WO2004026319A2 - Compositions pharmaceutiques utilisees pour le traitement de cancers - Google Patents

Compositions pharmaceutiques utilisees pour le traitement de cancers Download PDF

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WO2004026319A2
WO2004026319A2 PCT/EP2003/010280 EP0310280W WO2004026319A2 WO 2004026319 A2 WO2004026319 A2 WO 2004026319A2 EP 0310280 W EP0310280 W EP 0310280W WO 2004026319 A2 WO2004026319 A2 WO 2004026319A2
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camp
pharmacologically acceptable
retinoic acid
acceptable salts
derivatives
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PCT/EP2003/010280
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WO2004026319A3 (fr
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Hugues De The
Marie-Claude Colette Raymonde Guillemin-Debons
Michel Lanotte
Laurent Degos
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Centre National De La Recherche Scientifique
Institut National De La Sante Et De La Recherche Medicale (Inserm)
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Publication of WO2004026319A3 publication Critical patent/WO2004026319A3/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/285—Arsenic compounds
    • 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
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to new pharmaceutical compositions useful for the treatment of cancers.
  • Cancers are a group of pathologies characterized, in particular, by abnormal cell proliferation.
  • one of them relies on the induction of cell differentiation to halt the multiplication of cancerous cells.
  • certain leukemia notably acute myeloid leukemia
  • these malignancies are often associated to recurrent chromosomal translocations, most of which encode fusion proteins derived from transcription factors (1).
  • Functional analyses of several of these fusion proteins have shown that they behave as potent transcriptional repressors (2), often through modifications of chromatin structure by histone desacetylases, blocking expression of unidentified genes that control myeloid differentiation.
  • APL acute promyelocytic leukemia
  • RA retinoic acid
  • As 2 O 3 arsenic trioxide
  • Cyclic AMP (cAMP, adenosine 3 '-5' cyclic monophosphate), or its derivatives, could also be viewed as a drug of choice for the induction of differentiation. Indeed, ex vivo, activation of the cAMP signal transduction pathway differentiates many acute myeloid leukemia cell-line and strongly synergizes with other differentiating agents
  • an object of the present invention is to provide new pharmaceutical compositions, comprising at least one compound activating the cAMP signal transduction pathway, useful for the treatment of cancers.
  • the present invention relates to the use of at least one agent enabling to increase the cellular content of cAMP or derivatives thereof with respect to the originally present cellular content of said cAMP or said derivatives, for the preparation of a drug for the treatment of cancers.
  • cAMP corresponds to the following formula:
  • cAMP derivatives of cAMP are well known to the man skilled in the art, they notably comprise 8-Cl-cAMP, 8-CPT-cAMP, 8-Br-cAMP and dibutyryl-cAMP, or pharmacologically acceptable salts thereof.
  • the "originally present cellular content of cAMP" relates to the cAMP content of cells prior to the addition to said cells of any compound liable to modify the cellular concentration of cAMP .
  • cAMP cyclopentasergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic asergic phosphate, or of its derivatives, can be measured according to methods well known to the man skilled in the art.
  • the cAMP content of a cell results from an equilibrium between two opposite reaction types, i.e. reaction concurring to the synthesis of cAMP, such as reactions catalyzed by adenylate cyclases, and reactions concurring to the degradation of cAMP, such as reactions catalyzed by phosphodiesterases (PDE). Consequently, a rise in the cellular content of cAMP can be observed following addition of compounds either activating cAMP synthesis or inhibiting cAMP degradation.
  • reaction concurring to the synthesis of cAMP such as reactions catalyzed by adenylate cyclases
  • PDE phosphodiesterases
  • an "agent enabling to increase the cellular content of cAMP or derivatives thereof can be for instance, cAMP or a derivative thereof in itself, or an agent activating the intracellular synthesis of cAMP, or an agent inhibiting the intracellular degradation of cAMP or derivatives thereof, provided it is added to cells in an amount sufficient to lead to an increase of the cAMP content of said cells.
