WO2019196965A2 - Pharmacy preparation for malignant melanoma treatment - Google Patents

Pharmacy preparation for malignant melanoma treatment Download PDF

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WO2019196965A2
WO2019196965A2 PCT/CZ2019/000018 CZ2019000018W WO2019196965A2 WO 2019196965 A2 WO2019196965 A2 WO 2019196965A2 CZ 2019000018 W CZ2019000018 W CZ 2019000018W WO 2019196965 A2 WO2019196965 A2 WO 2019196965A2
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concentration
nmol
cells
pmol
obatoclax
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PCT/CZ2019/000018
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French (fr)
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WO2019196965A3 (en
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Jiri VACHTENHEIM
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Univerzita Karlova
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to a pharmacy preparation for malignant melanoma treatment by combining three known active ingredients.
  • the application generally solves the issue of targeted treatment for tumor cells. Specifically, the issue of annihilation of cells of one type of tumor (melanoma) is addressed, employing a synergic combination of active ingredients, described below in the application.
  • Targeted treatment for neoplastic diseases means treatment by an active chemical (and/or chemicals), certified for use in human medicine by a state authority, for instance by the American agency FDA (Food and Drug Administration) or a transnational agency such as EMEA.
  • an active chemical and/or chemicals
  • a state authority for instance by the American agency FDA (Food and Drug Administration) or a transnational agency such as EMEA.
  • consent granted by Statni listav pro kontrolu leciv SKL - State Institute for Drug Control
  • tumor acquires (owing to many mutations occurring during tumor progression) resistance to the original treatment and becomes even“addicted” to administered medication (this condition is labelled as“drug addiction”) (3-5) and produces a pro-oncogenic“secretome”, supporting tumorous growth (6). It is therefore more complicated to respond to this situation compared to administration of the first medication.
  • administration of the first medication is naturally discontinued, and second medication is put on a course to continue therapy. Gradual resistance to this second medication develops very often.
  • Melanoma shows strong phenotypic heterogeneity already since the early stages (7, 8) and heterogeneity gradually increases. Presence of many various subpopulations of cells builds up its resistance as only a small part of subpopulations is sensitive to administered medication. Microheterogeneity and plasticity of phenotype are general treatment problems indicated also in other types of tumors (9,10).
  • Sidaway P Targeted therapies: Drug addiction revealed in BRAF and MEK inhibitor- resistant melanoma cells. Nat Rev Clin Oncol. 2015, 12(4): 189.
  • Faiao-Flores F Alves-Femandes DK
  • Pennacchi PC et al. Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells.
  • Oncogene. 2017, 36(13).T849-1861 18.
  • Stecca B Mas C, Clement V et al.: Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A. 2007, l04(14):5895-900.
  • the summary of the invention is to provide five different combinations of three agents - effective antineoplastic medications in one preparation on cells in the cell culture, specifically targeted against human malignant melanoma (advanced stages II - IV). In these stages, follow up treatment is largely ineffective (except for immunotherapy, which however works only in small percentage of cases).
  • the state of the art indicates that tumor cells must be eliminated in as short time as possible to make treatment effective.
  • cancer stem cells cancer stem cells
  • GANT61 and Obatoclax constituted the base of our triple-combination agent.
  • GANT61 is a potent agent, specifically inhibiting the activity of GLI factors, which are effectors of the Hedgehog signaling pathway (17-19), significant for progression of melanoma.
  • Obatoclax is a very strong inhibitor of the anti-apoptotic BCL2 family of genes and also inhibits anti- apoptotic protein Mcl-l (20, 21). In each case, one of the following five chemical was added to the referred base of two agents. JQ1, which is a very strong inhibitor of activity of epigenetic factor BRIM, significant for progression of melanoma (22).
  • concentration of active ingredients in the given triple-combination necessary to eradicate tumor cells is as follows: a) GANT61 from 10 to 20 pmol/l; b) Obatoclax from 150 to 300 nmol/l; cl) (+)-JQl from 125 to 500 nmol/l; c2) SGI-7079 from 125 to 500 nmol/l; c3) GSK343 from 0.25 to 1.0 pmol/l; c4) GSK126 from 25 to 100 nmol/l; and c5) HA15 from 2.5 to 10 pmol/l.
  • the objective of the solution was to find appropriate combinations of medications, file most effective to quickly eradicate tumor cells, a pre-requisite for successful targeted treatment.
