EP2496229A1

EP2496229A1 - Pharmaceuticals containing choline

Info

Publication number: EP2496229A1
Application number: EP10771780A
Authority: EP
Inventors: Ernst-Maria App
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-11-06
Filing date: 2010-11-03
Publication date: 2012-09-12
Also published as: CA2780199A1; JP2013510126A; DE102009053157A1; US20130058922A1; WO2011054875A1

Abstract

The invention relates to pharmaceuticals in particular for intravenous administration, containing choline or pharmaceutically acceptable salts or analogs thereof. The invention further relates to pharmaceuticals, in particular for intravenous administration, containing choline or pharmaceutically acceptable salts or analogs thereof, alone or in combination with vitamin C and/or L-arginine and/or vitamin D3 (cholecalciferol) for use in fighting CTCs, DTCs or inactive leukocyte precursors in the blood and bone marrow.

Description

Medicaments containing choline

The invention relates to pharmaceutical compositions containing choline or pharmaceutically acceptable salts and analogs thereof for use in the control of blood circulating tumor cells (CTCs) and disseminated tumor cells in bone marrow (DTCs) or morphologically undifferentiated and nonfunctioning leukocyte precursors in blood and bone marrow.

More particularly, the present invention relates to pharmaceutical compositions for intravenous administration containing choline or pharmaceutically acceptable salts and analogs thereof for use in the early treatment of a tumor disease in patients without a manifest primary tumor in existing CTCs, DTCs or morphologically undifferentiated and nonfunctioning leucocyte precursors in the blood and bone marrow.

The invention further relates to medicaments, in particular for intravenous administration, containing choline or pharmaceutically acceptable salts and analogs thereof for use in tumor therapy for the reduction of metastasis risk or for the prophylaxis and early treatment of metastases (distant metastases), as well as in the therapy of leukemias.

In addition, the invention relates to pharmaceutical compositions, in particular for intravenous administration, containing choline or pharmaceutically acceptable salts and analogs thereof, for use in tumor therapy when, after surgical, radiotherapy or chemotherapy, diagnosing a tumor (no detection of tumor and metastases) by imaging although CTCs or DTCs are still present in the blood or bone marrow (delayed therapy), and in the treatment of conventional criteria without success tumor patients treated for ultima ratio therapy.

The invention further relates to medicaments, in particular for intravenous administration, containing choline or pharmaceutically acceptable salts thereof in combination with vitamin C and / or L-Argi in and / or vitamin D3 (cholecalciferol) or pharmaceutically acceptable salts thereof.

Tumor diseases according to the present invention are in particular carcinomas, sarcomas, neuroendocrine tumors, hemato-oncological tumors such as leukemias and lymphomas, as well as dysontogenetic tumors, i. both solid tumors and tumors of the hematopoietic system.

Prior art UWUI II ι ιυιιΓι uui i iciib Diö v iicii ι ιιΠ B ₄ UNU in CMEI eu OCI ιΓιι ικι ι duui i cus> among other things, is referred to J, it is actually not an essential nutrient choline is in monogastric mammals by the food since choline is present as part of phosphatidylcholines in the cell membrane.

When adequately supplied with amino acids, choline can normally be taken from the diet in physiologically sufficient quantities and formed in the body. For example, 5 grams of lecithin contains 1 gram of phosphatidylcholine, which should meet the minimum daily requirement. However, ingestion of choline into the human body may be affected by ingestion of certain substances such as sugar, alcohol and tea, while intake of folic acid, inositol and vitamin B12 may assist in the absorption of choline. In case of stress, it can lead to increased consumption, which then leads to choline deficiency. Therefore, improper diet, disease and stress lead to choline deficiency, which can be offset by the administration of the drug of the invention in the milieu interieur.

As a component of phosphatidyl-Gholm (lecithin), choline is ubiquitous in cell membranes and thus contained in all cells of the body. The literature describes the beneficial effect of choline on memory and concentration.

