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WO2003082337A1 - Combinaison comprenant un inhibiteur de cdk et de la doxorubicine - Google Patents

Combinaison comprenant un inhibiteur de cdk et de la doxorubicine Download PDF

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Publication number
WO2003082337A1
WO2003082337A1 PCT/GB2003/001282 GB0301282W WO03082337A1 WO 2003082337 A1 WO2003082337 A1 WO 2003082337A1 GB 0301282 W GB0301282 W GB 0301282W WO 03082337 A1 WO03082337 A1 WO 03082337A1
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WIPO (PCT)
Prior art keywords
doxorubicin
cdk inhibitor
combination
disorder
cdk
Prior art date
Application number
PCT/GB2003/001282
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English (en)
Inventor
Roger Neil Sleigh
Anton Berns
Helen Mary Coley
Scott Lyons
Original Assignee
Cyclacel Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0207228A external-priority patent/GB0207228D0/en
Priority claimed from GB0222408A external-priority patent/GB0222408D0/en
Priority claimed from GB0225876A external-priority patent/GB0225876D0/en
Application filed by Cyclacel Limited filed Critical Cyclacel Limited
Priority to BR0308756-5A priority Critical patent/BR0308756A/pt
Priority to JP2003579873A priority patent/JP2005527560A/ja
Priority to EP03712412A priority patent/EP1487495A1/fr
Priority to AU2003217024A priority patent/AU2003217024A1/en
Priority to MXPA04009396A priority patent/MXPA04009396A/es
Publication of WO2003082337A1 publication Critical patent/WO2003082337A1/fr
Priority to US10/952,575 priority patent/US20050222054A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a pharmaceutical combination suitable for the treatment of cancer and other proliferative disorders.
  • CDK cyclin-dependent kinase
  • CDK1 - also known as cdc2, and CDK2 cyclin A
  • CDK8 cyclin B1-B3
  • CDK8 cyclin C
  • CDK8 cyclin D1-D3
  • CDK9 cyclin H
  • CDK7 cyclin H
  • CDKs The activity of CDKs is regulated post-translationally, by transitory associations with other proteins, and by alterations of their intracellular localisation. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin A/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cytotoxic and cytostatic drugs.
  • CDKs The function of CDKs is to phosphorylate and thus activate or deactivate certain proteins, including, for example, retinoblastoma proteins, lamins, histone HI, and components of the mitotic spindle.
  • the catalytic step mediated by CDKs involves a phospho-transfer reaction from ATP to the macromolecular enzyme substrate.
  • Several groups of compounds (reviewed in N. Gray, L. Detivaud, C. Doerig, L. Meijer, Curr. Med. Chem. 1999, 6, 859) have been found to possess anti-pro liferative properties by virtue of CDK-specific ATP antagonism.
  • Roscovitine is the compound 6-benzylamino-2-[(R)-l-ethyl-2-hydroxyethylamino]-9- isopropylpurine. Roscovitine has been demonstrated to be a potent inhibitor of cyclin dependent kinase enzymes, particularly cdk2. This compound is currently in development as an anti-cancer agent. Cdk inhibitors are understood to block passage of cells from the Gl/S and the G2/M phase of the cell cycle. Roscovitine has also been shown to be an inhibitor of retinoblastoma phosphorylation and therefore implicated as acting more potently on Rb positive tumors.
  • the present invention therefore seeks to provide a new combination of known pharmaceutical agents that is particularly suitable for the treatment of prohferative disorders, especially cancer. More specifically, the invention centres on the surprising and unexpected effects associated with using certain pharmaceutical agents in combination.
  • the invention provides a combination comprising a CDK inhibitor and doxorubicin.
  • a second aspect provides a pharmaceutical composition
  • a pharmaceutical composition comprising a combination according to the invention admixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • a third aspect relates to the use of a combination according to the invention in the preparation of a medicament for treating a prohferative disorder.
  • a fourth aspect relates to a pharmaceutical product comprising a CDK inhibitor and doxorubicin as a combined preparation for simultaneous, sequential or separate use in therapy
  • a fifth aspect relates to a method of treating a prohferative disorder, said method comprising simultaneously, sequentially or separately administering a CDK inhibitor and doxorubicin to a subject.
