MX2008001972A - Staurosporine derivatives for treating non-small cell lung cancer - Google Patents
Staurosporine derivatives for treating non-small cell lung cancerInfo
- Publication number
- MX2008001972A MX2008001972A MXMX/A/2008/001972A MX2008001972A MX2008001972A MX 2008001972 A MX2008001972 A MX 2008001972A MX 2008001972 A MX2008001972 A MX 2008001972A MX 2008001972 A MX2008001972 A MX 2008001972A
- Authority
- MX
- Mexico
- Prior art keywords
- lung cancer
- cell lung
- small cell
- treatment
- cancer
- Prior art date
Links
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Abstract
The present invention relates to a method of treating non-small cell lung cancer with FLT-3 kinase inhibitor such as PKC412. The invention also relates to a pharmaceutical combination of a FLT-3 kinase inhibitor and an activator of permeablization of the mitochondrial outer membrane, such as an activator of BAK. It also relates to the use of a pharmaceutical combination of an activator of permeablization of the mitochondrial outer membrane and a FLT-3 kinase inhibitor for the treatment of non-small cell lung cancer and the use of such a pharmaceutical composition for the manufacture of a medicament for the treatment of same.
Description
DERIVADOS DE ESTAU ROSPORINA FOR THE TREATMENT OF CANCER PU LMONAR NO OF CÉLU THE SMALL
INTRODUCTION Molecular understanding of the transduction pathways of regular signals that regulate survival, genetic stability, metabolic activity, and proliferation has greatly increased over the past decades. In accordance with the above, the careful analyzes conducted in the pre-clinical cancer models and in the tumor samples, led to the identification of specific deregulations of these pathways as contributing or even causative factors during malignant transformation and cancer progression ( 1 ) . Against this background, there are efforts to develop tailored therapies for specific objectives that separate cancer cells from their non-malignant counterparts. The clinical application of the success of the small drug kinase inhibitor imatinib in the positive leukemias for BC R-ABL and gastrointestinal stromal tumors has impressively provided an initial proof of this concept (2). However, pharmacological inhibitors of apparently less essential signal transduction pathways exhibited only minor clinical activity in populations of unselected patients. In addition, the combination of cytotoxic drugs with inhibitors that are not antibodies has so far failed to produce better clinical results in lung cancer or colorectal cancer (3-6). Based on these observations, we reason that the death of cancer cells induced by pharmacological kinase inhibitors is actually performed by means of molecular pathways different from those triggered by conventional cytotoxic cancer drugs. In an alternative way, both pathways could converge on a common step in signal transduction, which would then be a strategic goal to break the resistance to the drug. Cytotoxic treatments for patients with advanced non-small cell lung cancer (NSCLC) have only moderate clinical activity. Recently, inhibitors of epidermal growth factor receptor signaling showed efficacy in a subgroup of non-small cell lung cancer patients, and the modulation of additional signaling pathways is a significant promise. There is a need for therapeutic products for cancer that are directed to the molecular pathways to which currently existing anti-cancer drugs are not directed. BRIEF DESCRIPTION OF THE INVENTION We study the induction of apoptosis by specific inhibitors of protein kinase C (PKC), staurosporine and PKC412 in non-small cell lung cancer cells. Interestingly, we found that cell lines resistant to cytotoxic cancer drugs were also protected against specific inhibitors of protein kinase C. The combination of protein kinase C inhibitors with cytotoxic agents produced variable results, such as greater or lesser cytotoxicity. In contrast, the direction toward the mitochondrial pathway of apoptosis through the conditional expression of BAK reliably sensitized non-small cell lung cancer resistant to the drug specific inhibitors of protein kinase C. In conclusion, therapeutic targeting of the BCL-2 protein family in combination with a specific inhibitor of protein kinase C, such as PKC41 2, is a promising strategy for improving the efficacy of kinase inhibitors in the treatment of cancer. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1B are graphical representations showing similar patterns of resistance of non-small cell lung cancer cell lines treated with cytotoxic cancer drugs and specific inhibitors of protein kinase C in vitro. Figures 2A-2E are graphical representations showing that the combination of cytotoxic cancer drugs with specific inhibitors of protein kinase C, fails to result in predictable synergistic cytotoxicity in vitro. Figures 3A-3D are pictorial and pictorial representations that show that non-lung cell lung cancer cell lines resistant to specific protein kinase C inhibitors exhibit a delayed release of mitochondrial cytochrome c, maintain? M, and fail to activate the caspases. Figures 4A-4D are pictorial and graphic representations that show that the conditional expression of BAK sensitizes lung cancer cell lines not from drug-resistant small cells to apoptosis. Figures 5A-5D are graphical representations showing that the mitochondrial BAK digestion sensitizes the cell lines of non-small cell lung cancer resistant to apoptosis induced by PKC412. DETAILED DISCUSSION Molecular understanding of the cellular signal transduction pathways that regulate survival, genetic stability, metabolic activity, and proliferation has greatly increased over the past decades. In accordance with the above, the careful analyzes conducted in the pre-clinical cancer models and in the tumor samples, led to the identification of specific deregulations of these pathways as contributing or even causative events during malignant transformation and cancer progression ( 1 ) . Against this background, efforts are being made to develop tailored therapies for specific objectives that separate cancer cells from their non-malignant counterparts. The BCL2 oncogene (OM I M 1 51430) functions as a potent suppressor of apoptosis under various conditions. It was discovered that the Bcl-2 antagonist protein, Killer-1 ("BAK1" OM IM 60051 6), a homolog of Bcl-2, antagonizes Bcl-2, promotes cell death, and counteracts the protection of the apoptosis provided by Bcl-2. Overexpression of BAK induces a rapid and extensive apoptosis of serum-deprived fibroblasts, suggesting that BAK is directly involved in the activation of the cell death machinery. BAK primarily potentiates apoptotic cell death following an appropriate stimulus. Therefore, BAK modulators are useful in modulating the transduction pathways of apoptotic signals. The successful clinical application of the small drug kinase inhibitor imatinib in BCR-ABL-positive leukemias and in gastrointestinal stromal tumors has impressively provided a proof of principle for this concept (2). However, pharmacological inhibitors of apparently less essential signal transduction pathways exhibited only minor clinical activity in populations of unselected patients. In addition, the combination of cytotoxic drugs with inhibitors that are not antibodies have so far failed to produce better clinical results in patients with lung cancer or colo-rectal cancer (3-6). Based on these observations, we hypothesize that the death of cancer cells induced by pharmacological kinase inhibitors is carried out by molecular pathways different from those triggered by conventional cytotoxic cancer drugs. In an alternative way, both pathways could converge on a common step in signal transduction, which would then be a strategic goal to break drug resistance. For this purpose, we compared the sensitivity of a panel of well-characterized non-small cell lung cancer cell lines to cell death induced by the specific inhibitors of staurosporine protein kinase C (STS), its clinically applied N derivative. -benzoyl-staurosporine (PKC41 2, Novartis Pharma), and common cytotoxic cancer drugs. The inhibition model of protein kinase C was selected based on the role of protein kinase C as a central mediator of a variety of signal transduction pathways that are considered critical for tumor growth and survival (7)., 8). Despite this potentially broad therapeutic spectrum, we found that specific inhibitors of protein kinase C failed to induce apoptosis in non-small cell lung cancer cells that were also