  • the present invention also relates to the use of:
  • - at least one apoptotic inducer for the preparation of a drug for the treatment of cancers.
  • a “cell differentiation factor” refers to compounds liable to induce cellular differentiation, such as retinoic acid, interferons, cytokines or growth factors.
  • an "apoptotic inducer” refers to compounds liable to induce programmed cell death, such as cancer chemotherapeutic agents or arsenic derivatives (As 2 O 3 , As 4 S 4 ).
  • the invention relates to the use of:
  • - at least one agent enabling to increase the cellular content of cAMP or derivatives thereof with respect to the originally present cellular content of said cAMP or said derivatives and - at least one cellular differentiating factor or precursors or derivatives thereof for the preparation of a drug for the treatment of cancers.
  • the invention relates to the use of:
  • the invention relates to the use of:
  • - at least one apoptotic inducer for the preparation of a drug for the treatment of cancers.
  • the agent enabling to increase the cellular content of cAMP or derivatives thereof with respect to the originally present cellular content of said cAMP or said derivatives is selected from the group comprising cAMP, 8-Cl-cAMP, 8-CPT-cAMP, 8-cAMP, dibutyryl-cAMP or pharmacologically acceptable salts thereof.
  • Particular cAMP derivatives can be selected according to their respective properties, well known to the man skilled in the art, such as stability, solubility, efficacity, or toxicity, as compared to cAMP or other cAMP derivatives, for a given use.
  • the invention relates more particularly to the abovementioned uses, wherein the agent enabling to increase the cellular content of cAMP or derivatives thereof with respect to the originally present cellular content of said cAMP or said derivatives is a phosphodiesterase inhibitor.
  • cAMP, and other cyclic nucleotides are respectively hydrolyzed to AMP, and to the corresponding acyclic nucleotide, by phosphodiesterases (PDE); phosphodiesterase inhibitors limit the hydrolysis of cAMP, and of other cyclic nucleotides, and thus enable to increase the cellular content of cAMP, and of other cyclic nucleotides, as discussed above.
  • the invention also relates to the preceding use, wherein the phosphodiesterase inhibitor is selected from the group comprising methylxanthines such as caffeine or theophylline or aminophylline or isobutyl-methylxanthine, rolipram, sildenafil, vardenafil, zaprinast, or methoxyquinazoline.
  • methylxanthines such as caffeine or theophylline or aminophylline or isobutyl-methylxanthine, rolipram, sildenafil, vardenafil, zaprinast, or methoxyquinazoline.
  • Xanthine corresponds to the following formula:
  • Methylated derivatives of xanthine are phosphodiesterase inhibitors well known to the man skilled in the art and correspond for example to:
  • Aminophylline (1,3 dimethylxanthine complexed to diaminoethan):
  • aminophylline has an increased solubility as compared to theophylline.
  • Rolipram, sildenafil (Viagra®), vardenafil, zaprinast, or methoxyquinazoline, are phosphodiesterase inhibitors well known to the man skilled in the art.
  • the invention more particularly relates the above mentioned use, wherein the phosphodiesterase inhibitor is theophylline or aminophylline.
  • the invention relates to the preceding uses wherein the cell-differentiation factor or precursors or derivatives thereof is selected from the group comprising retinoic acid, particularly all-trans retinoic acid or 9-cis retinoic acid or 13-cis retinoic acid, or pharmacologically acceptable salts thereof, vitamin A (retinol), carotene or rexinoids.
  • retinoic acid particularly all-trans retinoic acid or 9-cis retinoic acid or 13-cis retinoic acid, or pharmacologically acceptable salts thereof, vitamin A (retinol), carotene or rexinoids.
  • Rexinoids are specific ligands of the RXR receptors, they notably comprise LG 100268 (LG268) or LGD 1068 (Targretin) for example.