  • Concentrations of agents, used in the patent application are most likely usable also for human application to the tumor tissue (verification demands further pharmacological studies already in the clinical testing stage).
  • Another objective of the invention was the requirement so that the combination of three agents would eradicate all molecular types of malignant melanoma, for example with mutations and without mutations of oncogenes BRAF, NRAS, RAC1, and others. Similar approach is original to the melanoma as well as all five applied combinations of targeted medications are original.
  • Fig. 3 shows four types of tumor cells of pancreatic cancers (application of the highest concentration of agents, i.e., experiments No. 16-20, see Tab. 2), affected by agents only slightly less than melanoma cells, only one pancreatic tumor line (PANC-l) is resistant to substances.
  • the lowest concentrations of agents applied to melanoma cells (Tab. 3 exp. 6-10, and Fig. 4) increased their resistance, with the lowest concentration of agents (Tab. 2. exp. 11-15, and Fig.
  • the first two agents i.e., GANT61 and Obatoclax
  • GANT61 and Obatoclax act in synergy and exhibit the so-called synthetic lethality in their combined application on melanoma cells
  • GANT61 kills melanoma cells and acts in synergy with Obatoclax. Int J Oncol. 2016, 49(3):953-60). Therefore, GANT61 and Obatoclax were selected as the base of each of five triple-combinations. Additional one agent was added to these two compounds. Five additional active ingredients were used (one in each triple-combination) thus, five different mixtures (“cocktails”) were made, tested in various concentrations as to their speed of eradication of melanoma cell.
  • the compound 3 ((+)-JQl): It is an inhibitor of the so-called BET bromodomain, which strongly and specifically inhibits BET domain, which is contained in the epigenetic factor BRD4.
  • JQ1 acts as inhibitor of many tumors, including melanoma. Its extremely powerful effect assumes the importance of BRD4 factor in oncogenesis. Therefore, substance 3 ((+)-JQl) was selected for its very strong and specific effect on many types of tumor cells including melanoma.
  • BRD4 is an oncogene protein with recurrent translocation in many tumors and competitive binding by JQ1 displaces the BRD4 oncoprotein from chromatin.
  • the compound 4 (SGI-7079): It is a strong inhibitor to Axl kinase protein which, recently, has been shown as a marker of invasive and oncogene properties of melanoma cells (Sensi M, Catani M, Castellano G, et al.: Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional Axl receptor kinase. J Invest Dermatol. 2011, 13 l(l2):2448-57). Its level is increased in subpopulations with high invasiveness and its increase is accompanied with drop of the key transcription factor of melanoma MITF (Muller J, Krijgsman O, Tsoi J. et al.: Low MITF/Axl ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Common. 2014, 5:5712).
  • GSK343 is a potent and selective EZH2 inhibitor (an enhancer of zeste homolog 2). It is strongly specific to EZH2 with 60-fold higher selectivity of inhibition compared to the related protein EZH1 and shows >1, 000-fold higher selectivity compared to other histone methyltransferases.
  • EZH2 is a histone methyltransferase, causing trimethylation of histone 3 at lysine 27 (H3K27me3), thus representing a typical epigenetic modulator.
  • EZH2 is a subunit of the so-called“polycomb repressive complex 2 (PRC2)”.
  • GSK126 Similarly to the compound 5, this compound is a potent inhibitor of EZH2.
  • GSK126 is a potent and selective inhibitor of EZH2 methyltransferase, also more than 1, 000-fold more selective for EZH2 than for twenty other human methyltransferases. I.e., we used this agent as the second alternative with similar chemical and biological properties as the agent No. 5.
  • EZH2 acts as a transcription activator or repressor, depending on the cell context
  • the agent overcomes known resistance caused by application of BRAF inhibitor (mutated and activated oncogene in ca. 60% of cases of melanoma).
  • the specific target of this agent is a chaperone complex BiP/GRP78/HSPA5 and activity of HA15 in the cell induces endoplasmic reticulum stress with subsequent cell death by autophagy and apoptosis (Cerezo M, Rocchi S.: New anti-cancer molecules targeting HSPA5/BIP to induce endoplasmic reticulum stress, autophagy and apoptosis. Autophagy. 2017, 13(1):216-217).