Choline is also considered to play a role in the metabolism and transport of triglycerides and other fats. As such, it is also used in oral therapy to aid the liver and bile function in fat utilization and to lower cholesterol levels. Due to the above properties, choline is also used as an oral nutritional supplement in capsules of up to 200 mg.

From nuclear spin spectroscopic studies it is known that the concentration of choline in the prostate cancer cells is significantly increased compared to normal cells. Therefore, choline in the form of C-1 1-choline, administered intravenously, is used for diagnostic imaging of prostate cancer.

In Giambarresi et. al. (Br. J. Cancer (1982) 46, 825-829) it is described that a choline-free diet favors the development of liver carcinomas in the mouse model.

Becker J., Journal of Cancer Research, 1948, Vol. 56, pp. 171-175 describes the use of choline as a chemotherapeutic agent in manifest malignant tumors.

WO 94/06413 discloses the use of compounds of the class of trimethylamine oxides for the prophylaxis of cancer.

In Xu et. al. (The FASEB Journal, published online on July 27, 2009: High intakes of choline and betaine reduce breast cancer mortality in a population-based study) describes a study examining the relationship between the development of breast cancer and the oral intake of choline and betaine. This article postulates a prophylactic effect against breast cancer by high oral intake of choline and betaine. In these patients, a total amount of choline taken from the diet was calculated to be between <196.5 mg / day and> 455.8 mg / day. Furthermore, Xu, et al., FASEB Journal 2008; 22: 2045-2052 that in one study, breast cancer risk was inversely proportional to the amount of choline ingested with food.

It has recently become known that circulating tumor cells can be detected not only in a clinically manifest tumor disease in the blood, but also in advance, before a tumor can be detected by imaging techniques.

The detection of tumor circulating tumor cells (CTCs) is of particular importance in tumors, as the blood reflects a dynamic process. The survival time of 24 hours of CTCs in the blood is relatively short, such. Patel et al. 2002, Ann Surg 235 (2): 226-31. Accidental detection of these cells seems unlikely unless there is a permanent influx of tumor cells. Therefore, CTCs are most likely to be detected during ongoing tumor development, which, in addition to predicting the prognosis, also allows assessment of therapeutic outcome.

This relationship has been demonstrated in a variety of clinical studies, such as By, inter alia, Stathopoulou A., et al. (2002), "Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance." J Clin Oncol 20 (16): 3404-12. Xenidis et al. (2003), "Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer" Ann Oncol 14 (6): 849-55, Giatromanolaki et al. (2004), "Assessment of highly angiogenic and disseminated in peripheral blood disease in breast cancer patients predicts resistance to adjuvant chemotherapy and early relapse." I tJ Cancer 108 (4): 620-7 and Jotsuka T. et al. (2004), "Persistent evidence of circulating tumor cells detected by means of RT-PCR for CEA mRNA predicts early relapse: a prospective study in node-negative breast cancer." Surgery 135 (4): 419-26. Both disseminated tumor cells in the bone marrow (DTCs) and in the blood (CTCs) are thus responsible for several forms of solid tumors, eg. Breast cancer, an early marker of primary tumorigenesis and possible metastasis, as well as a poor survival prognosis for diseased individuals.

A variety of different methods for determining CTCs and DTCs are known (see Riethdorf et al., International Journal of Cancer, Vol. 123, Issue 9, pp. 1991-2006 (November, 2008).

As stated above, it is known that CTCs and DTCs not only occur in clinically evident, manifest tumors. Thus, CTCs were observed even in undetectable tumors in isolated patients. Again, the CTCs are considered to be a surrogate marker for the presence of a minimal or developing tumor disease (Hirsch-Ginsberg (1998) Ann. Rev. Med. 49. 1 1 1-122).

It is known from the prior art that the tumor size positively correlates with the number of CTCs in the blood, but imaging techniques (such as CT / NMR / PET / sonography) for tumor diagnosis have a resolution (detection limit) which is best Case is 5 mm. At this time, however, there are already more than 500,000 tumor cells in the field. Smaller tumors can therefore not be detected by imaging techniques.