  • a sixth aspect relates to the use of a CDK inhibitor in the preparation of a medicament for the treatment of a prohferative disorder, wherein said treatment comprises simultaneously, sequentially or separately administering a CDK inhibitor and doxorubicin to a subject.
  • a seventh aspect relates to the use of a CDK inhibitor and doxorubicin in the preparation of a medicament for treating a prohferative disorder.
  • An eighth aspect relates to the use of a CDK inhibitor in the preparation of a medicament for the treatment of a prohferative disorder, wherein said medicament is for use in combination therapy with doxorubicin.
  • a ninth aspect relates to the use of doxorubicin in the preparation of a medicament for the treatment of a prohferative disorder, wherein said medicament is for use in combination therapy with a CDK inhibitor.
  • the present invention relates to a combination comprising a CDK inhibitor and doxorubicin.
  • the combination is a synergistic combination.
  • Doxorubicin is the compound (8S-cis)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-alpha-L- lyxo-hexopyranosyl)oxy]7,8,9, 10-tetrahydro-6,8, 11 -trihydroxy- 1 -methoxy-5, 12- naphthacenedione which is an anthracycline antibiotic.
  • Anthracycline antibiotics were first isolated from microorganisms in 1939, and their antibiotic properties were studied in the 1950s. These antibiotics killed bacteria quite readily, but were too toxic to be used for treating infections in humans. It was not until the 1960s that anthracycline antibiotics were tested for antitumor properties and found to be active against cancer cells.
  • the anthracyclines all bind to DNA and their cyto toxicity largely results from this binding. More specifically, they bind to double stranded DNA. In human chromosome preparations treated with anthracyclines the bound drug is observed as well-defined, orange-red fluorescent bands. This interaction with DNA is by intercalation and has been identified as such by several methods. If the structure of the anthracyclines is modified so as to alter the binding to DNA, there is usually a decrease or loss of antitumor activity. Thus, DNA binding seems to be critical for the anticancer activity of these drugs. However, the pathway leading to cytotoxicity has not been clearyly elucidated. Inhibition of DNA and RNA synthesis is not thought to be critical for cytotoxicity as it only occurs at high drug concentrations.
  • Anthracyclines have a number of important effects, any one or all of which have a role in the cytotoxic actions of these drugs. First of all, they can intercalate with DNA, thereby affecting many functions of the DNA, including DNA and RNA synthesis. Breakage of the DNA strand can also occur. This is believed to be mediated either by the enzyme DNA topoisomerase II or by the formation of free radicals. Inhibition of the enzyme topoisomerase II, for example, can lead to a series of reactions leading to double strand breaks in the DNA.
  • Temporary double-strand breaks are induced by topoisomerase II in the course of its normal catalytic cycle, by the formation of a cleavable complex. Disruption of this complex, which results in a permanent double-strand break, occurs infrequently in the absence of drugs. Inhibitors of topoisomerase II cause the cleavable complex to persist, thereby increasing the probability that the cleavable complex will be converted to an irreversible double-strand break.
  • Anthracyclines can also cause the formation of active oxygen species that then cause predominantly single-strand breakage.
  • the anthracycline chromophore contains a hydroxyquinone, which is a well-described iron chelating structure.
  • the drug-Fe- DNA complex catalyzes the transfer of electrons from glutathione to oxygen, resulting in the formation of active oxygen species.
  • Another aspect of the invention relates to a combination comprising a CDK inhibitor and an anthracycline.
  • Yet another aspect relates to a pharmaceutical product comprising a CDK inhibitor and an anthracycline.
  • one aspect of the invention relates to a pharmaceutical product comprising a CDK inhibitor and doxorubicin as a combined preparation for simultaneous, sequential or separate use in therapy.
  • the CDK inhibitor and doxorubicin may be administered simultaneously, in combination, sequentially or separately (as part of a dosing regime).
