cancer or vulvar cancer, germ cell tumors, prostate cancer, thyroid cancer, liver cell cancer, liver metastases, colon cancer or colorectal cancer, non-cancerous, colorectal cancer, non-cancerous cancer, colorectal cancer, non-cancerous cancer Lymph gland cancer or Hodgkin and non-Hodgkin lymphoma, pancreatic cancer or pancreatic carcinoma, connective tissue tumor or soft tissue sarcoma, adenocarcinoma such as gastric, pancreatic, bile-esophageal carcinoma, other gastric carcinoma, osteolytic carcinoma. u. osteoplastic carcinomas, renal cell carcinomas, malignancies of the gastrointestinal tract, brain tumors such as glioblastoma, astrocytomas, tumors of the ear, nose, and throat, malignant neoplasm, neuroblastoma, choroidal melanoma, acute leukemia, acoustic cancer, cancer of the anus, bladder cancer, bladder cancer Lymphoma, corpus carcinoma, CUP syndrome, small bowel cancer, small bowel tumors, ependymoma, epithelial cancers, Ewing tumors, gastrointestinal tumors, gallbladder cancer, uterine cancer, cervical cancer, gynecological tumors, haematological neoplasia, hairy cancer, skin cancer, skin cancer, skin cancer, leukemia cancer , Kaposi's sarcoma, larynx cancer, bone cancer, colon carcinoma, craniopharyngioma, cancer of the mouth and lip, leukemia, eyelid tumor, lymphoma, rectal cancer, medulloblastoma, melanoma, meningioma, Hodgkin's disease, mycosis fungoides, nasal cancer, neurocancer cancer, neurocancer cancer, neurocancer cancer, neurocancer cancer, neurocancer cancer, neurocancer cancer, neurocancer cancer, neurocancer cancer, neurocancer cancer, neurocancer cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer, neuroma cancer and neuroma cancer , Osteosarcoma, P ice cancer, plasmacytoma, throat cancer, retinoblastoma, vaginal cancer, Schneeberger disease, T-cell lymphoma (mycosis fungoides), thymoma, tube carcinoma, eye tumors, urethral cancer, urological tumors, urothelial cancer, Wilms tumor and / or tongue cancer.

9. Use according to claim 7 or 8, wherein the radio waves are used simultaneously with the active ingredient or up to 72 hours, preferably 48 hours and particularly preferably up to 24 hours later.

10. Use according to any one of claims 7-9, wherein the radio wave field generated by the radio waves is applied extratumorally.

11. Use of radio waves to increase the activity of an active ingredient selected from the group comprising a) monoclonal antibodies and / or b) tyrosine kinase inhibitors and / or c) angiogenesis inhibitors and / or d) farnesyl transferase inhibitors and / or e) topoisomerase I or II inhibitors and / or f) cytokines and / or g) antisense oligonucleotides and / or h) chemotherapeutic agents.

12. Use of radio waves to reduce the side effects of chemotherapy drugs.

13. Use according to one of claims 11 or 12, wherein the chemotherapeutic agents are selected from the group comprising: folic acid antagonists, methotrexate, antagonists of purine and pyrimidine bases, fluorouracil, capecitabih, gemcitabine, cytarabine, pentostatin, cytosine arabinoside, mercaptopurine, fludarabine, Cladribine, thioguanine, paclitaxel, nitrosourea, etoposide, campathecin, bleomycin, plicamycin, mitoxantrone, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, tenoposide, colchicine, mithramycin, tolodroprocainolone, 1-dehydrocortolone, 1-dehydrocortolone, 1-dehydrocortainone, 1-dehydrocortainone Puromycin, streptozotocin, alkylating cytostatics, cyclophosphamide, ifosfamide, melphalan, thiotepa, busulfan, cisplatin, carboplatin, oxaliplatin, procarbazine, dacarbazine, temozolomide, etoposide, teniposide, mitotic inhibitors, vinblastine, vincrininlaxin, vincristinitoxin, vincristinitoxin, vincrininloxin, vincristinelax , Treosulfan, estramustine, nimustine, carmustine, lomustine, cytostat Effective antibiotics such as dactinomycin, anthracycline, daunorubicin, doxorubicin (adriamycin), doxorubicin lipo, idarubicin, epirubicin, bleomycin, mitomycine, mitoxantrone, amsacrine, actinomycin D, hormones and hormone leuromatin, anti-melonin anti-toxin, anti-hormone anti-toxin, anti-inflammatory drugs, anti-inflammatory drugs, anti-inflammatory drugs , Aminoglutethimide, anastrozole, letrozole, exemestane, formestane, testolactone, glucocorticoids, miltefosine, hydroxyurea, tretinoin, topoisomerase inhibitors, camptothecin derivatives, irinotecan, hycamtin, topotecan, imatinib and aspatinarotenase, amatinacrine.

14. Use according to any one of claims 11-13, wherein the monoclonal antibodies, tyrosine kinase inhibitors, angiogenesis inhibitors, farnesyl Transferase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, cytokines and / or antisense oligonucleotides are selected from the group comprising cetuximab, trastuzumab, alemtuzumab, rituximab, bevacizumab, EMD7200, Rencarex, HeFi-1, Apositumabab ABX-EGF, HuMAx-EGFR, Labetuzumab, Pemtumomab, Triab, Mab17-1A (Panorex), MDX-210, MDX-220, MDX-447, MDX-H210, Gemtuzumab, Ozogamicin, radiolabeled antibodies, Indium-111 (In— 111) Ibritumomab Tiuxetan, Yttrium-90 (Y-90) Ibritumomab Tiuxetan, Anti-CD80 mAb, WX-G250RIT (131Jodine), Gefitinib, Imatinib, PKI-166, CI-1033, SU- 6668, Cilengitide, Neovastat, IM862, SU5415, SU5416, Suramin, BMS214662, R115777 (Zarnesta tipifarnib), aldesleukin, interleukin-2, interleukin-12, interferons, interferon-alpha 2a, interferon-alpha 2b, interferon beta, interferon gamma, tasonermin, AP12009.

15. Use according to any one of claims 11-14, wherein the radio waves are in the frequency range from 3 to 30 MHz, preferably 5 to 20 MHz and particularly preferably 10 to 15 MHz.

16. A method for the prophylaxis and / or treatment of cancer, tumors and / or metastases by radio waves in combination with at least one active ingredient selected from the group a) monoclonal antibodies and / or b) tyrosine kinase inhibitors and / or c) angiogenesis Inhibitors and / or d) farnesyl transferase inhibitors and / or e) topoisomerase I or II inhibitors and / or f) cytokines and / or g) antisense oligonucleotides are used.