  • LGD 1068 LG268 The invention also relates to the abovementioned use wherein the cell- differentiation factor or precursors or derivatives thereof is retinoic acid, particularly all-trans retinoic acid, or pharmacologically acceptable salts thereof.
  • the invention relates to the above mentioned use, wherein the apoptotic inducer is selected from the group comprising arsenic trioxide (As 2 O 3 ) or arsenic sulfide (As 4 S 4 ).
  • Arsenic trioxide is notably described in Chen et al. (1996) Blood 88:1052-1061.
  • Arsenic sulfide is notably described in Lu et al. (2002) Blood 99:3136-3143. . Both compounds have similar properties and act on similar cellular targets.
  • the invention relates to the above mentioned use of theophylline or aminophylline and retinoic acid or pharmacologically acceptable salts thereof, for the preparation of a drug for the treatment of cancers.
  • theophylline, or aminophylline synergizes with retinoic acid.
  • the present invention also relates to the abovementioned use of theophylline or aminophylline and arsenic trioxide or arsenic sulfide, for the preparation of a drug for the treatment of cancers.
  • theophylline, or aminophylline synergizes with arsenic trioxide, or arsenic sulfide.
  • the present invention equally relates to the abovementioned use of theophylline or aminophylline, retinoic acid or pharmacologically acceptable salts thereof and arsenic trioxide or arsenic sulfide, for the preparation of a drug for the treatment of cancers.
  • the association of theophylline, or aminophylline, and retinoic acid, and arsenic trioxide, or arsenic sulfide, is synergic.
  • the invention relates in particular to abovementioned uses, wherein the cancers are selected from the group comprising solid tumor cancer, neuroblastoma, skin cancer, oral cavity cancer, lung cancer, mammary gland cancer, prostatic cancer, bladder cancer, liver cancer, pancreatic cancer, cervical cancer, ovarian cancer, head and neck cancer, colon cancer, germ cell cancer, leukemia, acute leukemia, acute myelocytic leukemia, acute promyelocytic leukemia, aleukemic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia.
  • the cancers are selected from the group comprising solid tumor cancer, neuroblastoma, skin cancer, oral cavity cancer, lung cancer, mammary gland cancer, prostatic cancer, bladder cancer, liver cancer, pancreatic cancer, cervical cancer, ovarian cancer, head and neck cancer, colon cancer, germ cell cancer, leukemia, acute leukemia, acute myelocytic leukemia, acute promyelocytic leukemia, aleukemic leuk
  • the invention relates to products containing 8-Cl-cAMP or pharmacologically acceptable salts thereof and retinoic acid or pharmacologically acceptable salts thereof and/or arsenic trioxide or arsenic sulfide, as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
  • the invention relates in particular to products as defined above, containing 8-C1- cAMP or pharmacologically acceptable salts thereof and retinoic acid or pharmacologically acceptable salts thereof, as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
  • the invention more particularly relates to the above defined products, containing 8- Cl-cAMP or pharmacologically acceptable salts thereof and arsenic trioxide or arsenic sulfide, as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
  • the invention further relates to the abovementioned products, containing 8-C1- cAMP or pharmacologically acceptable salts thereof, retinoic acid or pharmacologically acceptable salts thereof and arsenic trioxide or arsenic sulfide, as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
  • the invention relates to products containing aminophylline or theophylline and retinoic acid or pharmacologically acceptable salts thereof and/or arsenic trioxide or arsenic sulfide, as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
  • the invention relates in particular to products as defined above, containing aminophylline or theophylline and retinoic acid or pharmacologically acceptable salts thereof, as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
  • the invention also relates to products as defined above, containing aminophylline or theophylline and arsenic trioxide or arsenic sulfide, as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
  • the invention relates to products as defined above, containing aminophylline or theophylline, retinoic acid or pharmacologically acceptable salts thereof and arsenic trioxide or arsenic sulfide, as a combined preparation for simultaneous, separate or sequential use in cancer treatment.