resistant to conventional cytotoxic cancer drugs. Molecular dissection revealed that functional defects at the level of BCL-2 family proteins critically contributed to resistance to apoptosis in these non-small cell lung cancers. The therapeutic direction of the mitochondrial passage in the transduction of apoptotic signals could also circumvent the cross-resistance against inhibitors of protein kinase C and cytotoxic drugs. During oncogenesis and tumor progression, cancer cells acquire a large number of functional defects in the tumor suppressor pathways. This is often achieved by mutational inactivation or loss of expression of tumor suppressor genes, or by genetic amplification and genetic deregulation of factors that promote survival or proliferation. In addition, it was shown that epigenetic mechanisms contribute to the aberrant expression patterns observed in malignant phenotypes (1). Apoptosis is one of the main tumor suppressor pathways that must be overcome on the road to cancerous transformation. In accordance with the above, it was demonstrated that the inhibition of apoptosis promotes tumor development in different pre-clinical cancer models (20-22), and defects in the transduction of apoptotic signals in human cancers are frequently found (23, 24). ). In addition to promoting the development of cancer, defects of apoptosis also appear to confer resistance to common cytotoxic therapies (24, 25), which are still the main place of cancer treatment in clinical oncology. Recently, novel therapies have been introduced into cancer medicine, which aim to specifically target tumor cells by means of immuno-mediated mechanisms, or by interfering with deregulated signal transduction pathways. Examples of success of immuno-mediated cancer therapies are the transfer of T-lymphocytes during or after transplantation of hematopoietic totipotent cells for leukemia, the administration of monoclonal antibodies, such as trastuzumab or rituximab for cancer patients. breast or B-cell lymphoma, or the use of interferon-alpha in patients with malignant melanoma and at high risk of recurrence. Signal transduction inhibitors that have been shown to be clinically effective include imatinib in patients with chronic myeloid leukemia and gastrointestinal stromal tumors, bevacizumab and cetuximab in patients with colorectal cancer, erlotinib in patients with recurrent lung cancer, or sorafinib. in patients with metastatic renal cell cancer. These examples have nurtured the identification of a large number of novel compounds and treatment strategies, some of which have already entered the clinical development. There remains an open question in the field about whether these new modalities can in fact cure cancers resistant to conventional cytotoxic therapies. In a transplantation model of allogeneic hematopoietic totipotent cells, we recently demonstrated that genetic inhibitors of apoptotic signal transduction can confer cancer cell resistance to antigen-specific cytotoxic T-lymphocytes, in vitro and in vivo (26). This formality demonstrates that resistance factors, which protect cancer cells against conventional cytotoxic therapies, can also lead to escape from immuno-mediated tumor suppression. In the present study, we extend the concept of "cross-resistance" to pharmacological inhibitors of signal transduction. Like a model, we have used non-small cell lung cancer, and protein kinase C inhibitors. Non-small cell lung cancer is a highly prevalent malignancy, and a leader in cancer-related deaths in the Western world. The majority of non-small cell lung cancer is diagnosed in the advanced stages of the disease, and therefore requires drug therapy and radiation. Current conventional therapies for non-resectable advanced non-resectable small cell lung cancer achieve clinically significant tumor regressions in only a small fraction of patients. The average survival of patients with advanced non-small cell lung cancer treated in large clinical studies is from 1 to 12 months. Due to this high medical need, novel therapies that include inhibitors of signal transduction pathways in non-small cell lung cancer have been studied extensively. Until now, many efforts have focused on inhibitors of signaling through epidermal growth factor receptors (EFG R). It was shown that compounds such as gefitinib and erlotinib result in some clinical improvement, and even produce a short prolongation of the average survival of patients with recurrent non-small cell lung cancer (27, 28). However, when studied in large cohorts of patients as first-line therapy in combination with conventional cytotoxic drug regimens, none of these compounds led to clinical benefit (3-5). It was found that only patients with certain activating mutations of the epidermal growth factor receptor have a high probability of response to treatment with gefitinib (29, 30). Unfortunately, the vast majority of patients with non-small cell lung cancer fail to exhibit these mutations, which presents the problem of a broad clinical applicability of highly specific kinase inhibitors in non-small cell lung cancer. In contrast, the family of protein kinase C enzyme is involved in several signal transduction pathways that may contribute to the development of cancer. These include mitogenic signaling by means of the platelet-derived growth factor receptor (PGDF), regulation of cell cycle checkpoints in the G1 and G2 phases, and signaling by means of endothelial growth factor receptors. vascular (VEGF) on endothelial cells and cancer cells (7). In accordance with the foregoing, inhibitors specific for protein kinase C, such as STS or PKC412, induced cell cycle arrest or apoptosis in cancer cell lines, and exhibited anti-tumor and anti-angiogenic effects in a mouse xenograft model of lung cancer (8, 31, 32). It was demonstrated that oral administration of PKC412 is safe and feasible in a phase I study conducted in patients with advanced cancers (33). In addition, we established the safety of combining PKC41 2 with a conventional cytotoxic regimen of CDDP / gemcitabine in a phase I study in patients with advanced non-small cell lung cancer (34). Against this background, we found that inhibitors specific for protein kinase C, such as STS and PKC41 2, were more effective in these non-small cell lung cancer cell lines that exhibit a good response to cytotoxic cancer drugs. conventional In contrast, non-drug-resistant small cell lung cancer cell lines were also less sensitive to apoptosis induced by inhibition of protein kinase C. Unfortunately, this pattern of resistance could not be overcome by combining cytotoxic cancer drugs with protein kinase C inhibitors. Unlike other studies conducted in a limited number of non-small cell lung cancer cell lines (32, 35), the combination therapy in our hands generally did not result in synergistic cytotoxicity. Unexpectedly, PKC412 even antagonized the activity of cytotoxic drugs in some models. These results should be taken into consideration when designing clinical efficacy studies of protein kinase C inhibitors in combination with cytotoxic cancer drugs in non-small cell lung cancer, and also in other malignancies. Currently, the selection of patients for these studies is usually based on the histopathological classification of the tumors. All the cell lines used in the present study were originated from non-small cell lung cancer, demonstrating once again that histopathology alone is unable to discover functional heterogeneity. Moreover, the functional status of the tumor suppressor gene TP53, as well as the analysis of expression of different regulators of apoptosis, failed to predict the sensitivity to cytotoxic cancer drugs, as well as specific inhibitors of protein kinase C in vitro In contrast, functional analyzes of the apoptotic signal transduction pathways revealed defects at the level of permeabilization of the mitochondrial outer membrane in the non-small cell resistant lung cancer cell lines. The therapeutic direction towards this defect through the conditional expression of pro-apoptotic BAK, reliably surpassed the resistance to protein kinase C inhibitors and / or to other conventional cytotoxic drugs. Certainly, these extensive biochemical analyzes can not be carried out easily in tumor biopsies obtained from cancer patients. However, our results may have many implications for the development of strategies for transferring novel compounds to clinical oncology. First, the combination of kinase inhibitors with conventional cytotoxic regimens may not be informative, because