  • “simultaneously” is used to mean that the two agents are administered concurrently, whereas the term “in combination” is used to mean they are administered, if not simultaneously, then “sequentially” within a timeframe that they both are available to act therapeutically within the same time-frame.
  • administration “sequentially” may permit one agent to be administered within 5 minutes, 10 minutes or a matter of hours after the other provided the circulatory half- life of the first administered agent is such that they are both concurrently present in therapeutically effective amounts.
  • the time delay between administration of the components will vary depending on the exact nature of the components, the interaction therebetween, and their respective half-lives.
  • the CDK inhibitor and doxorubicin are administered simultaneously or sequentially.
  • One aspect of the present invention relates to the use of a CDK inhibitor in the preparation of a medicament for the treatment of a prohferative disorder, wherein said treatment comprises administering to a subject simultaneously, sequentially or separately doxorubicin and a CDK inhibitor.
  • the CDK inhibitor is administered to the subject prior to sequentially or separately administering doxorubicin to said subject.
  • doxorubicin is administered to the subject prior to sequentially or separately administering a CDK inhibitor to said subject.
  • the CDK inhibitor and doxorubicin are each administered in a therapeutically effective amount with respect to the individual components.
  • the CDK inhibitor and doxorubicin are each administered in a subtherapeutic amount with respect to the individual components.
  • Another aspect of the invention relates to the use of a CDK inhibitor and doxorubicin in the preparation of a medicament for treating a prohferative disorder.
  • Yet another aspect of the invention relates to the use of a CDK inhibitor in the preparation of a medicament for the treatment of a prohferative disorder, wherein said medicament is for use in combination therapy with doxorubicin.
  • a further aspect ofthe invention relates to the use of doxorubicin in the preparation of a medicament for the treatment of a prohferative disorder, wherein said medicament is for use in combination therapy with a CDK inhibitor.
  • the term “combination therapy” refers to therapy in which the doxorubicin and CDK inhibitor are administered, if not simultaneously, then sequentially within a timeframe that they both are available to act therapeutically within the same time-frame.
  • preparation of a medicament includes the use of the components ofthe invention directly as the medicament in addition to their use in any stage ofthe preparation of such a medicament.
  • prohferative disorder is used herein in a broad sense to include any disorder that requires control of the cell cycle, for example cardiovascular disorders such as restenosis and cardiomyopathy, auto-immune disorders such as glomerulonephritis and rheumatoid arthritis, dermatological disorders such as psoriasis, anti-inflammatory, anti-fungal, antiparasitic disorders such as malaria, emphysema and alopecia.
  • cardiovascular disorders such as restenosis and cardiomyopathy
  • auto-immune disorders such as glomerulonephritis and rheumatoid arthritis
  • dermatological disorders such as psoriasis, anti-inflammatory, anti-fungal, antiparasitic disorders such as malaria, emphysema and alopecia.
  • the components of the present invention may induce apoptosis or maintain stasis within the desired cells as required.
  • the prohferative disorder is a cancer or leukaemia, most preferably cancer.
  • the invention relates to the use of the combination described herein in the treatment of a CDK dependent or sensitive disorder.
  • CDK dependent disorders are associated with an above normal level of activity of one or more CDK enzymes.
  • Such disorders preferably associated with an abnormal level of activity of CDK2 and/or CDK4.
  • a CDK sensitive disorder is a disorder in which an aberration in the CDK level is not the primary cause, but is downstream of the primary metabolic aberration.
  • CDK2 and/or CDK4 can be said to be part of the sensitive metabolic pathway and CDK inhibitors may therefore be active in treating such disorders.
  • Such disorders are preferably cancer or leukaemic disorders.
  • the CDK inhibitor is an inhibitor of CDK2 and/or CDK4. More preferably the CDK inhibitor is selected from roscovitine, purvalanol A, purvalanol B, olomucine and other 2,6,9-trisubstituted purines as described in WO97/20842, WO98/05335 (CN Therapeutics), WO99/07705 (Regents of the University of California).
  • the CDK inhibitor is selected from roscovitine and purvalanol A.
  • the CDK inhibitor is roscovitine.