  • the present invention also relates to a pharmacological composition
  • a pharmacological composition comprising as active substance 8-Cl-cAMP or pharmacologically acceptable salts thereof and retinoic acid or pharmacologically acceptable salts thereof and/or arsenic trioxide or arsenic sulfide, in association with a pharmacologically acceptable vehicle.
  • the invention relates in particular to a pharmacological composition as defined above, wherein the active substance is 8-Cl-cAMP or pharmacologically acceptable salts thereof and retinoic acid or pharmacologically acceptable salts thereof, in association with a pharmacologically acceptable vehicle.
  • the invention also relates to a pharmacological composition as defined above, wherein the active substance is 8-Cl-cAMP or pharmacologically acceptable salts thereof and arsenic trioxide or arsenic sulfide, in association with a pharmacologically acceptable vehicle.
  • the invention further relates to a pharmacological composition as defined above, wherein the active substance is 8-Cl-cAMP or pharmacologically acceptable salts thereof, retinoic acid or pharmacologically acceptable salts thereof and arsenic trioxide or arsenic sulfide, in association with a pharmacologically acceptable vehicle.
  • the present invention also relates to a pharmacological composition comprising as active substance theophylline or aminophylline and retinoic acid or pharmacologically acceptable salts thereof and/or arsenic trioxide or arsenic sulfide, in association with a pharmacologically acceptable vehicle.
  • the invention relates in particular to a pharmacological composition as precedingly defined, wherein the active substance is theophylline or aminophylline and retinoic acid or pharmacologically acceptable salts thereof, in association with a pharmacologically acceptable vehicle.
  • the invention relates to a pharmacological composition as defined above, wherein the active substance is theophylline or aminophylline and arsenic trioxide or arsenic sulfide, in association with a pharmacologically acceptable vehicle.
  • the invention also relates to an abovementioned pharmacological composition, wherein the active substance is theophylline or aminophylline, retinoic acid or pharmacologically acceptable salts thereof and arsenic trioxide or arsenic sulfide, in association with a pharmacologically acceptable vehicle.
  • the invention relates in particular to a pharmacological composition as defined above, in a form appropriate for the administration of about 0.36 mg/kg/day to about 14.3 mg/kg/day of theophylline or aminophylline, of about 4.5 mg/m 2 /day to about 135 mg/m 2 /day of all-trans retinoic acid and of about 0.014 mg/kg/day to about 0.43 mg/kg/day of arsenic trioxide.
  • a pharmacological composition as defined above, in a form appropriate for the administration of about 0.36 mg/kg/day to about 14.3 mg/kg/day of theophylline or aminophylline, of about 4.5 mg/m 2 /day to about 135 mg/m 2 /day of all-trans retinoic acid and of about 0.014 mg/kg/day to about 0.43 mg/kg/day of arsenic trioxide.
  • Figure 1 A represents the spleen weight (vertical axis, mg) of retinoic acid sensitive mice treated (+) or untreated (-) by 8-Cl-cAMP during 7 days.
  • Figure IB represents the spleen weight (vertical axis, mg) of retinoic acid sensitive mice treated (+) or untreated (-) by 8-Cl-cAMP during 7 days.
  • Figures 1C, ID, IE et IF represent pictures of bone marrow samples, after May-
  • MMGG Gr ⁇ nwald-Giemsa
  • Figures 1G, 1H, II et 1 J represent pictures of liver samples, after hematoxylin-eosin staining, taken from retinoic acid sensitive mice treated (figure 1G) or untreated
  • Figure 2A represents the spleen weight (vertical axis, mg) of a retinoic acid sensitive mouse model of APL treated during 3 days by 8-Cl-cAMP (cAMP), As 2 O 3 (As), 8-C1- cAMP and As 2 O 3 (cAMP + As), or untreated (0).