the result of this combined treatment can not be predicted for the heterogeneous population of patients with histopathologically classified cancers. The positive effects of the combination in some patients can be overcome by the detrimental effects in others, resulting in much similar net results following combination therapy (3-6). Second, the efficacy of novel targeted drugs can be hampered by the same resistance mechanisms that lead to the failure of cytotoxic cancer drugs. In the present study, this was demonstrated for defects in the transduction of apoptotic signals. The same may be true for defects in cell cycle regulation, or on alternate death pathways. Third, careful functional analyzes conducted in pre-clinical cancer models can identify molecular targets that are strategically placed at a point of convergence of various paths of death and survival. In our present study, retroviral gene transfer and the conditional expression of BAK were devised to model the therapeutic modulation of this objective. The transfer to the clinical reality most probably requires different pharmacological strategies, such as modulators of small compounds of the pro- and anti-apoptotic rheostat at the level of BCL-2 family proteins (36, 37). The present invention relates to a method for the treatment of solid tumors, such as, for example, colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) with a protein kinase C inhibitor. It also relates to the use of a pharmaceutical combination of a FLT-3 kinase inhibitor and a BAK inhibitor for the treatment of the aforementioned diseases or malignancies., and the use of this pharmaceutical composition for the manufacture of a medicament for the treatment of these diseases or malignancies. Surprisingly, it has now been found that inhibitors of FLT-3 kinase in combination with activators of mitochondrial outer membrane permeability, such as BAK activators, possess therapeutic properties that make them particularly useful for treatment, example, of non-small cell lung cancer (NSCLC). ABR EVIATURES ActD - actinomycin D, CDDP - cisplatin, DOX - doxycycline, DXR - doxorubicin, EGFP - green fluorescent enhanced protein, EGFR - epidermal growth factor receptor, MOM - mitochondrial outer membrane, NSCLC - non - small cell lung cancer, PDGF - platelet-derived growth factor, PKC - protein kinase C, PKC412 - N-benzoyl-staurosporine, STS - staurosporine, VEGF - vascular endothelial growth factor, VP16 - etoposide. FLU-3 KINASE INHIBITORS The FLT-3 kinase inhibitors of a particular interest to be used in the combination of the invention are the staurosporine derivatives. Preferably, the inhibitor of FLT-3 is N - [(9S, 10R, 11R, 13R) -2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo- 9,13-epoxy-1H, 9H-di-indole- [1,2,3-gh: 3 ', 2', 1'-lm] -pyrrolo- [3,4-j] - [1,7] -benzodiazonin-11 -yl] -N-methyl-benzamide of Formula I:
(I) or a salt thereof, including especially a pharmaceutically acceptable salt. The compound of Formula I is also known as MIDOSTAURIN [International Non-Registered Name], or PKC412. PKC412 is a derivative of the alkaloid that naturally occurs staurosporine.
In alternative embodiments, suitable Flt-3 inhibitors include, for example: compounds as disclosed in International Publication Number WO 03/037347, for example the staurosporine derivatives of Formula (II) or (III) :
wherein the compound (III) is the partially hydrogenated derivative of the compound (II); or the staurosporine derivatives of the Formula (IV) or (V) or (VI) or (Vil): wherein R 1 and R 2 are, independently of each other, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxyl, etherified hydroxyl or esterified, amino, mono- or di-substituted amino, cyano, nitro, mercapto, substituted mercapto, carboxyl, esterified carboxyl, carbamoyl, N-mono- or N, N-di-substituted carbamoyl, sulfo, substituted sulfonyl, amino-sulfonyl , or N-mono- or N, N-di-substituted amino-sulfonyl; n and m are, independently of each other, a number from and including 0 up to and including 4; n 'and m' are, independently of each other, a number from and including 0 up to and including 4; R3, R4, Rs, and R10 are, independently of one another, hydrogen, -O ", acyl with up to 30 carbon atoms, an aliphatic, carbocyclic, or carbocyclic-aliphatic radical with up to 29 carbon atoms in each case, heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, an acyl with up to 30 carbon atoms, where R4 may also be absent, or if R3 is acyl with up to 30 atoms of carbon, R4 is not an acyl, p is 0 if R4 is absent, or is 1 if R3 and R4 are both present, and in each case are one of the radicals mentioned above, R5 is hydrogen, an aliphatic radical, carbocyclic, or carbocyclic-aliphatic with up to 29 carbon atoms in each case, or a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, or acyl with up to 30 carbon atoms; , Re. And R9 are acyl or - (alkyl) or lower) -acyl, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxyl, etherified or esterified hydroxyl, amino, mono- or di-substituted amino, cyano, nitro, mercapto, substituted mercapto, carboxyl, carbonyl, carbonyldioxyl, esterified carboxyl, carbamoyl, N-mono- or N, N-di-substituted carbamoyl, sulfo, substituted sulfonyl, amino-sulfonyl, or amino-sulfonyl N-mono- or N, N-di-substituted; X represents 2 hydrogen atoms; 1 hydrogen atom and hydroxyl; OR; or hydrogen and lower alkoxy; Z represents hydrogen or lower alkyl; and whether the two bonds characterized by wavy lines are absent in ring A and replaced by 4 hydrogen atoms, and the two wavy lines in each ring B, together with the respective parallel link, mean a double bond; or, the two bonds characterized by the wavy lines are absent in ring B and are replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel link, mean a double bond; or, both in ring A and in ring B, all four wavy bonds are absent, and are replaced by a total of 8 hydrogen atoms;
or a salt thereof, if at least one salt forming group is present. The general terms and definitions used hereinbefore and hereinafter, preferably have the meanings for the staurosporine derivatives as provided in International Publication Number WO 03/037347, which is incorporated herein by reference In its whole. However, when discrepancies appear between International Publication Number WO 03/037347 and the present disclosure, will govern the present disclosure. By their nature, the compounds of the invention may be present in the form of pharmaceutically acceptable salts, ie, physiologically acceptable, as long as they contain salt-forming groups. For the isolation and purification, pharmaceutically unacceptable salts can also be used. For therapeutic use, only pharmaceutically acceptable salts are used, and these salts are preferred. Accordingly, compounds of Formula I having free acid groups, for example a sulfo, phosphoryl, or free carboxyl group, may exist as a salt, preferably as a physiologically acceptable salt, with a basic salt-forming component. . These may be primarily metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium, or calcium salts, or ammonium salts with ammonia or with suitable organic amines, especially monoamines. tertiary and heterocyclic bases, for example triethylamine, tri- (2-hydroxy-ethyl) -amine, N-ethyl-piperidine, or N, N'-dimethyl-piperazine. The compounds of the invention having a basic character can also exist as addition salts, especially as acid addition salts, with inorganic and organic acids, but also as the quaternary salts. Thus, for example, compounds having a basic group, such as an amino group, as a substituent, can form acid addition salts with the common acids. Suitable acids are, for example, hydrohalic acids, for example hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, or perchloric acid.; or aliphatic, alicyclic, aromatic, or heterocyclic carbocyclic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, fumaric, maleic, hydroxymaleic, oxalic, pyruvic, phenyl- acetic, benzoic, p-amino-benzoic, anthranilic, p-hydroxy-benzoic, salicylic, p-amino-salicylic acid, pamoic acid; methanesulfonic, ethanesulfonic, hydroxy ethanesulfonic, ethylene disulfonic, halobenzenesulfonic, toluenesulphonic, naphthalene sulphonic, or sulfanilic acids, and also methionine, tryptophan, potassium, or arginine, as well as ascorbic acid. In view of the close relationship between the compounds (especially of Formula I) in free form and in the form of their salts, including salts that can be used as intermediates, for example, in the purification or identification of novel compounds , and of