  • Roscovitine is the compound 2-[(l-ethyl-2-hydroxyethyl)amino]-6-benzylamine-9- isopropylpurine, also described as 2-(l-D,L-hydroxymethylpropylamino)-6- benzylamine-9-isopropylpurine.
  • Roscovitine encompasses the resolved R and S enantiomers, mixtures thereof, and the racemate thereof.
  • the combination has a synergistic effect, i.e., the combination is synergistic.
  • the effect of drug combinations is inherently unpredictable and there is often a propensity for one drug to partially or completely inhibit the effects of the other.
  • the present invention is based on the surprising observation that administering doxorubicin and roscovitine in combination, either simultaneously, separately or sequentially, does not lead to any adverse interaction between the two agents. The unexpected absence of any such antagonistic interaction is critical for clinical applications.
  • doxorubicin is frequently administered as part of cocktail or dosing regime of chemo therapeutic agents, see for example the database of chemotherapeutic combinations at http://www.indiacancer.org/prof/acdl l.html.
  • Doxorubicin has been proposed for use in sequential regime of docetaxal, doxorubicin and cyclophosphamide in the treatment of breast cancer (Journal of Clinical Oncology, Nolume 19, No 14, pp 3367-3375, 2001).
  • doxorubicin has been proposed for use in sequential regime of docetaxal, doxorubicin and cyclophosphamide in the treatment of breast cancer (Journal of Clinical Oncology, Nolume 19, No 14, pp 3367-3375, 2001).
  • doxorubicin has been proposed for use in sequential regime of docetaxal, doxorubicin and cyclophosphamide in the treatment of breast cancer (Journal of Clinical Oncology, No
  • the combination of doxorubicin and roscovitine produces an enhanced effect as compared to either drug administered alone.
  • the surprising nature of this observation is in contrast to that expected on the basis ofthe prior art.
  • cancers may be classified not only by their location (breast, lung, kidney etc.) and nature (small cell, solid, soft etc.) but also biochemically on the basis of the genotype associated with a particular tumor.
  • location breast, lung, kidney etc.
  • nature small cell, solid, soft etc.
  • biochemically on the basis of the genotype associated with a particular tumor Considering a wide range of cancers, there are sub-populations within different cancers that exhibit p53 mutations.
  • a subset based on genotypic characterisation would be those exhibiting a brcal or brca 2 mutation.
  • the prohferative disorder is an Rb deficient prohferative disorder.
  • doxorubicin and roscovitine produced a maximal effect as compared to either drug administered alone upon administration to an Rb deficient cancer cell line.
  • the surprising nature of this observation is in contrast to that expected, especially in view of the described activity of roscovitine in inhibiting Rb phosphorylation.
  • one preferred embodiment of the invention relates to a method of treating Rb deficient prohferative disorders comprising the administration of a therapeutically effective amount of CDK inhibitor and a therapeutically effective amount of doxorubicin.
  • another preferred embodiment of the invention relates to the use of a CDK inhibitor in the manufacture of a medicament for use in the treatment of Rb deficient prohferative disorders comprising administration of a therapeutically effective amount of CDK inhibitor and a therapeutically effective amount of doxorubicin.
  • Rb deficient is used herein to refer to a genotype that is different from the wild-type Rb gene.
  • the Rb genotype may be mutated or deleted, or the wild-type Rb gene may be present heterozygously.
  • the reference taken for the wild-type Rb gene is that given in Lee et al (Lee W.H , Booksten, R, Hong, FD, Toung, LJ, Shew JY, Lee, EY-HP, 1987; Human retinoblastoma susceptibility gene: cloning, identification and sequence, et al Science 235:1394- 1399).
  • Restinoblastoma protein is a expressed by a gene originally identified in the context of an inherited eye tumor (Nevins JR, Human Molecular Genetics 2001, 10, 699- 703). In its phosphorylated form it has been observed to be involved in the control of transcription factors such as E2F. Loss of Rb function has now been observed in a wide array of human cancers (Hunter T, Ceil (1997) 88, 333-346, Sherr CJ, (1996) Science 274, 1672-1677 and Weinberg RA (1995) Cell 81, 537-548). Thus, within the different types of cancer sub-populations have been observed exhibiting a mutation in the Rb gene, hereinafter referred to as Rb deficient cancers.