However, CTCs are <5 mm even with the smallest tumors, i. already detectable in the early stages of the tumor and in the blood clinically with imaging techniques (such as CT / NMR / PET / sonography) yet undetectable tumors.

CTC diagnostics is therefore used for the early diagnosis of tumors that are not yet detectable with imaging techniques: such. The Kuhn Lab · 10550 North Torrey Pines Road · GAC-1200 · La Jolla · CA • 92037; Zeidmann I: The Fate of Circulating Tumor Cells Passage of cells through capillaries, Cancer Re 21 (1961) 38-39 and Hirsch-Ginsberg C. Annu Rev Med. 1998: 49: 1 1 1 -22. Detection of minimal residual disease: relevance for diagnosis and treatment of human malignancies).

CTCs also provide information on seeding, the seeding of CTCs from tumors, and therefore also provide better indication of lymph node status (afflicted or not) in cancer patients compared to imaging techniques.

CTC diagnostics offers many advantages over conventional tumor diagnostics, as it allows a much more differentiated diagnosis.

In the past, immediate therapy success during and after therapy could only be determined by tumor markers such as CEA, PSA, CA15-3, CA125, CA19-9, NSE, TPA and CYFRA21-1.

A decrease in these tumor markers during or after therapy is attributable to a therapy requirement. However, if these tumor markers increase during or after a therapy, no distinction can be made between the success or failure of the disease (progression of the tumor disease), since in both cases the tumor marker generally increases. With the introduction of CTC detection, a differentiated diagnosis is now possible.

A simultaneous increase in tumor markers and increase in CTCs means a therapy failure (progression of the tumor disease).

An increase in tumor markers and a concomitant decrease in CTCs means a therapeutic success: The increase in tumor markers correlates here with an increased release of proteins from the tumor cells as they die off through therapy, and thus fewer CTCs are detectable.

Only both detection methods in combination therefore provide accurate information about the underlying events. Description of the invention

In contrast, the present invention provides a drug which is directed directly to disseminated tumor cells in the blood as well as in the bone marrow as a therapeutic target in order to counteract a manifest primary tumor of metastasis, in particular of solid tumors by a timely therapy (distant metastasis). Since CTCs are already found in the blood prior to the conventional detection of tumors, an early therapy is also provided in patients with CTCs without a manifest primary tumor.

In addition, the present invention provides a pharmaceutical composition for use in early or late relapse therapy when, after surgical removal of the tumor or radiation or chemotherapy, complete remission (ie, no detection of tumor and metastases) is diagnosed by imaging techniques, although always in the blood still CTCs are present. Another object of the invention includes end-stage therapy for tumor diseases, i. in patients who have exhausted the repertoire of conventional therapeutic regimens without therapeutic success (i.e., in well-treated patients) for ultima ratio therapy.

The present invention is based on the surprising discovery that choline or pharmaceutically acceptable salts and analogs thereof act directly on the CTCs, DTCs and pathologically altered leukocytes and their nonfunctional precursors in the blood and bone marrow.

Since they are detectable prior to the formation of metastases and are detectable even in small tumors even before the primary tumor, CTCs and DTCs can thus be considered as a separate cancer entity or at least have their own cancer quality, which is not necessarily and not linear with the primary tumor or metastases related. If CTCs are already detectable in the early phases of a tumor disease, a therapy can also be carried out sooner, with an expected better therapeutic outcome initially independent of the primary tumor. Thus, the pharmaceutical composition of the present invention enables the treatment of cancers at an early stage, at a time when the cancer is not yet clinically manifest and yet can not be detected by imaging techniques such as CT, NMR, PET or sonography.

According to the current conventional medical understanding this can also be called early therapy.

Thus, it has now surprisingly been found that choline or pharmaceutically acceptable salts and analogues thereof can be used as drugs for use in the early treatment of a tumor disease in patients without manifest primary tumor in existing CTCs, DTCs or dysfunctional leucocyte precursors in the blood and bone marrow.

Since CTCs and DTCs are often present even in the case of complete remission of a tumor, the medicament according to the invention can also be used for early relapse therapy or late therapy.