their solvates, any reference hereinbefore and hereinafter to the free compounds, should be understood to refer also to the corresponding salts, and to the solvates thereof, for example hydrates, as appropriate and convenient . The staurosporine derivatives and their manufacturing process have been specifically described in many previous documents, well known to one skilled in the art. The compounds of Formula I and their manufacturing processes have been described in a specific manner in European Patent Number 0,296,110 published on December 21, 1988, as well as in United States Patent No. 5,093,330. published March 3, 1992, and in Japanese Patent Number 2,708,047, each of which is incorporated herein by reference. In each case where citations of patent applications or scientific publications are given, in particular for the compounds derived from staurosporine, the subject matter of the final products, the pharmaceutical preparations, and the claims, are incorporated in the present application by reference to these publications. The structure of the active agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck I ndex", or from the databases, for example International Patents (for example, IMS World Publications). The corresponding content thereof is incorporated herein by reference. BAK ACTIVATORS BAK modulators are useful for modulating the transduction pathways of apoptotic signals. BAK activators enhance apoptotic cell death, and counteract the anti-apoptotic effects of BCL2. BAK activators include, but are not limited to, inhibitors of BCL-2 / BCL-XL. Examples of the Bcl-2 / Bcl-XL inhibitor compounds include, but are not limited to, anti-Bcl-2 / Bcl-XL antibodies, RNAi constructs that target Bcl-2 or Bcl-XL, the BH3 helix peptides stapled with hydrocarbons, and the chemical inhibitors such as N-. { 4- [4- (4'-chloro-biphenyl-2-yl-methyl) -piperazin-1-yl] -benzoyl} -4- (3-dimethyl-amino-1-phenyl-sulfanyl-methyl-propyl-amino) -3-nitro-benzenesulfonamide (composed of Abbott ABT-737) (36, 37). Recently, apoptosis therapies were reviewed, including additional BAK activators (40). THERAPEUTIC PRODUCTS, MEDICATIONS, AND METHODS OF USE The present invention provides in particular a method for the treatment of non-small cell lung cancer (NSCLC), which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of an inhibitor. of FLT-3 kinase, either in free form or in the form of a pharmaceutically acceptable salt, or of a pro-drug. A preferred FLT-3 kinase inhibitor is PKC41 2. Preferably, the present invention provides a method for the treatment of mammals, especially humans, suffering from non-small cell lung cancer (NSCLC)., which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of an inhibitor of FLT-3, or a pharmaceutically acceptable salt or prodrug thereof. A preferred FLT-3 kinase inhibitor is PKC41 2. In another embodiment, the present invention relates to the use of a FLT-3 kinase inhibitor, in free form or in the form of a pharmaceutically acceptable or pro-drug salt, for the treatment of non-small cell lung cancer. A preferred FLT-3 kinase inhibitor is PKC41 2. In a further embodiment, the present invention relates to the use of a FLT-3 kinase inhibitor, in free form or in the form of a pharmaceutically acceptable or pro-drug salt, for the preparation of a pharmaceutical composition for the treatment of non-small cell lung cancer. A preferred FLT-3 kinase inhibitor is PKC412. The precise dosage of the FLT-3 inhibitor and the compound to be employed for the treatment of the diseases and conditions mentioned herein, depend on several factors, including the host, the nature and severity of the condition being treated. , and the mode of administration. However, in general, satisfactory results are achieved when the FLT-3 inhibitor is administered parenterally, for example intraperitoneally, intravenously, intramuscularly, subcutaneously, intratumorally, or rectally, or enterally, for example orally, preferably intravenously, or preferably orally, intravenously in a daily dosage of 0.1 to 10 milligrams / kilogram of body weight, preferably 1 to 5 milligrams / kilogram of body weight. In studies with humans, a total dose of 225 milligrams / day was more presumably the Maximum Tolerated Dose (MTD). A preferred intravenous daily dosage is 0.1 to 10 milligrams / kilogram of body weight, or for most higher primates, a daily dosage of 200 to 300 milligrams. A typical intravenous dosage is 3 to 5 milligrams / kilogram, 3 to 5 times a week. Most preferably, inhibitors of FLT-3, especially midostaurin, are administered orally, by dosage forms such as microemulsions, soft gels, or solid dispersions in dosages up to about 250 milligrams / day, in particular 225 milligrams. / day, administered one, two, or three times a day. Usually, a small dose is administered initially, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined. The upper dosage limit is that imposed by side effects, and can be determined by studying the host being treated. COMBINED TREATMENT In one aspect, the present invention also relates to a combination, such as a combined preparation or a pharmaceutical composition, which comprises: (a) an inhibitor of FLT-3, especially inhibitors of FLT-3 specifically mentioned hereinabove, in particular those mentioned as preferred, and in the treatment of non-small cell lung cancer resistant to cytotoxic drugs; (b) an activator of mitochondrial outer membrane permeabilization, such as a BAK activator; or alternatively, in the treatment of non-small cell lung cancer responsive to cytotoxic drugs, (b ') a topoisomerase inhibitor; wherein the active ingredients (a) and any of (b) or (b ') (hereinafter referred to as ("b or b')") are present in each case in free form or in the form of a salt pharmaceutically acceptable, for simultaneous, concurrent, separate, or sequential use. The term "a combined preparation" defines in particular a "kit of parts", in the sense that the combination components (a) and (b or b '), as defined above, can be dosed independently or by using different fixed combinations with distinguished quantities of the combination components (a) and (b or b '), that is, in a simultaneous, concurrent, separate, or sequential manner. The parts of the part list, for example, can then be administered in a simultaneous or chronologically staggered manner, that is, at different points in time and with the same or different time interval for any part of the kit of parts. The ratio of the total amounts of the combination component (a) to the combination component (b or b ') to be administered in the combined preparation can be varied, for example, in order to deal with the needs of a sub-population of patients to be treated, or with the needs of the individual patient, whose different needs may be due to the particular disease, the severity of the disease, age, sex, body weight, etc. , from the patients. Suitable clinical studies are, for example, dose-scale, open-label studies in patients with proliferative diseases. These studies prove in particular the synergism of the active ingredients of the combination of the invention. The beneficial effects on non-small cell lung cancer can be directly determined through the results of these studies, which are known as such for a person skilled in the art. These studies are particularly suitable for comparing the effects of a monotherapy using the active ingredients and a combination of the invention. Preferably, the dose of the agent (a) is scaled until the Maximum Tolerated Dosage is reached, and the agent (b or b ') is administered at a fixed dose. Alternatively, the agent (a) is administered in a fixed dose, and the agent dose (b or b ') is scaled. Each patient receives doses of the agent (a) either daily or intermittently. The effectiveness of the treatment can be determined in these studies, for example, after 12, 18, or 24 weeks, by evaluating the symptom scores every six weeks. The administration of a pharmaceutical combination of the invention results not only in a beneficial effect, for example, a synergistic therapeutic effect, for example with respect to relieving, slowing the progress of, or inhibiting symptoms, but also additional surprising beneficial effects. , for example less side effects, a better quality of life, or a reduced pathology, compared with a monotherapy applying only one of the pharmaceutically active ingredients used in the combination of the invention. An additional benefit is that lower doses of the active ingredients of the combination of the invention