  • a CDK inhibitor preferably roscovitine
  • doxorubicin in combination with doxorubicin has been observed to be particularly effective in Rb deficient cancers.
  • a comprehensive, but non-exhaustive list of cancers is given below. Patients exhibiting a particular cancer in an Rb deficient manner may be identified by a simple genotypic assay. Assays for decreased or increased Rb expression via irnmunohistochemistry are described in:
  • the present combination is particularly effective in the treatment of Rb deficient malignant and pre-neoplastic disorders.
  • the invention is especially useful in relation to the treatment of Rb deficient adeno carcinomas such as: small cell lung cancer, and cancer of the kidney, uterus, prostrate, bladder, ovary, colon and breast.
  • malignancies which may be treatable according to the present invention include Rb deficient acute and chronic leukemias, lymphomas, myelomas, Rb deficient sarcomas such as fibrosarcoma, myxosarcoma, liposarcoma, lymphangioendotheliosarcoma, angiosarcoma, endotheliosarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, lymphangiosarcoma, synovioma, mesothelioma, leimyosarcoma, rhabdomyosarcoma, and the following cancers when present in the Rb deficient genotype: colon carcinoma, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystaden
  • components of the present invention can be administered alone, for human therapy they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent.
  • a preferred embodiment of the invention therefore relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a CDK inhibitor and doxorubicin admixed with a pharmaceutically acceptable excipient, diluent or carrier.
  • suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the "Handbook of Pharmaceutical Excipients, 2 nd Edition, (1994), Edited by A Wade and PJ Weller.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, marmitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • SALTS/ESTERS sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the agents of the present invention can be present as salts or esters, in particular pharmaceutically acceptable salts or esters.
  • compositions of the agents of the invention include suitable acid addition or base salts thereof.
  • suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
  • sulphuric acid, phosphoric acid or hydrohalic acids with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C ⁇ -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.
  • Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified.
  • Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C ⁇ -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-tol
  • Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide.
  • Alcohols include alkanealcohols of 1-12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).
  • the invention also includes where appropriate all enantiomers and tautomers of the agents.
  • the man skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics.
  • the corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.
  • agents of the invention may exist as stereoisomers and/or geometric isomers, e.g. they may possess one or more asymmetric and/or geometric centres and so may exist in two or more stereoisomeric and/or geometric forms.
  • the present invention contemplates the use of all the individual stereoisomers and geometric isomers of agents, and mixtures thereof.
  • the terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).
  • the present invention also includes all suitable isotopic variations of the agents or pharmaceutically acceptable salts thereof.
  • An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 3, P, 32 P, 35 S, I8 F and 36 C1, respectively.
  • isotopic variations ofthe agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agents of the present invention and pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • the present invention also includes solvate forms of the agents of the present invention.
  • the terms used in the claims encompass these forms.
  • the invention furthermore relates to agents of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.
  • the invention further includes agents of the present invention in prodrug form.
  • prodrugs are generally compounds wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject.
  • Such reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo.
  • esters for example, any of those described above
  • the reversion may be carried out be an esterase etc.
  • Other such systems will be well known to those skilled in the art.
  • the invention also relates to combinations which comprise derivatives of the agents.
  • derivatives as used herein includes chemical modification of an agent. Illustrative of such chemical modifications would be replacement of hydrogen by a halo group, an alkyl group, an acyl group or an amino group.
  • compositions of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, mtrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.
  • compositions For oral administration, particular use is made of compressed tablets, pills, tablets, gellules, drops, and capsules. Preferably, these compositions contain from 1 to 2000 mg and more preferably from 50-1000 mg, of active ingredient per dose.
  • compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • transdermal administration is by use of a skin patch.
  • the active ingredients can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • the active ingredients can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
  • Injectable forms may contain between 10 - 1000 mg, preferably between 10 - 500 mg, of active ingredient per dose.
  • Compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.