In addition, it has now surprisingly been found that choline or pharmaceutically acceptable salts and analogues thereof can be used as drugs for use in tumor therapy to reduce the risk of metastasis or for the early treatment of metastases, as well as in the therapy of leukemias.

Tumor diseases according to the invention are in particular breast cancer, prostate cancer, pancreatic cancer, gastrointestinal cancer, skin cancer such as malignant melanoma, sarcoma such as histiocytoma sarcoma and leukemia forms.

Since CTCs and DTCs are even more present in end-stage disease patients with unsuccessful therapy according to conventional clinical criteria and are of pathological and prognostic relevance, the medicament according to the invention can also be used for therapy (ultima ratio therapy) of these patients. Thus, in a first embodiment, the present invention relates to novel drugs, especially for intravenous administration, containing choline or pharmaceutically acceptable salts and analogs thereof.

Furthermore, the present invention relates to pharmaceutical compositions, in particular for intravenous administration, which comprise the abovementioned compounds, optionally together with vitamin C and / or L-arginine and / or vitamin D3 (cholecalciferol), or pharmaceutically acceptable salts and analogs thereof.

In the context of the present invention, "pharmaceutically acceptable salts" are in particular salts of choline which are mixed with organic acids such as tartaric acid, acetic acid, lactic acid, succinic acid, mandelic acid, malic acid or citric acid, or with inorganic acids such as hydrochloric acid, hydrobromic acid , Sulfuric acid or nitric acid are understood.

In the context of the present invention, the term "analogs" is understood to mean sphingomyelin, glycerophosphocholine, phosphatidylcholine, lecithin and phosphochoiin and, in particular, esters of choline with C 1 to C 2 mono- and di-carboxylic acids.

Medicaments for intravenous administration are preferred according to the invention, the salts of choline being in particular selected from choline hydrogen tartrate and choline chloride and the likewise contained salt of L-arginine preferably being present as L-arginine * HCl. Further, the drug of the present invention may optionally further include amino acids such as L-lysine, L-cysteine and taurine, and vitamin D3 (cholecalciferol).

Furthermore, the present invention relates to pharmaceutical compositions for intravenous administration comprising the above-mentioned compounds, optionally together with one or more pharmaceutically acceptable excipients, adjuvants and additives customary in the art. The excipients and adjuvants to be used according to the invention in this case comprise one or more selected from aqua distillata, Ringer's lactate, hypertonic saline solution, further electrolytes, fat solutions comprising medium-chain triglycerides, and omega-3 fat solutions.

In a preferred embodiment, fatty acids such as neutral fats and omega-3 fatty solutions are infused in parallel and simultaneously with the administration of the medicament according to the invention in order to maximize the action.

In this case, additives to be used according to the invention include one or more selected from vitamin B6, vitamin B12, folic acid and other amino acids, in particular L-lysine, L-cysteine and taurine, as well as electrolytes such as magnesium, calcium, manganese and molybdenum.

In a further preferred embodiment of the present invention, the medicaments described above are used in tumor therapy for the reduction of metastasis risk or for the prophylaxis of metastases.

The drug of the present invention is preferably used in a tumor therapy of mammary carcinomas (breast cancer), gastrointestinal carcinoma, prostate cancer, pancreatic cancer, skin cancer such as malignant melanoma, sarcoma such as histiocytoma sarcoma, and leukemia forms, whereby acute or maintenance therapy can be performed.

In general, the daily intravenous choline dose in a patient weighing 80 kg is in a range equivalent to 0.5 g to 100 g choline-hydrogen tartrate, or in a range equivalent to 6 mg / kg to 1, 4 g / kg (body weight) of choline hydrogen tartrate, and preferably equivalent to 30 mg / kg to 1.25 g / kg of choline hydrogen tartrate.