can be used, for example, that the dosages not only need to be often smaller, but also that they are applied less frequently, which can decrease the incidence or severity of side effects. This is in accordance with the wishes and requirements of the patients to be treated. The terms "co-administration" or "combined administration", or the like, as used herein, are intended to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens wherein the agents are not necessarily administered by the same administration route or Same time. It is an object of this invention to provide a pharmaceutical composition comprising an amount that is therapeutically effective together to direct or prevent proliferative diseases, of a combination of the invention. In this composition, the agent (a) and the agent (b or b ') can be administered together, one after the other, or separately in a combined unit dosage form, or in two separate unit dosage forms. The unit dosage form can also be a fixed combination. The pharmaceutical compositions for the separate administration of the agent (a) and the agent (b or b '), or for administration in a fixed combination, is to say, a single pharmaceutical composition comprising at least two combination components (a) and (b or b '), according to the invention, can be prepared in a manner known per se, and are those suitable for enteral administration, such as orally or rectally, and parenterally to mammals (warm-blooded animals), including human beings, which comprise a therapeutically effective amount of at least one pharmacologically active combination component alone, for example, as indicated above, or in combination with one or more pharmaceutically acceptable carriers or diluents, especially suitable for enteral application or parenteral. Suitable pharmaceutical compositions contain, for example, from about 0.1 percent to about 99.9 percent, preferably from about 1 percent to about 60 percent of the active ingredients. Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those which are in unit dosage forms, such as sugar-coated tablets, tablets, capsules, or suppositories, or ampoules. If not stated otherwise, they are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar coating, dissolving, or freezing processes. It will be appreciated that the unit content of a combination component contained in an individual dose of each dosage form does not need to constitute an effective amount by itself, because the effective amount needed can be achieved by administering a plurality of dosage units. dosage In particular, a therapeutically effective amount of each of the components of the combination of the invention can be administered in a simultaneous or sequential manner and in any order, and the components can be administered separately or as a fixed combination. For example, the method for preventing or treating proliferative diseases according to the invention may comprise: (i) administration of the first agent (a) in free or pharmaceutically acceptable salt form, and (ii) administration of an agent (b) or b ') in free or pharmaceutically acceptable salt form, in a simultaneous or sequential manner in any order, in mutually therapeutically effective amounts, preferably in synergistically effective amounts, for example in daily or intermittent dosages corresponding to the amounts described in the present. The individual combination components of the combination of the invention can be administered separately at different times during the course of therapy, or in a concurrent manner in divided or individual combination forms. Additionally, the term "administer" also encompasses the use of a pro-drug of a combination component that is converted in vivo to the combination component as such. Therefore, it should be understood that the present invention encompasses all of these simultaneous or alternate treatment regimens, and the term "administer" should be interpreted in accordance with the same. The effective dosage of each of the combination components used in the combination of the invention may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition that is being treated. I'm trying. Accordingly, the dosage regimen of the combination of the invention is selected according to a variety of factors, including the route of administration, and the renal and hepatic function of the patient. A clinician or physician of ordinary experience can easily determine and prescribe the effective amount of the individual active ingredients required to alleviate, counteract, or halt the progress of the condition. The optimal precision to reach the concentration of the active ingredients within the range that produces efficacy without toxicity, requires a regime based on the kinetics of the availability of the active ingredients for the target sites. Of course, the daily dosages for agent (a) or (b or b ') will vary depending on a variety of factors, for example, the selected compound, the particular condition to be treated, and the desired effect. However, in general satisfactory results are achieved with the administration of the agent (a) in daily dosage rates of the order of about 0.03 to 5 milligrams / kilogram per day, in particular from 0.1 to 5 milligrams / kilogram per day, for example from 0.1 to 2.5 milligrams / kilogram per day, as a single dose or in divided doses. The agent (a) and the agent (b or b ') can be administered by any conventional route, in particular enterally, for example orally, for example in the form of tablets, capsules, solutions for drinking, or parenterally, for example in the form of injectable solutions or suspensions. Unit dosage forms suitable for oral administration comprise from about 0.02 to 50 milligrams of active ingredient, usually from 0.1 to 30 milligrams, for example agent (a) or (b or b '), together with one or more diluents or carriers pharmaceutically acceptable for the same. The agent (b or b ') can be administered to a human in a daily dosage range of 0.5 to 1, 000 milligrams. Unit dosage forms suitable for oral administration comprise from about 0.1 to 500 milligrams of active ingredient, together with one or more pharmaceutically acceptable diluents or carriers therefor. The administration of a pharmaceutical combination of the invention results in not only a beneficial effect, for example a synergistic therapeutic effect, for example with respect to the inhibition of unregulated proliferation of, or to slow down the progress of lung cancer not of small cells, but also additional surprising beneficial effects, for example fewer side effects, a better quality of life, or a reduced pathology, compared with a monotherapy applying only one of the pharmaceutically active ingredients used in the combination of the invention. An additional benefit is that lower doses of the active ingredients of the combination of the invention can be used, for example, that the dosages not only need to be frequently smaller, but that they are also applied less frequently, or can be used in order to reduce the incidence of side effects. This is in accordance with the wishes and requirements of the patients to be treated. The compound (a) and the compound (b or b ') can be combined with one or more pharmaceutically acceptable carriers, and optionally, with one or more additional conventional pharmaceutical adjuvants., and can be administered enterally, for example orally, in the form of tablets, capsules, caplets, etc. , or parenterally, for example intraperitoneally or intravenously, in the form of sterile injectable solutions or suspensions. The enteric and parenteral compositions can be prepared by conventional means. The solutions for infusion according to the present invention are preferably sterile. This can be carried out easily, for example, by filtration through sterile filtration membranes. The aseptic formation of any composition in liquid form, the aseptic filling of flasks, and / or the combination of a pharmaceutical composition of the present invention with a suitable diluent under aseptic conditions, are well known to the skilled artisan. The FLT-3 inhibitors can be formulated in parenteral and parenteral pharmaceutical compositions containing an amount of the active substance that is effective for the treatment of the diseases and conditions mentioned hereinabove, these compositions being in a unit dosage form, and said compositions comprising a pharmaceutically acceptable carrier. The disclosed pharmaceutical compositions comprise a solution or dispersion of the compounds of Formula I, such as