  • GANT61 is an inhibitor for GLI1 as well as GLI2 -induced transcription by disabling the binding activity of mentioned transcription factors to DNA.
  • GANT61 is an inhibitor for GLI1 as well as GLI2-induced transcription, inhibits Hedgehog signalling pathway with IC50 of 5 mM in GLI1 -expressing HEK293T cells.
  • GLI inhibitor GANT61 kills melanoma cells and acts in synergy with obatoclax. Int J Oncol. 2016, 49(3):953-60 (12);
  • GLI1 inhibitor GANT61 exhibits antitumor efficacy in T-cell lymphoma cells through down-regulation of p-STAT3 and SOCS3. Oncotarget. 2017, 8(30):48701-487l0.
  • Pharmacological activity (according to selleckchem.com): an antagonist of BCL-2 with Kj of 0.22 mM.
  • Obatoclax a BH3 mimetic, is capable of binding and inhibiting a broad spectrum of members of the BCL-2 family, i.e., BCL-2, Bcl-xL as well as Mcl-l.
  • Obatoclax is used as the mesylate salt, in the literature can also be found references to tartrate salt (tartaric acid salt) or hydrochloride salt.
  • GLI inhibitor GANT61 kills melanoma cells and acts in synergy with obatoclax. Int J Oncol. 2016, 49(3):953-60 (12);
  • Pan-Bcl-2 inhibitor obatoclax delays cell cycle progression and blocks migration of colorectal cancer cells.
  • Compound 3
  • (+)-JQl is a BET bromodomain inhibitor, IC50 of 77 nM/33 nM for BRD4(l/2) protein in vitro, binding is specific only to the BET family of proteins.
  • (+)-JQl 500 nM decreases the rapid proliferation of NMC 797 and Per403 cells in the culture.
  • (+)- JQ1 50 mg/kg inhibits growth of tumors from NMC 797 cells in nude mice.
  • the agent is a BET bromodomain inhibitor, with IC50 of 77 nM and 33 nM for BRD4(l), resp. BRD4(2) in the non-cell experiment in vitro.
  • Pharmacological activity (according to selleckchem.com): a potent and selective EZH2 protein inhibitor with IC50 of 4 nM in the in vitro reaction, showing 60-fold higher selectivity compared to EZH1, and 1,000-fold more selective for EZH2 also in comparison with twenty other human methyltransferases.
  • Example of biological effect in vitro or in vivo (according to selleckchem.com): inhibits trimethylation of lysine H3K27 (H3K27me3) with IC50 of 174 nM in tumor cells of mammary gland HCC1806, strongly inhibits cell proliferation in tumor cells in mammary gland and prostate gland (tumor line of the prostate gland LNCaP is the most sensitive to GSK343, with IC50 of 2.9 mM).
  • Pharmacological activity (according to selleckchem.com): a potent, highly selective EZH2 methyltransferase inhibitor with IC50 of 9.9 nM, >1, 000-fold more selective for EZH2 compared with twenty other human methyltransferases.
  • Example of biological effects in vitro or in vivo potently inhibits methylation to H3K27me3 (histone H3 lysine 27 trimethylation) and H3K27me3 in both EZH2 wild-type and mutant DLBCL cells. Effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and induces transcriptional activation of EZH2 target genes in sensitive cell lines.
  • H2087 cells inhibits expression of VEGF-A and phosphorylase kinase Ser(473)-AKT, thus triggering inhibition of cell proliferation, migration, and metastases.
  • HA15 is a molecule specifically inhibiting protein complex BiP/GRP78/HSPA5.
  • HA15 induces endoplasmic reticulum stress leading to cell death in vitro and overcomes BRAF inhibitor resistance in melanoma cells.
  • IC50 has not been determined yet.
  • Fig. 1 Published (citation (12) experimental therapy for the cell culture by double- combination of compounds GANT61 and Obatoclax (in this experiment in the concentration of only 100 nM, contrary to triple-combinations, and showing hardly any effect on melanoma cells as an independently applied agent). The picture is borrowed from the publication (12).
  • Fig. 2 Experiments carried-out with the highest concentrations of agents (unpublished experiment). It can therefore be clearly concluded that all six types of melanoma cells in the culture were totally eradicated in a very short time (max. in five days) by all five triple- combinations of antineoplastic compounds applying the highest concentrations (Tab. 2, experiments No. 1-5). Identification C.I, C.II, etc. in Fig. 2 always indicates number of the applied triple-combination (C as a“combination” or“cocktail”). This is the main (and remarkably successful) result of experimental part of the application.