  • the combination or pharmaceutical composition ofthe invention is administered intravenously.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity ofthe specific agents employed, the metabolic stability and length of action of that agent, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the agent may be administered at a dose of from 0.1 to 30 mg/kg body weight, or from 2 to 20 mg/kg body weight. More preferably the agent may be administered at a dose of from 0.1 to 1 mg kg body weight.
  • each active component, the CDK inhibitor and doxorubicin are preferably administered in therapeutically effective amounts, preferably in the form of pharmaceutically acceptable amounts. These amounts will be familiar to those skilled in the art.
  • doxorubicin is typically administered intravenously, or orally, most typically intravenously.
  • Intravenous doses typically 60 mg/m 2 once every 21 days as a single agent or doses ranging from 20 to 30 mg/m 2 in combination therapies again once every 21 or 28 days.
  • Further suitable dosing regimes may include 250 mg or 500 mg doxorubicin and are administered intravenously in accordance to a physicians direction at a total dosage depending on the weight of a patient e.g.
  • Dosages and frequency of application are typically adapted to the general medical condition ofthe patient and to the severity of the adverse effects caused, in particular to those caused to the hematopoietic, hepatic and to the renal system.
  • Doxorubicin is available in several dosage forms; powder for reconstitution, in solution, as well as in lipid formulations encapsulated within liposomes. The skilled physician will be able to determine the most suitable dosage and dosage form for the particular patient and cancer type.
  • Roscovitine is typically administered orally or intravenously at a dosage of from about 0.05 to about 5g/day, preferably from about 0.5 to about 5 g/day or 1 to about 5 g/day, and even more preferably from about 1 to about 3 g/day.
  • roscovitine is preferably administered at a dosage of about 0.4 to about 3 g/day.
  • Roscovitine is preferably administered orally in tablets or capsules.
  • the total daily dose of roscovitine can be administered as a single dose or divided into separate dosages administered two, three or four times a day.
  • Figure 1 shows the effects of combination treatment with doxorubicin and roscovitine usign median effect analysis: HTB88. Data obtained using the CalcuSyn program. Combination indices (CI) ⁇ 1.0 are indicative of synergism.
  • Figure 2 shows the effects of combination treatment with doxorubicin and roscovitine usign median effect analysis: HTB114. Data obtained using the CalcuSyn program. Combination indices (CI) ⁇ 1.0 are indicative of synergism.
  • Figure 3 shows tumour development in a POMC-Cre POMC-Luc;Rb-flox/flox compound mutant mouse. Top: tumour development after 12, 14 and 16 weeks; Middle: bioluminescence (BLU) versus time, for eight different mice; Bottom: BLU versus tumour weight (mg).
  • Figure 4 shows the tumour response in POMC-Cre/POMC-Luc;Rb-flox/flox compound mutant mice to treatment with doxorubicin (4 5 mg/kg; intravenously).
  • Figure 5 shows a drug administration schedule in which doxorubicin is administered once a weeks for four weeks (5 mg/kg; intravenously), and preceding each doxorubicin administration, roscovitine is administered orally twice daily for two days (500 mg/kg).
  • Figure 6 shows the fold difference in bioluminscence relative to day 1 for untreated mice.
  • Figure 7 shows the fold difference in bioluminscence relative to day 1 for untreated mice, and mice treated with either doxorubicin or roscivitine alone.
  • Figure 8 shows the fold difference in bioluminscence relative to day 1 for untreated mice, mice treated with either doxorubicin or roscivitine alone, and mice treated with doxorubicin/roscovitine in combination.
  • Figure 9 shows the fold difference in bioluminscence relative to day 1 for mice treated with doxorubicin alone, and mice treated with doxorubicin/roscovitine in combination.
  • Figure 10 shows Western immunoblotting analysis of Cyclin A; A: control (48h); B: 10 ⁇ M roscovitine: C: 20 ⁇ M roscovitine; D: 5nM doxorubicin: E: lOnM doxorubicin; F: roscovitine/doxorubicin.
  • HTB-88 SK-LMS-1 cell line was obtained from ATCC; human vulval primary leiomyosarcoma, p53 mutant (Patterson et al. (1994) Br J Cancer 69:1052-1058), pRb wild-type, pl6 deleted.