midostaurin, in a saturated polyalkylene glycol glyceride, wherein the glycol glyceride is a mixture of glyceryl esters and polyethylene glycol of one or more saturated fatty acids. from 8 to 18 carbon atoms. Preferably, there is at least one beneficial effect, for example a mutual improvement of the effect of the first and second active ingredients, in particular a synergism, for example an effect rather than an additive, additional convenient effects, fewer side effects, a therapeutic effect combined in an otherwise ineffective dosage of one or both of the first and second active ingredients, and especially a strong synergism of the active ingredients. The efficacy of PKC412 for the treatment of non-small cell lung cancer is illustrated by the results of the following Examples. These Examples illustrate the invention without limiting its scope in any way. EXAMPLES Example 1: Cell lines and vectors Non-small cell lung cancer cell lines known in the art were obtained. Unless otherwise specified, non-small cell lung cancer cells were cultured in tissue culture dishes (BD Falcon), in Dulbecco's Modified Eagle's Medium supplemented with 10 percent fetal bovine serum, glucose, L-glutamine, and penicillin / streptomycin, in a humidified atmosphere with 5% CO 2. Non-small cell lung cancer cells conditionally expressing transgenic BAK were obtained using the BD RevTet-On vector system (BD Clontech). A BamH I fragment encoding the full-length human BAK cDNA was generated by polymerase chain reaction, confirmed by sequencing, and cloned into the pRevTRE vector. Previously, a retroviral BCL-XL expression vector (26) has been described. Replicable defective retroviral virions were produced by transfection of standard calcium phosphate in the FNX Ampho packaging cell line (a present from Dr. G. P. Nolan, Stanford). Transductions were carried out using the filtered supernatants, and populations were selected with hygromycin B and puromycin, in the absence of tetracycline, or were obtained by fluorescence-activated cell selection (Coulter) of the cells positive for the green fluorescent enhanced protein. Example 2: Apoptosis assays Quantification of cells with fragmented DNA, activated caspases, lost mitochondrial transmembrane potential, and measurements of cell cycle distribution by flow cytometry (Coulter) as previously described was carried out ( 26, 38, 39). N-benzoyl-staurosporine (PKC412) was obtained from Novartis Pharma, Basel, Switzerland, and zVAD-fmk was obtained from ICN. All other drugs were obtained in Sigma. Example 3: Immunostaining Immunostaining and cell fractionation were carried out as previously described (38, 39), using primary antibodies against caspase-9 (Chemicon), caspase 3, BCL-XL, cytochrome c (BD Pharmingen) , BAX, BAK, PARP (Upstate), AKT, phospho-AKT, GSK-3teta, phospho-GSK3beta (Cel Signaling), and actin (ICN). Example 4: Resistance of non-small cell lung cancer cell lines In Figure 1A, NCI-460 non-small cell lung cancer cells efficient in TP53 (open boxes) and A549 (black boxes), NCI-H322 mutant of 7P53 (hollow triangles) and NCI-H23 (black triangles), and NCI-H1299 deficient in TP53 (hollow circles) and Calu-6 (black circles), were treated with etoposide (left column), cisplatin (column of right, lower panel), or doxorubicin (right column, upper and middle panel) in the indicated doses. After 48 hours, the percentage of cells with a subdiploid DNA content (sub-G1) was measured by flow cytometry, as an indicator of apoptosis. In Figure 1B, the same non-small cell lung cancer cell lines as those of Figure 1A, were treated with scaled doses of the protein kinase C-specific inhibitor PKC41 2. The percentages of cells with a DNA content were quantified. Subdiploid by flow cytometry after 48 hours of treatment. The average values + standard deviations (SD) of at least three independent experiments are given. In Figure 1 C, drug-sensitive NCI-H460 cells, and drug-resistant NCI-H 1299 cells were pretreated with PKC412 (1 to 10 μM) or with dimethyl sulfoxide for 2 hours, followed by stimulation. with PMA (1 μM) for 10 minutes. Whole cell extracts were analyzed by immunostaining using the indicated primary antibodies. Example 5: Synergy analysis of drugs NCI-H460 cells efficient in TP53 (Figure 2A, black bars), A549 cells (Figure 2B, white bars), and NCI-H 1 299 cells deficient in TP53 (Figure 2C, gray bars), were treated simultaneously with 25 μM etoposide, and with scaled doses of PKC41 2 (0, 5, 1 0, 50, 1 00 μM), and the cells were quantified with a subdiploid DNA content after 48 hours. The average values + standard deviation of at least three independent experiments are given. In Figure 2D, the cell cycle distribution of NCI-H1299 treated with dimethyl sulfoxide or with 50 μM PKC412 is given for 24 hours. In Figure 2E, the NC I-H 1299 cells were first treated with 25 μM etoposide for 24 hours, followed by the addition of 50 μM PKC41 for another 24 hours (black bars). Alternatively, the cells were treated with 50 μM PKC412 for 24 hours, followed by the addition of 25 μM etoposide for another 24 hours (gray bars). After 48 hours, the fraction of cells with a subdiploid DNA content (sub-G1) was quantified by flow cytometry. Cells treated with dimethyl sulfoxide (white bars) served as negative controls. The average values + standard deviation of at least three independent experiments are given. Example 6: Mitochondrial Function In Figure 3A, non-small cell lung cancer cells NCI-H460 (open boxes), A549 (black boxes), and NCI-H1299 (open circles), were treated with the indicated doses of PKC412 . After 48 hours, the cells were stained with the FITC-VAD fluorescent caspase substrate (Oncogene), and the fraction of FITC-positive cells with activated caspases (FITC +) was measured by flow cytometry. In Figure 3A, non-small cell lung cancer cells NCI-H460 (hollow boxes), A549 (black boxes), and NCI-H1299 (hollow circles), were treated with the indicated doses of PKC412. After 48 hours, the cells were stained with the mitochondrial dye of tetramethyl-rhodamine ethyl ester (TMRE, Molecular Probes), and the fraction of cells positive for TMRE with the conserved mitochondrial transmembrane potential (TMRE +) was quantified. by flow cytometry The average values + standard deviation of at least three independent experiments are given. In Figure 3C, non-small cell lung cancer cells NCI-H460 and A549 were treated with 25 μM etoposide, and cytosolic fractions were obtained at the indicated time points. The release of mitochondrial cytochrome c in the cytosol was detected by immunostaining, using a primary antibody specific for cytochrome c. In Figure 3D, whole cell extracts were prepared from non-small cell lung cancer cells A549 and NCI-H460 efficient in TP53, NCI-H23 and NCI-H322 mutants of TP53, and Calu-6 and NCI- H1299 deficient in TP53. The constitutive expression of BAX, BAK, and BCL-XL was detected by immunostaining. Example 7: BAK Conditional Expression In Figure 4A, A549 cells expressing BAK under the control of a tetracycline-regulated promoter were cultured in the absence (-) or presence (+) of doxycycline (DOX). Whole cell extracts were prepared 24 hours after induction of DOX, and analyzed for BAK expression by immunoassay. The cellular extracts of the NCI-H460 cells served as a control for the levels of endogenous BAK expression. In Figure 4B, non-small cell lung cancer cells NCI-H460, A549, and NCI-H1299 expressing BAK under the control of a tetracycline-regulated promoter were cultured in the absence (white bars) or in the presence ( black bars) of DOX, and cells with a subdiploid DNA content (sub-G1) were quantified by flow cytometry after 24 hours. The average values + standard deviation of three independent experiments are shown. In Figure 4C, A549 cells expressing BAK under the control of a tetracycline-regulated promoter were treated with 25 μM etoposide in the presence of DOX, and whole cell extracts were obtained at the indicated time points. The expression of BAK, and the dissociation of caspase 9, caspase 3, and the caspase substrate PARP, were detected by immunostaining. Figure 4D, A549 cells expressing BAK under the control of a tetracycline-regulated promoter were transduced to express BCL-XL (black bars) or a control vector (white bars) in conjunction with the green fluorescent enhanced protein, and selected positive populations for the green fluorescent protein enhanced by fluorescence-activated cell selection. BAK expression was induced by the addition of DOX, and cells with a subdiploid DNA content were