In maintenance therapy, the daily choline dose is preferably in a range of 80 kg patients in a range equivalent to 0.5 g to 10 g choline hydrogen tartrate, or equivalent to 6 mg / kg to 125 mg / kg choline. Hydrogen tartrate is. In the acute therapy, the daily choline dose is preferably in a range that is equivalent to 2 g to 30 g choline hydrogen tartrate in an 80 kg patient range, or equivalent to 0.03 g / kg to 1.25 g / kg and more preferably equivalent to 0.6 g / kg to 1.25 g / kg choline hydrogen tartrate.

The initial choline dose can then be gradually increased to the maximum dose according to the therapeutic results.

When using the medicaments according to the invention, the daily dose of vitamin C dose / L-arginine is in each case in a range from 1 g to 100 g, preferably in a range from 4.21 g to 22.5 g, and very particularly preferably in a range of 7.5 g to 22.5 g. For vitamin D3 (cholecalciferol), the daily dose is in the range of 100,000 I.U. to 1 million,000 I.U., and preferably in a range of 200,000 I.U. up to 500,000 I.E.

The medicament according to the invention can also be administered in combination with other medicaments, in particular conventional antitumor agents. This can be done either simultaneously (simultaneously) or at different times (sequentially). According to the invention, it has been found that a synergistic, but at least additive or even potentiating effect occurs here. On the one hand comparable cytosensitivity of these drugs with the drug according to the invention, however, differ significantly underlying mechanisms of action. As a result, the side effects that are often severe in established tumor therapies can be massively reduced and thus the acceptance of these established forms of therapy can be significantly improved.

In particular, the combined application with chemotherapeutic agents such. Taxanes such as paclitaxel or docetaxel; humanized monoclonal antibodies such as bevacizumab or trastuzumab; Anthrazyclines or capecitabine or combinations thereof, preferred.

When using the medicaments according to the invention in combination with already established tumor therapies, the dosage for established tumor therapies is in their recommended standard dosage. According to the invention it was found that in tumor diseases, such as especially breast cancer, prostate cancer, gastric cancer and pancreatic cancer, an anti-tumor effect by the in w ^'fro treatment of tumor cells in the blood of patients with the inventive drug (Zytosensitivität) could be achieved which corresponds in its extent to the currently used clinically antitumoral agents (see Fig. 1 a and 1 b). This is especially true in human medicine. This means that the medicament according to the invention acts directly on the CTCs and thus for early therapy without tumor detection, after complete removal in CTC detection for early recurrent therapy or late therapy in unsuccessfully treated tumor patients in the final stage of the disease for Ultima Ratio therapy and to reduce the risk of metastasis or Early treatment of metastases in clinically manifest primary tumor is applicable.

The medicaments according to the invention can be formulated / prepared by customary methods and techniques known to the person skilled in the art. such as In Remington's Pharmaceutical Sciences, 15th Edition, Mack Publishing Co., New Jersey (1991).

In addition to the preferred intravenous dosage form, dosage forms for oral, parenteral (eg sc, lp., Ie, intrathecal) and local (eg topical, rectal, vaginal, buccal, administration in the eye or by inhalation) are likewise optionally available. Application possible.

Thus, in addition to i.v. Administration, the medicaments according to the invention as tablets (also enteric-coated tablets or modified-release tablets), capsules (hard and soft gelatin capsules), pills, granules, suppositories, ovules, ointments, creams, gels, patches, TTS or else as emulsions, suspensions , Solutions or reconstitutable powders (also for parenteral administration).

The following examples demonstrate the efficacy of the drug of the invention. Examples

1. In y / ro Results - Effect on Disseminated Tumor Cells in the Blood (CTCs)

In 13 patients with proven tumors (breast, colon, prostate, pancreatic), the direct effect of choline (cytosensitivity) on tumor cells in the blood of patients was examined using the MAINTRAC® method. This method allows the detection of minute amounts of tumor cells in blood and other body fluids (Pachmann K., Clement JH, Schneider C.-P., Willen B., Camara O., Pachmann U., Hoeffken K., Standardized quantification of circulating peripheral tumor cells from lung and breast cancer Clin. Chem. Lab. Med., 2005, 43; 617-627).