  • cAMP retinoic acid sensitive mouse model of APL treated during 3 days by 8-Cl-cAMP
  • As 2 O 3 As
  • 8-C1- cAMP As 2 O 3
  • cAMP + As As 2 O 3
  • Figure 2B represents a western blot of protein extracts of bone of retinoic acid f sensitive APL mice revealed by an anti-p21 antibody (arrow).
  • the APL mice were either treated 24 h in vivo by retinoic acid (RA), As 2 O 3 (As), 8-Cl-cAMP (cAMP), or untreated (0).
  • the star (*) denotes to a cross-reactive protein.
  • Figure 2C represents a picture of a bone marrow sample, after May-Griinwald-Giemsa
  • MMG retinoic acid sensitive APL mice treated by 8-Cl-cAMP (cAMP), As O 3 (As), 8-Cl-cAMP and As 2 O 3 (cAMP + As), during 3 days, or untreated (0).
  • Figure 2D represents a picture of a liver sample, after hematoxylin-eosin staining, taken from retinoic acid sensitive APL mice treated by 8-Cl-cAMP (cAMP), As 2 O 3
  • Figure 2E represents a picture of a bone marrow sample, after May-Griinwald-Giemsa (MGG) staining, taken from retinoic acid sensitive APL mice treated by theophylline (T), As 2 O 3 (As), theophylline and As 2 O 3 (T + As), during 3 days, or untreated (0).
  • MMG May-Griinwald-Giemsa
  • Figure 2F represents the percentage of NBT positive NB4 cells (vertical axis) treated by As 2 O 3 at various concentrations (from left to right) 0, 10 "10 , 10 “9 , 10 “8 , 10 “7 , 10 “6 M, in the presence (+) or the absence (-) of 8-Cl-cAMP.
  • Figure 3 A represents the spleen weight (vertical axis, mg) of a retinoic acid sensitive mouse model of APL treated during 7 days by retinoic acid (RA), 8-Cl-cAMP
  • cAMP retinoic acid
  • RA + cAMP 8-Cl-cAMP
  • Figure 3B represents a picture of a bone marrow sample, after May-Griinwald-Giemsa
  • FIG. 3C represents a picture of a bone marrow sample, after May-Griinwald-Giemsa
  • MCG retinoic acid sensitive APL mice treated by retinoic acid and 8-Cl-cAMP during 7 days.
  • Figure 3D represents the number of bone marrow blasts (horizontal axis) marked by an anti-CD 11 antibody (vertical axis) of APL mice treated for 24 hours by cAMP (cAMP), As 2 O 3 (As), 8-Cl-cAMP and As 2 O 3 (As + cAMP) or untreated (0).
  • cAMP cAMP
  • As 2 O 3 As
  • 8-Cl-cAMP As 2 O 3
  • As + cAMP untreated (0).
  • Figure 4A represents the spleen weight (vertical axis, mg) of a retinoic acid resistant mouse model of APL treated during 7 days by 8-Cl-cAMP (cAMP), As 2 O 3 (As), retinoic acid (RA), retinoic acid and 8-Cl-cAMP (RA + cAMP), As 2 O 3 and 8-C1- cAMP (As + cAMP), retinoic acid and As 2 O 3 (RA + As), or untreated (0).
  • cAMP 8-Cl-cAMP
  • As 2 O 3 As
  • RA retinoic acid
  • RA + cAMP As 2 O 3 and 8-C1- cAMP
  • RA + As As 2 O 3
  • untreated (0) untreated
  • Figures 4B, 4C, 4D, 4E, 4F, 4G, 4H, 41, 4J represent pictures of bone marrow samples, after May-Griinwald-Giemsa (MGG) staining, taken from retinoic acid resistant APL mice treated by 8-Cl-cAMP (Figure 4C), As 2 O 3 ( Figure 4E), retinoic acid ( Figure 4D), retinoic acid and 8-Cl-cAMP ( Figure 4F, 4G), As 2 O 3 and 8-Cl-cAMP ( Figure 4H), retinoic acid and As 2 O 3 ( Figure 41), or untreated (Figure 4B).