quantified by flow cytometry after 48 hours. The average values + standard deviation of three independent experiments are shown. Example 8: Direction to Mitochondrial BAK Drug-resistant A549 cells (Figure 5A) and drug-sensitive NCI-H460 (Figure 5B) expressing BAK under the control of a tetracycline-regulated promoter were treated with escalating doses of PKC412 in absence (white bars) or in the presence (black bars) of DOX, to induce the expression of BAK. Cells with a subdiploid DNA content (sub-G1) were quantified by flow cytometry after 48 hours. The average values + standard deviation of at least three independent experiments are given. In Figure 5C, drug-resistant NCI-H1299 cells expressing BAK under the control of a tetracycline-regulated promoter were treated with escalating doses of PKC412 in the absence (white bars) or in the presence (black bars) of DOX, to induce the expression of BAK. The cells that maintained m m (TMRE +) were quantified by staining with TMRE and flow cytometry after 48 hours. The average values + standard deviation of at least three independent experiments are given. In Figure 5D, A549 cells expressing BAK under the control of a tetracycline-regulated promoter were treated with increasing doses of PKC412 (1 to 10 μM) in the absence or in the presence of DOX, to induce BAK expression. Whole cell extracts were obtained at 24 hours, and the dissociation of caspase 9, caspase 3, and caspase PARP substrate was detected by immunostaining. Example 9: Similar patterns of resistance to
Specific Inhibitors of Protein Kinase C and Cytotoxic Cancer Drugs in Non-Small Cell Lung Cancer In order to study a possible contribution of defects in the apoptotic core machine for drug resistance in non-cell lung cancer small, three pairs of cell lines that are efficient (A549, NCI-H460) deficient (NCI-H1299, Calu-6), or mutants (NCI-H23, NCI-H322) for the TP53 tumor suppressor gene were analyzed. Using a panel of clinically applied cytotoxic cancer drugs, including doxorubicin (DXR), cisplatin (CDDP), paclitaxel, actinomycin D (actD), and etoposide (VP16), we found a similar pattern of resistance to these cell lines that was independent of the respective cytotoxic agent (Figure 1A, and not shown). These results confirmed that the status of P53 is a poor predictor of sensitivity to cytotoxic therapies in non-small cell lung cancer. Because growth factor deprivation can induce apoptosis by mechanisms other than cell death triggered by DNA damage, we reason that inhibitors of growth factor signaling would be able to eliminate cancer cells resistant to these cytotoxic therapies. For this purpose, non-small cell lung cancer cell lines were treated with the specific inhibitors of staurosporine protein kinase C and its clinically applied derivative PKC412. Interestingly, cell lines that were protected against apoptosis induced by cytotoxic drugs, also showed reduced sensitivity to specific inhibitors of protein kinase C (Figure 1B, and not shown). This was not explained by the differences in inhibition of the target molecule, because PKC412 did indeed reduce the phosphorylation of targets downstream of the signal transduction of protein kinase C (9), such as protein kinase B / AKT, and 3-beta glycogen synthase kinase, in drug-resistant and drug-sensitive cell lines (Figure 1C, and not shown). Therefore, resistance to apoptosis induced by cytotoxic cancer drugs and protein kinase C inhibitors appeared to be determined by a common defect in the pathway of apoptotic signal transduction. Example 10: The Combination of PKC412 with Cytotoxic Cancer Drugs in Non-Small Cell Lung Cancer. Produced Variable Outcomes In order to explore whether the synergistic or additive effects of a combined treatment with PKC412 and cytotoxic cancer drugs can overcome drug resistance in non-small cell lung cancer, we first measured the induction of apoptosis following a simultaneous incubation with a fixed dose of topoisomerase inhibitor VP16, and increasing doses of PKC412. In sensitive cancer cell lines, such as NCI-H460, PKC412 did not result in any additional increase in apoptosis, compared to VP16 alone (Figure 2A), it is interesting that divergent results were obtained in cancer cell lines pulmonary, not drug-resistant small cell. Although combined treatment with PKC412 and VP16 produced additive cytotoxicity in A549 cells (Figure 2B), treatment with PKC412 actually protected NCI-H1299 cells against VP16-induced apoptosis (Figure 2C). To further delineate the influence of time and sequence of the application of PKC412 and VP16, the cells were previously treated with VP16 or with PKC412 for 24 hours, followed by the addition of the alternative drug for another 24 hours. Previous treatment with PKC412 resulted in a cell cycle arrest in the G2 / M phase, which is most likely explained by the inhibition of CDK1 activity (10) (Figure 2D). Interestingly, in NCI-H1299 cells, this G2 / M arrest reduced the amount of apoptosis induced by VP16 given subsequently to PKC412 (Figure 2E). In contrast, the amount of apoptosis found in the A549 previously treated with PKC412 was not significantly different from that observed following the previous treatment with VP16 (Figure 2E). Example 11: Defects in the Mitochondrial Path of the
Activation of Caspase in Non-Small Cell Lung Cancer Cells Resistant to PKC412 Apoptosis induced by DNA damaging agents and growth factor removal proceeds predominantly via the mitochondrial pathway of caspase activation (11, 12 ). To further dissect the mechanism of resistance to specific protein kinase C inhibitors in non-small cell lung cancer cell lines, we analyzed several steps of this pathway of apoptotic signal transduction. Non-resistant small cell lung cancer cell lines consistently shoa reduced activation of caspase, and a conserved mitochondrial transmembrane potential ("?? m") following treatment with specific inhibitors of protein kinase C or with the cytotoxic cancer drugs (Figures 3A, B, and not shown). The release of mitochondrial cytochrome c into the cytoplasm was also retarded, in the cell lines of non-small cell lung cancer resistant to drugs (Figure 3C). These results pointed to a block in the transduction of apoptotic signals at the level of BCL-2 family proteins. For this purpose, we studied the constitutive expression of the essential pro-apoptotic BH1-2-3 proteins BAX and BAK, and the anti-apoptotic protein BCL-XL in non-small cell lung cancer cell lines. Although BAX was consistently expressed in the six cell lines, the protein levels of BAK and BCL-XL shosome degree of variation (Figure 3D). However, none of these factors convincingly explained the pattern of resistance observed in non-small cell lung cancer cell lines. Example 12: Inducible Expression of Cancer Cells
Pulmonary No of Resistant Small Cells Sensitized to BAK. for PKC412 Mediated Apoptosis Based on our previous results, we reason that the therapeutic direction of pro-apoptotic BCL-2 family proteins would be able to overcome the functional block in caspase activation observed in non-pulmonary cancer cell lines. of small cells resistant to drugs. A pivotal step in this path is the permeabilization of the mitochondrial outer membrane (MOM), which is carried out by pro-apoptotic BCL-2 proteins BAX and BAK (1 3). Overexpression studies have shown that both molecules can directly induce permeabilization of the mitochondrial outer membrane and apoptosis (1 4-1 7). In a physiological context, BAX and BAK are negatively regulated by anti-apoptotic BCL-2 proteins, such as BCL-XL, MCL-1, or BCL-2. Direct or indirect positive regulation of BAX and BAK is achieved by the group of BH3 proteins only, including, but not limited to, BID and BIM, or PUMA, NOXA, BAD, and others (1 8, 1 9). In order to study the pharmacological modulation of BAK, which is directed constitutively towards the mitochondria, we generated a retroviral vector that made possible the conditional expression of the human BAK cDNA. In this system, the expression of transgenic BAK is induced at the level of transcription by the addition of doxycycline (DOX). The high transduction efficiencies achieved with this retroviral vector system allous to evaluate the populations of non-small cell lung cancer cell lines. This is a better reflection of a pharmacological treatment of a tumor, than studying the clones of individual cells. Furthermore, the levels of transgenic BAK expression in these populations did not exceed the levels of endogenous BAK observed in some non-small cell lung cancer cell lines (Figure 4A).