Here, a comparable effect of choline with the conventional active substances (see FIG. 1 a) with respect to the direct antitumoral effect of choline with a cytosensitivity of these tumor cells on choline could be shown up to 95% (see FIG. 1 b). For the first time in vitro, the direct effect of choline on tumor circulating tumor cells (CTCs) was demonstrated.

2. In vwo-Erge bn isse

In 9 patients with different tumor diseases (such as breast cancer, prostate cancer, pancreatic cancer gastric cancer, skin cancer, sarcoma and leukemia), the direct in vivo effect compared to before and after the choline infusions with the drug according to the invention on blood laboratory values (CTCs, leukocytes, inoperable Leukocyte precursors) of the patients. Before and after the infusion therapy, the patients were bled and their vital parameters determined hourly, before, during and after the infusion therapy (RR, pulse, S0 ₂ , ECG, temperature). The infusion therapy took 3 to 5 hours, depending on the dose. None of the patients experienced any significant change in vital signs during and after infusion therapy, which was usually well tolerated. Depending on the dose, side effects such as nausea and fever were occasionally observed, especially on the following day, usually only for a few hours. However, patients undergoing choline therapy regularly report a significant increase in their state of health and exercise capacity after only a few intravenous applications.

The values obtained are shown in Tables 1 and 2 below.

Table 1: In v / Vo effect of intravenous therapy with choline over 3 to 5 hours on the circulating in the blood of the patient tumor cells (CTCs) (MainTrac analysis).

As illustrated above, following only one intravenous choline therapy for 3 to 5 hours, those detected in the blood of patients with mammary CA, pancreatic CA, gastric CA, prostate CA, malignant melanoma (skin cancer), and histiocytoma sarcoma are reduced circulating tumor cells (CTCs), measured by MainTrac analysis, compared to an average of 46.75 million tumor cells before therapy, compared to 9.75 million tumor cells after therapy, and -37 million tumor cells at -54, 6% of baseline before therapy. A decrease in the circulating tumor cells detected in the blood of these patients correlates according to the literature with a better Prognosis of these diseases as well as with a reduced risk to develop metastases.

Table 2: In v / Vo effect of intravenous therapy with choline over 3 to 5 hours on the leukemia in the blood in leukemia patients existing and above all unserviceable precursors (laboratory test according to the quality regulation according to the guideline of the German Medical Association, Germany).

As is known, leukemias are characterized by a greatly increased formation of white blood cells (leukocytes) and especially their unserviceable precursors. These leukemia cells spread in the bone marrow, where they displace the usual blood formation and are usually also increased in the peripheral blood. It is these functionally ineffective precursors of leukocytes, such as the CTCs in tumor diseases, that are eliminated by choline infusion therapy.

In the use of the medicaments according to the invention, as shown in Tables 1 and 2, immediately before immediately after intravenous therapy both the circulating tumor cells (CTCs) detected in the blood in cancer patients and those detected in the blood in leukemia patients are reduced elevated and especially dysfunctional precursors of leukocytes.

The acute blood value changes of the patients, as shown in Tables 1 and 2, were also detectable in some significant way even after weeks. A Acute choline infusion therapy according to the invention in maximum dosage in leukemia and breast cancer could influence these values lasting positive for more than 4 weeks.

Table 3: Change in the values under therapy before / after and after 4 weeks. (Effect on the elevated and, above all, dysfunctional precursors of leucocytes present in the blood of a leukemia patient (laboratory test according to the quality regulation according to the guideline of the German Medical Association, Germany) and on the circulating tumor cells (CTCs) in the blood of a patient with breast cancer (MainTrac analysis)) ,

As illustrated by Table 3, above, after only one intravenous therapy with choline for 3 to 5 hours, leukocytes measured in the blood of a leukemia patient before and after therapy decrease by -13% and are -8% at -8% after 4 weeks Output still significantly reduced. In one patient with breast cancer, after only one intravenous choline therapy for 3 to 5 hours, the circulating tumor cells (CTCs) detected in the patient's blood before and after therapy with MainTrac analysis of 18.75 million tumor cells before treatment are reduced 10.00 million tumor cells after therapy by -46.00% of baseline before therapy. After a further 4 weeks without therapy, this value has reduced even further to 5.25 million tumor cells and is therefore at -72.00% of the baseline before therapy.