  • Figures 5A, 5B and 5C represent pictures of bone marrow samples taken at day 0 (figure 5A), at day 14 (figure 5B) or at day 28 (figure 5C) from a retinoic acid/As2O3 resistant APL patient treated by a combined retinoic acid As2O3 therapy.
  • Figures 5D, 5E and 5F represent pictures of bone marrow samples taken at day 0
  • FIG. 5D is a schematic representation of the clinical events of the treatment of a patient by a combined theophylline/ As2O3/RA therapy.
  • the horizontal axis represents the time course in weeks.
  • the left upward vertical axis and the corresponding curves represent hemoglobin concentration (Hb) in gr/1 and the platelet (Pit) count per mm 3 (times 10 3 ), the right upward vertical axis and the corresponding curve represent the white blood cells (WBC) count per mm 3 (times 10 3 ).
  • the left downward vertical axis and the left bars represent the blast count in percent
  • the right downward vertical axis and the right bars represent the erythroblast count in percent
  • the upper downward arrows represent red cells transfusions and the lower downward arrows represent platelet transfusions.
  • the three upper horizontal black bars at the bottom of the figure represent the periods of combined As2O3/all-trans retinoic acid treatment (As 2 O 3 /ATRA), the lower horizontal black bar at the bottom represent the period of theophylline treatment.
  • cAMP synergizes with AS2O 3 to differentiate APL cells ex vivo cAMP is well-known to greatly enhance RA-induced (retinoic acid) differentiation of many cell lines derived from embryonal carcinoma or myeloid leukemia, in particular APL (acute promyelocytic leukemia) (11). Low concentrations of As 2 O can induce incomplete differentiation in an APL cell line (7). The Inventors tested the hypothesis that cAMP would also enhance As O 3 -induced differentiation.
  • the APL model cell line NB4 was cultured as described previously in Lanotte et al.
  • the Inventors turned to a transplantation APL model (14) derived from RA-sensitive PML/RARa transgenics (18).
  • the Inventors similarly developed a transplantation model for RA-resistant APL using leukemic cells from PML/RARa transgenics in which a point mutation in the transgene impairs the binding of RA to PML/RARo: (16).
  • Alzet pumps (0.5 ⁇ l/h, Cupertino, CA) were loaded with 8-Cl-cAMP (20 mg/ml) and implanted subcutaneously on the back of treated mice.
  • Aminophylline a soluble precursor of theophylline, was injected intraperitonealy (100 ⁇ l/day of a 25 mg/ml solution, Renaudin, France).
  • All-trans retinoic acid (Innovative Research of America, Sarasota, FL) and As 2 O 3 treatments, autopsies and cellular or tissue analyses were performed as previously described (14).
  • Western-blot a p21 monoclonal antibody (Pharmingen, San Diego, CA) was used at a 1/500 dilution.
  • Dosage of plasma 8-C1- cAMP was performed by HPLC using a C18 column (Chromosep Inertil 5 ODS3) with a 15% methanol/50 mM pH 5.85 phosphate buffer as a mobile phase and UN. detection at 254 nm.
  • cAMP triggers a combination of growth arrest, differentiation and apoptosis, resulting in dramatic regressions of the leukemia. Yet, in most cases, cAMP was unable to eradicate APL. Since cAMP greatly increases As 2 O 3 -triggered differentiation ex vivo (see Example 1), the Inventors associated 8-Cl-cAMP and As 2 O 3 treatments in vivo in a RA- sensitive mouse model of APL. With this combined treatment, the spleen, liver and bone marrow became leukemia-free between days 1 and 3, while animals treated with As 2 O 3 alone retained a significant tumor burden consisting of differentiating leukemic cells ( Figures 2A, C and D).