Induction of transgenic BAK expression resulted in some degree of apoptosis in non-small cell lung cancer cell lines resistant to drugs (Figure 4B). The apoptosis facilitated by the transgenic BAK was accompanied by the dissociation and activation of caspases and caspase substrates (Figure 4C), loss of ?? m >; and was inhibited by the expression of BCL-XL or by the broad spectrum caspase inhibitor zVAD-fmk (Figure 4D, and not shown). These results confirm that the transgenic BAK acts as its physiological counterpart in this experimental system.It is interesting that the conditionally expressed BAK effectively sensitized non-small cell lung cancer cell lines resistant to apoptosis induced by specific inhibitors of Protein kinase C or cytotoxic cancer drugs (Figures 5A, C, and not shown) This was explained by caspase activation following treatment with specific protein kinase C inhibitors only in the presence but not in the absence of DOX in these cell lines (Figure 5D) In contrast, the induction of BAK expression in non-small cell lung cancer cells sensitive to drugs only marginally increased the amount of apoptosis observed after of the treatment with specific inhibitors of protein kinase C (Figure 5B).
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Claims (25)
1. A method for the treatment or prevention of non-small cell lung cancer, the method comprising administering a tyrosine kinase inhibitor comprising a staurosporine derivative selected from a compound of Formula (II) or (III): wherein the compound (III) is the partially hydrogenated derivative of the compound (II); or the staurosporine derivatives of the Formula (IV) or (V) or (VI) or (Vil): wherein R 1 and R 2 are, independently of each other, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxyl, etherified or esterified hydroxyl, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxyl, esterified carboxyl, carbamoyl, N-mono- or N, N-di-substituted carbamoyl, sulfo, substituted sulfonyl, amino-sulfonyl, or amino-sulfonyl N-mono- or N, N-di-substituted; n and m are, independently of each other, a number from and including 0 up to and including 4; n 'and m' are, independently of each other, a number from and including 0 up to and including 4; R3, R4, Re, and R10 are, independently of one another, hydrogen, -O ", acyl with up to 30 carbon atoms, an aliphatic, carbocyclic, or carbocyclic-aliphatic radical with up to 29 carbon atoms in each case, heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, an acyl with up to 30 carbon atoms, where R4 may also be absent, or if R3 is acyl with up to 30 atoms of carbon, R4 is not an acyl, p is 0 if R is absent, or is 1 if R3 and R4 are both present, and in each case are one of the radicals mentioned above, R5 is hydrogen, an aliphatic, carbocyclic radical, or carbocyclic-aliphatic with up to 29 carbon atoms in each case, or a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, or acyl with up to 30 carbon atoms; , R6, and R9 are acyl or - (alkyl lower) -acyl, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxyl, etherified or esterified hydroxyl, amino, mono- or di-substituted amino, cyano, nitro, mercapto, substituted mercapto, carboxyl, carbonyl, carbonyldioxyl, esterified carboxyl, carbamoyl , N-mono- or N, N-di-substituted carbamoyl, sulfo, substituted sulfonyl, amino-sulfonyl, or amino-sulfonyl N-mono- or N, N-di-substituted; X represents 2 hydrogen atoms; 1 hydrogen atom and hydroxyl; OR; or hydrogen and lower alkoxy; Z represents hydrogen or lower alkyl; and whether the two bonds characterized by wavy lines are absent in ring A and replaced by 4 hydrogen atoms, and the two wavy lines in each ring B, together with the respective parallel link, mean a double bond; or, the two bonds characterized by the wavy lines are absent in ring B and are replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel link, mean a double bond; or, both in ring A and in ring B, all four wavy bonds are absent, and are replaced by a total of 8 hydrogen atoms; or a salt thereof, if at least one salt forming group is present; wherein the tyrosine kinase inhibitor treats or prevents non-small cell lung cancer.
2. The method according to claim 1, wherein the non-small cell lung cancer is sensitive to cytotoxic cancer drugs.
3. The method according to claim 2, wherein the treatment further comprises administering a topoisomerase inhibitor.
4. The method according to claim 3, wherein the topoisomerase inhibitor is VP16.
The method according to claim 1, wherein the non-small cell lung cancer has resistance to cytotoxic cancer drugs.
6. The method according to claim 5, wherein the treatment further comprises administering a modulator of BAK activity.
The method according to claim 6, wherein the modulator is an activator of BAK activity.
The method according to claim 5, wherein the treatment further comprises administering a composition that enhances the permeabilization of the mitochondrial outer membrane.
The method according to claim 1, wherein the non-small cell lung cancer is associated with a FLT-3 mutation.
The method according to claim 1, wherein the tyrosine kinase inhibitor is a compound of Formula (I): (l) or pharmaceutically acceptable salts thereof.
11. The use of a compound of Formula (I): (I) or pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for the treatment of non-small cell lung cancer.
12. The use according to claim 11, for the treatment of non-small cell lung cancer.
13. A method for the treatment of mammals suffering from non-small cell lung cancer, which comprises administering to a mammal in need of such treatment, an inhibitory amount of tyrosine kinase of a compound of Formula (I): (I) or pharmaceutically acceptable salts thereof.
14. A method according to claim 13, wherein the mammal is a human being.
15. A pharmaceutical preparation for the treatment of non-small cell lung cancer, which comprises a compound of Formula (I): (I) or pharmaceutically acceptable salts thereof.
16. A method for the treatment of non-small cell lung cancer in a mammal, which comprises treating the mammal in need of such treatment in a concurrent, concurrent, separate, or sequential manner, with pharmaceutically effective amounts of: (a) ) an inhibitor of FLT-3, or a pharmaceutically acceptable salt or a prodrug thereof, and (b) a modulator of BAK activity, or a pharmaceutically acceptable salt or a prodrug thereof.
17. The use of a combination of: (a) an inhibitor of FLT-3, or a pharmaceutically acceptable salt or a prodrug thereof, and (b) a modulator of BAK activity, or a pharmaceutically acceptable salt or a pro-drug thereof, for the treatment of non-small cell lung cancer.
18. The use according to claim 17, for the treatment of non-small cell lung cancer (NSCLC).
19. The use according to claim 17, wherein the inhibitor of FLT-3 is N - [(9S, 10R, 11R, 13R) -2,3,10,11, 12,13-hexahydro-10 -methoxy-9-methyl-1-oxo-9,13-epoxy-1 H, 9H-di-indole- [1, 2,3-gh: 3 ', 2', 1'-lm] -pyrrolo- [ 3,4-j] - [1,7] -benzodiazonin-11 -yl] -N-methyl-benzamide of Formula I: or a salt of it.
The use of claim 17, wherein the salt is a pharmaceutically acceptable salt.
21. A method for inducing drug sensitivity in a drug-resistant cancer cell, the method comprising inducing the pathway of apoptotic signal transduction in the cancer cell.
22. The method of claim 21, wherein the method comprises administering at least one activator of BAK activity.
The method of claim 21, wherein the method comprises administering at least one inhibitor of Bcl-1 / Bcl-XL activity.
The method of claim 21, wherein the sensitivity induced in the cancer cell is to a drug comprising a staurosporine derivative.
25. A method for the treatment of drug resistant cancer cells, the method comprising administering to a cancer cell, an apoptosis inducer and a staurosporine derivative. SUMMARY The present invention relates to a method for the treatment of non-small cell lung cancer with a FLT-3 kinase inhibitor, such as PKC412. The invention also relates to a pharmaceutical combination of a FLT-3 kinase inhibitor and an activator of mitochondrial outer membrane permeabilization, such as a BAK activator. It also relates to the use of a pharmaceutical combination of a mitochondrial outer membrane permeabilization activator and a FLT-3 kinase inhibitor, for the treatment of non-small cell lung cancer, and to the use of this pharmaceutical composition for the manufacture of a medication for its treatment. * * * * *
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