  • HTB-114 SK-UT-1 was obtained from ATCC; human uterine grade III leiomyosarcoma, P53 mutant (Patterson et al. (1994) supra.), pRb deleted, pl6 wild-type.
  • Cells at a density of 3 x 10 4 cells /ml were seeded into 96-well plates in 200 ⁇ l aliquots.
  • the medium was minimum essential medium with added non-essential amino acids and sodium pyruvate and 10% FCS (Life Technologies/Invitrogen). Cells were left for 24h to equilibrate in a gassing humidifying incubator.
  • the drugs in combination were used at a fixed ratio to each other of DOX:roscovitine, 1 : 0.125, over the stepwise dilution series described above i.e starting at lOnM DOX: 1.25 ⁇ M roscovitine to 320nM DOX:40 ⁇ M roscovitine.
  • the cell viability was assessed following 72h and 96h for HTB114 and HTB88 respectively using the MTT method (according to Twentyman and Luscombe 1987, Br J Cancer 56: 279-285).
  • the combination index (CI) was assessed according to the CacuSyn program based on the median effect analysis method.
  • roscovitine and doxorubicin were investigated in a luminscent mouse model of pituitary tumours.
  • a conditional mouse model for retinoblastoma-dependent sporadic cancer was generated (Nooijs et al; Cancer Res 2002 Mar 15; 62(6): 1862-7; 2002) which permits non-invasive monitoring of pituitary tumour development in live animals via in vivo bioluminescence imaging of luciferase expression.
  • This mouse model permits the longitudinal monitoring of tumour onset, progression and response to therapeutic agents that specifically target the retinoblastoma pathway.
  • a retinoblastoma conditional KO line was crossed with a POMC- Cre/POMC-Luciferase transgenic line to generate POMC-Cre POMC-Luc;Rb- flox/flox compound mutant mice.
  • These mice develop POMC (Rb deficient) tumours (Nooijs et al, ibid) and as illustrated in Figure 3.
  • Treatment with doxorubicin (4 x 5 mg kg; intravenously) was shown to delay tumorigenesis.
  • Doxorubicin is S-phase specific and temporarily halts tumour progression (see Figure 4).
  • doxorubicin was administered once a week for four weeks (5 mg/kg; intravenously). Preceding each doxorubicin adminstration, roscovitine was administered orally twice daily for two days (500 mg/kg) in accordance with the schedule illustrated in Figure 5.
  • the results indicate that doxorubicin temporarily halts tumour progression, and that pre-administration of roscovitine potentiates this doxorubicin effect, resulting in temporary tumour regression. This is the first time that the synergistic effect between doxorubicin and roscovitine has been demonstrated in vivo.
  • Detection of protein levels was carried out using the NOVEX electrophoresis system using SDS-PAGE gels (10, 12 or 4-12%) and a MES or MOPS buffer. Whole cell lysates were prepared from appropriately treated cells harvested and prepared in TRIS buffer with SDS and protease inhibitors. An equal amount of protein was loaded in each lane.
  • Flow cytometry for DNA cell cycle analysis drug treated cells were harvested by centrifugation and washing in PBS, then fixed in 70 % ethanol/PBS. Cells were stained with PI and treated with ribonuclease prior to flow cytometric analysis using FL3 with appropriate gating.

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Abstract

Selon un premier aspect, l'invention concerne une combinaison comprenant un inhibiteur de CDK et de la doxorubicine. Selon un deuxième aspect, l'invention porte sur un produit pharmaceutique comprenant un inhibiteur de CDK et de la doxorubicine en tant que préparation combinée destinée à être utilisée simultanément, séquentiellement ou séparément dans une thérapie. Selon un troisième aspect, l'invention se rapporte à un procédé de traitement d'un trouble proliférant, consistant à administrer simultanément, séquentiellement ou séparément un inhibiteur de CDK et de la doxorubicine à un sujet.