  • the stable cAMP derivative used here induces massive diuresis, precluding any long-term use, and may further be metabolized into potentially cytotoxic nucleotide analogues (15).
  • the Inventors used theophylline (under its stabilized form aminophylline), a phosphodiesterase inhibitor which stabilizes pools of endogenous intracellular cAMP, in our RA-sensitive APL model.
  • Theophylline similar to 8-C1- cAMP, blocked APL growth and induced some apoptosis, accompanied by nonterminal differentiation (Figure 2E).
  • enhancement of differentiation was more pronounced for As 2 O 3 than for RA ( Figure 2E).
  • EXAMPLE 3 Theophylline induces remission in aRA- and As- resistant APL patient
  • the patient gave informed consent for use of theophylline to enhance RA/ As 2 O 3 differentiation.
  • the daily treatment was with RA 45 mg/m 2 P.O., As 2 O 3 : 10 mg IN., theophylline 250 mg P.O.
  • Cyclic AMP -triggered growth arrest may result from induction of the cell-cycle inhibitor p21, which was previously implicated in RA-induced APL differentiation (20). Cyclic AMP enhancement of RA-, As 2 O 3 - or rexinoids- triggered differentiation may also result from induction of the G-CSF receptor (21). In F9 embryonal carcinoma cells, cAMP was shown to modulate RA-triggered differentiation through RAR ⁇ phosphorylation (22).
  • RARa plays a critical role in myeloid differentiation, including in IL3 or GM-CSF response (23), such modulation of RARc signaling may also contribute to cAMP response.
  • Therapy-resistant patients only exceptionally exhibit mutations in PML/RAR ⁇ , particularly in European trials, which does not favor a direct parallelism between the cases of this patient and of the RA-resistant APL mice.
  • the RA/8-Cl-cAMP synergy for differentiation in RA- resistant APL was unexpected. It is possible that this reflects the in vivo conversion of RA to rexinoids, allowing the cAMP/rexinoid triggered differentiation demonstrated in cell-lines (21).
  • As 2 O alone triggered a modest anti-proliferative effect in the absence of significant differentiation, the RA/As O combination triggered a minor, but reproducible, differentiation (Fig. 4 b).
  • cAMP induces the rapid regrowth of normal erythroblasts and megakaryocytes. This could result from a direct positive effect on the normal progenitors, as reported ex vivo (24).
  • APL cells secrete inhibitors of normal haematopoiesis (25, 26) whose synthesis or downstream signaling, could be blocked by cAMP.
  • in vivo stimulatory- effect on normal haematopoiesis could be as important as leukemia inhibition.
  • the low toxicity of theophylline, its ability to accelerate RA- or As 2 O 3 -triggered remissions favor the use of theophylline in de novo patients.
  • Cyclic AMP is active both in RA-sensitive and RA-resistant APLs. Moreover, in contrast to RA and As 2 O 3 , cAMP does not obviously target PML/RAR ⁇ and therefore might be valuable in malignancies other that APL. Non-APL myeloid cells are also very sensitive to cAMP triggered differentiation, particularly in the presence of other differentiation inducers. Similar to histone desacetylase inhibitors, which unravel RA- induced differentiation in acute myeloid leukemia (3, 27), theophylline may greatly j increase the potency of other differentiation inducers in vivo. '
  • Histone deacetylases a common molecular target for differentiation treatment of acute myeloid leukemia? Oncogene 20:3110-3115.
  • Nalproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.
  • Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia.
  • arsenic trioxide As 2 O 3
  • APL acute promyelocytic leukaemia
  • BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia. J Exp. Med. 193:531-544.
  • PMLRARalpha promyelocytic leukemia retinoic acid receptor alpha chimeric protein
  • Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 61:2-7.

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Abstract

La présente invention concerne l'utilisation d'au moins une substance pouvant augmenter le teneur en cellules de cAMP ou de ses dérivés, relativement à la teneur initiale en cellules de cAMP ou de ses dérivés. Cette substance est utilisée dans la préparation d'un médicament destiné au traitement de cancers.