  • Fig. 3 Comparison of effectiveness of applied triple-combinations on tumor cells of the pancreas (unpublished experiment). These cells were slightly more resistant in the highest concentration of agents (other concentrations were not tested), PANC-l cell line was totally resistant, eradicated only by the first triple-combination as late as on the 7 day after its application on the cells. Identification C.I, C.II, etc. in Fig. 3 always indicates number of the applied triple combination.
  • Fig. 4 Experiments carried-out with the medium concentrations of agents (unpublished experiment). It can therefore be concluded that the medium concentrations of applied agents (Tab. 2, exp. 6-10) eradicated the cells and period of their survival extends (except for the line SK-MEL-3, which is highly sensitive). Nevertheless, except for the cell line SK-MEL-28, all cells are eradicated as late as on the 7 th day of the experiment also with these concentrations, applying all five types of combinations. Identification C.I, C.II, etc. in Fig. 4 always indicates number of the applied triple combination.
  • Fig. 5 Experiments carried-out with the lowest concentrations (unpublished experiment). It can therefore be clearly concluded that with the lowest applied concentrations of agents (Tab. 2, exp. 11-15) by the triple-combination of antineoplastic compounds two cell lines of melanoma cells (50lmel and SK-MEL-3) were completely eradicated in a very short period of time (max. after five days) when applying the triple-combination of antineoplastic compounds, specifically all cells in all five“cocktails”. On the contrary, two cell lines (MeWo and SK- MEL-28) were resistant to the application of medications as late as on the 7 th day, except for the combination No. 5, where cells were eradicated already on the 3 rd , resp. 5 th day of the experiment. Identification C.I, C.II etc. in Fig. 5 always indicates number of the applied triple combination. It appeared again that the cell line SK-MEL-3 was highly sensitive also to low concentrations of agents.
  • Day-by-day cell survival test used the method of the so-called“colony forming assay”.
  • Cells were disseminated into wells; after their adhesion to the plastic surface (all types of cells represented adherent cells), the next day was considered as the day 0, when agent combinations were added. The next day was identified as the day 1 etc.
  • Quantity of remaining cells was analysed on the days 1, 3, 5 and 7. Dark fields illustrate presence of cells, light fields illustrate absence of cells.
  • Each cell line contains controlling segment, where only solvent was added (left column in Fig. 2-5, in Fig. 1 controls are in the upper line).
  • Some agents were dissolved in dimethyl sulfoxide (DMSO), some in ethanol. I.e., only mixture of DMSO/ethanol 3:2 was added to the controlling segments.
  • DMSO dimethyl sulfoxide
  • This application deals with a unique embodiment of the invention, falling into the broad spectrum of solutions to an“appropriate combination of antineoplastic medicaments applicable from the beginning of tumor treatment”. 100% effectiveness of all five triple combinations of medicaments on cell cultures of melanoma cells in one (the highest) concentration was confirmed. Various, precisely defined, concentrations of agents were applied, and authentic results are displayed in the pictures. Applications of lower concentrations revealed varied sensitivity of melanoma lines to the individual triple-combinations; naturally, period of eradication of cells prolonged. In summary, melanoma cells were eradicated in all experiments (except for two extraordinary resistant cell lines with the lowest concentrations of compounds - Fig. 5) not later than 7 days from administration of the medicament.
  • control solution without added inhibitors
  • a solution (2 parts of ethanol (100%) + 3 parts of dimethyl sulfoxide (DMSO, 100%)) was used as a vehicle in control cells.
  • all combinations in 1,000- fold working concentrations were 1,000-fold diluted to the final concentration lx in the appropriate cultivation media and applied on the cells.
  • 1,000-fold diluted control solution, as already lx control solution does not affect cell growth at all.
  • Final (“working”) concentrations of all agents (applied on cells) are shown for each experiment in Tab. 2.

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PCT/CZ2019/000018 2018-04-11 2019-04-10 Pharmacy preparation for malignant melanoma treatment WO2019196965A2 (en)

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CZ2018-181A CZ308400B6 (cs) 2018-04-11 2018-04-11 Farmaceutický přípravek pro léčení maligního melanomu
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