PCT/GB2003/001282 2002-03-27 2003-03-25 Combinaison comprenant un inhibiteur de cdk et de la doxorubicine WO2003082337A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR0308756-5A BR0308756A (pt) 2002-03-27 2003-03-25 Combinação compreendendo um inibidor de cdk e doxorrubicina
JP2003579873A JP2005527560A (ja) 2002-03-27 2003-03-25 Ｃｄｋ阻害剤とドキソルビシンとを含む組合せ
EP03712412A EP1487495A1 (fr) 2002-03-27 2003-03-25 Combinaison comprenant un inhibiteur de cdk et de la doxorubicine
AU2003217024A AU2003217024A1 (en) 2002-03-27 2003-03-25 Combination comprising a cdk inhibitor and doxorubicin
MXPA04009396A MXPA04009396A (es) 2002-03-27 2003-03-25 Combinacion que comprende un inhibidor cdk y doxorubicina.
US10/952,575 US20050222054A1 (en) 2002-03-27 2004-09-27 Combination comprising a CDK inhibitor and doxorubicin

Applications Claiming Priority (6)

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GB0207228.8 2002-03-27
GB0207228A GB0207228D0 (en) 2002-03-27 2002-03-27 Use
GB0222408.7 2002-09-26
GB0222408A GB0222408D0 (en) 2002-09-26 2002-09-26 Use
GB0225876.2 2002-11-06
GB0225876A GB0225876D0 (en) 2002-11-06 2002-11-06 Use

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WO2005044275A1 (fr) * 2003-11-06 2005-05-19 Cyclacel Limited Utilisation
JP2007513132A (ja) * 2003-12-04 2007-05-24 サイクラセル リミテッド Ｃｄｋ阻害剤、及びｃｓ−６８２又はその代謝産物との組合せ
WO2007132220A1 (fr) * 2006-05-12 2007-11-22 Cyclacel Limited Combinaison de 4-hétér0aryl-pyrimidine amine substituée en 2 et d'un médicament cytotoxique, son utilisation dans le traitement d'un trouble prolifératif

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Publication number Priority date Publication date Assignee Title
CN103169720B (zh) * 2011-12-21 2016-12-07 张雅珍 蒽环类抗生素及其可药用盐在治疗视网膜静脉阻塞中的用途

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WO2002046182A1 (fr) * 2000-12-08 2002-06-13 Bristol-Myers Squibb Pharma Company Semi-carbazides et leurs utilisations en tant qu'inhibiteurs de kinases dependantes des cyclines

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WO2002044174A2 (fr) * 2000-12-01 2002-06-06 Bristol-Myers Squibb Pharma Company Derives de 3-(2,4-dimethylthiazol-5-yl)indeno[1,2-c]pyrazol-4-one et leur utilisation
WO2002046182A1 (fr) * 2000-12-08 2002-06-13 Bristol-Myers Squibb Pharma Company Semi-carbazides et leurs utilisations en tant qu'inhibiteurs de kinases dependantes des cyclines

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W.W.LI E.A.: "Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 kinase activity", CANCER RESEARCH, vol. 61, no. 6, 2001, pages 2579 - 2582, XP001159723 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044275A1 (fr) * 2003-11-06 2005-05-19 Cyclacel Limited Utilisation
JP2007513132A (ja) * 2003-12-04 2007-05-24 サイクラセル リミテッド Ｃｄｋ阻害剤、及びｃｓ−６８２又はその代謝産物との組合せ
JP4778910B2 (ja) * 2003-12-04 2011-09-21 サイクラセル リミテッド Ｃｄｋ阻害剤、及びｃｓ−６８２又はその代謝産物との組合せ
WO2007132220A1 (fr) * 2006-05-12 2007-11-22 Cyclacel Limited Combinaison de 4-hétér0aryl-pyrimidine amine substituée en 2 et d'un médicament cytotoxique, son utilisation dans le traitement d'un trouble prolifératif

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MXPA04009396A (es) 2005-01-25
CN1655821A (zh) 2005-08-17
AU2003217024A1 (en) 2003-10-13
BR0308756A (pt) 2004-12-28
JP2005527560A (ja) 2005-09-15

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