PCT/EP2003/010280 2002-09-17 2003-09-16 Compositions pharmaceutiques utilisees pour le traitement de cancers WO2004026319A2 (fr)

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EP1838319A2 (fr) * 2005-01-07 2007-10-03 The Johns Hopkins University Compositions d'inhibiteur des pde5 et procedes pour l'immunotherapie
WO2009147169A1 (fr) * 2008-06-03 2009-12-10 Universite Paris Diderot-Paris 7 Compositions pharmaceutiques utiles pour le traitement de cancers, en particulier d'une leucémie myéloïde aiguë et d'une leucémie promyélocytique aiguë
WO2011119125A1 (fr) * 2010-03-25 2011-09-29 Mazilnikov Gennadiy Vasilevich Utilisation de l'oxalate de lithium dans la fabrication d'une préparation médicinale qui possède une action antitumorale vis-à-vis des cellules malignes, préparation médicinale sur cette base et procédé de traitement
WO2011119126A1 (fr) * 2010-03-25 2011-09-29 Mazilnikov Gennadiy Vasilevich Utilisation de l'acide oxalique dans la fabrication d'une préparation médicinale qui possède une action antitumorale vis-à-vis des cellules malignes, préparation médicinale sur cette base et procédé de traitement
WO2014153001A1 (fr) * 2013-03-14 2014-09-25 Epizyme, Inc. Polythérapie pour traiter un cancer
US20150273088A1 (en) * 2014-03-28 2015-10-01 Washington University Zaprinast analogues as glutaminase inhibitors and methods to predict response thereto
US9446064B2 (en) 2013-03-14 2016-09-20 Epizyme, Inc. Combination therapy for treating cancer

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1838319A2 (fr) * 2005-01-07 2007-10-03 The Johns Hopkins University Compositions d'inhibiteur des pde5 et procedes pour l'immunotherapie
EP1838319A4 (fr) * 2005-01-07 2009-12-09 Univ Johns Hopkins Compositions d'inhibiteur des pde5 et procedes pour l'immunotherapie
US9468643B2 (en) 2005-01-07 2016-10-18 The Johns Hopkins University PDE5 inhibitor compositions and methods for immunotherapy
WO2009147169A1 (fr) * 2008-06-03 2009-12-10 Universite Paris Diderot-Paris 7 Compositions pharmaceutiques utiles pour le traitement de cancers, en particulier d'une leucémie myéloïde aiguë et d'une leucémie promyélocytique aiguë
WO2011119125A1 (fr) * 2010-03-25 2011-09-29 Mazilnikov Gennadiy Vasilevich Utilisation de l'oxalate de lithium dans la fabrication d'une préparation médicinale qui possède une action antitumorale vis-à-vis des cellules malignes, préparation médicinale sur cette base et procédé de traitement
WO2011119126A1 (fr) * 2010-03-25 2011-09-29 Mazilnikov Gennadiy Vasilevich Utilisation de l'acide oxalique dans la fabrication d'une préparation médicinale qui possède une action antitumorale vis-à-vis des cellules malignes, préparation médicinale sur cette base et procédé de traitement
WO2014153001A1 (fr) * 2013-03-14 2014-09-25 Epizyme, Inc. Polythérapie pour traiter un cancer
JP2016517434A (ja) * 2013-03-14 2016-06-16 エピザイム，インコーポレイティド 癌を処置するための併用療法
US9446064B2 (en) 2013-03-14 2016-09-20 Epizyme, Inc. Combination therapy for treating cancer
US10525074B2 (en) 2013-03-14 2020-01-07 Epizyme, Inc. Combination therapy for treating cancer
US20150273088A1 (en) * 2014-03-28 2015-10-01 Washington University Zaprinast analogues as glutaminase inhibitors and methods to predict response thereto

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