A decrease in the number of circulating tumor cells and non - functioning precursors of leukocytes detected in the blood of these patients correlates with the Specialized literature with a better prognosis of these diseases as well as with a reduced risk to develop metastases.

Claims

claims

Medicaments containing choline or pharmaceutically acceptable salts and

Analogs thereof for use in the elimination or reduction of CTCs, DTCs or dysfunctional leukocyte precursors in the blood and bone marrow.

Medicament for use according to claim 1, for use in tumor therapy for the reduction of metastasis risk or for the prophylaxis of metastases (distant metastases) in clinically manifest primary tumor.

A medicament for use according to claim 1, for use prior to the occurrence of a clinically manifest primary tumor for early therapy.

Medicament for use according to claim 1, for use after full remission for delayed therapy.

A medicament for use according to claim 1, for use in end stage tumor disease for Ultima Ratio Therapy unsuccessfully treated by conventional criteria.

The pharmaceutical composition of claim 1, for use in the therapy of leukemias.

Medicament for use according to one of the preceding claims, further containing vitamin C and / or vitamin D3 (cholecalciferol).

A pharmaceutical composition for use according to any one of the preceding claims further containing L-arginine or pharmaceutically acceptable salts thereof.

A pharmaceutical composition for use according to any one of the preceding claims, wherein the pharmaceutically acceptable salt of choline is selected from choline hydrogen tartrate and choline chloride.

A pharmaceutical composition for use according to any one of the preceding claims wherein the pharmaceutically acceptable salt of L-arginine is L-arginine HCl.

1 1. A pharmaceutical composition for use according to any one of the preceding claims, wherein the tumor disease is selected from breast cancer, colon carcinoma, gastric carcinoma, prostate cancer, pancreatic cancer, skin cancer, sarcoma and leukemia.

A medicament for use according to any one of the preceding claims, wherein the daily choline dose is in a range equivalent to 0.5 to 100 g choline hydrogen tartrate, or equivalent to 6 mg / kg to 1.4 g / kg choline Hydrogen tartrate, and preferably equivalent to 30 mg / kg to 1, 25 g / kg of choline hydrogen tartrate.

A pharmaceutical composition for use according to any one of the preceding claims, wherein the tumor therapy is selected from maintenance therapy and acute therapy.

14. A medicament for use according to claim 13, wherein in maintenance therapy the daily choline dose is in a range equivalent to 0.5 g to 10 g choline hydrogen tartrate, or equivalent to 6 mg / kg to 125 mg / kg choline. Hydrogen tartrate is.

15. A medicament for use according to claim 13, wherein in acute tumor therapy the daily choline dose is in a range equivalent to 2 g to 30 g choline hydrogen tartrate or equivalent to 0.03 g / kg to 1, 25 g / kg and more preferably equivalent to 0.6 g / kg to 1.25 g / kg of choline hydrogen tartrate.

16. Medicament for use according to one of claims 1 to 15, wherein the daily dose of vitamin C and L-arginine each in a range of 1 g to 100 g, preferably in a range of 4.21 g to 22.5 g and more preferably in a range of 7.5 g to 22.5 g.

17. Medicament for use according to one of claims 1 to 16, wherein the daily dose of vitamin D3 is in a range of 100,000 IU to 1,000,000 IU, and preferably in a range of 200,000 IU to 500,000 IU.

18. Medicament for use according to one of the preceding claims for intravenous administration.

19. A medicament for use according to any one of the preceding claims for use in combination with one or more antitumor agents.

20. Medicament for use according to claim 19, for simultaneous or sequential application.

21. A medicament for use according to claim 19 or 20, wherein the antitumor agent is selected from taxanes such as paclitaxel or docetaxel; humanized monoclonal antibodies such as bevacizumab or trastuzumab; Anthrazyclines or capecitabine or combinations thereof.