1 1288 122 DECITABINE. PURPOSE OF REVIEW: DECITABINE IS A CYTOSINE ANALOGUE SYNTHESIZED IN THE 1960S THAT IS CURRENTLY ENJOYING A REVIVAL OF INTEREST PROMPTED BY THE ELUCIDATION OF DNA METHYLATION INHIBITION AS ITS MAJOR MECHANISM OF ACTION, ALONG WITH INCREASED UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN EPIGENETIC DYSREGULATION IN CANCER. THESE ADVANCES HAVE TURNED THIS AGENT FROM JUST ANOTHER CYTOSINE ANALOGUE INTO A TARGETED DRUG AIMED AT REVERSING EPIGENETIC SILENCING IN CANCER CELLS. HERE, RECENT CLINICAL AND TRANSLATIONAL STUDIES WITH DECITABINE ARE REVIEWED. RECENT FINDINGS: SCIENTISTS ARE NOW TAKING A CLOSER LOOK AT THIS DRUG AS A TARGETED AGENT, WITH PARTICULAR ATTENTION TO SCHEDULES OF ADMINISTRATION AND MECHANISMS OF IN VIVO EFFICACY. TWO PHASE II TRIALS HAVE REPORTED SUBSTANTIAL CLINICAL ACTIVITY OF DECITABINE IN THE MYELODYSPLASTIC SYNDROME AND IN CHRONIC MYELOGENOUS LEUKEMIA. THERE IS CONSIDERABLE INTEREST IN COMBINING DECITABINE WITH HISTONE DEACETYLASE INHIBITORS AND IN USING IT TO SENSITIZE CELLS TO CHEMOTHERAPY OR TO BIOLOGIC THERAPY. FINALLY, ONGOING EFFORTS ARE DECIPHERING THE IN VIVO MECHANISMS OF RESPONSES SEEN AFTER DECITABINE ADMINISTRATION. SUMMARY: DECITABINE, AN OLD DRUG, HAS NOW MADE A COMEBACK AS A TARGETED AGENT AND A PROTOTYPE FOR EPIGENETIC THERAPY IN CANCER. DOSES, SCHEDULES OF ADMINISTRATION, AND THE DEVELOPMENT OF RATIONAL COMBINATIONS INCLUDING THIS AGENT MUST ALL TAKE THIS CRITICAL MECHANISM OF ACTION INTO ACCOUNT. 2003 2 1046 48 CLINICAL DEVELOPMENT OF DECITABINE AS A PROTOTYPE FOR AN EPIGENETIC DRUG PROGRAM. THIS REVIEW HIGHLIGHTS DECITABINE AS A PROTOTYPE EPIGENETIC MODIFYING DRUG TO SHOW HOW THE CLINICAL DEVELOPMENT OF EPIGENETIC AGENTS DIFFERS FROM THAT OF TRADITIONAL CYTOTOXIC CHEMOTHERAPIES. DECITABINE, A CYTOSINE ANALOGUE, IS CYTOTOXIC AT HIGH DOSES BUT HAS SELECTIVE DNA DEMETHYLATING ACTIVITY AT LOW DOSES. THE FOCUS OF CURRENT DECITABINE INVESTIGATIONS IS TWOFOLD: TO ELUCIDATE ALL OF THE MECHANISMS OF ACTION AND TO DETERMINE THE OPTIMAL DOSE, SCHEDULE, AND CONCOMITANT THERAPIES. NEW PHASE I TRIALS HAVE IDENTIFIED A "BIOLOGICALLY EFFECTIVE DOSE," WHICH IS 1 TO 2 LOGS LOWER THAN THE CYTOTOXIC DOSE. A CLINICAL DEVELOPMENT PROGRAM WITH LOW-DOSE DECITABINE IN MALIGNANT DISEASES IS FOCUSED ON MYELODYSPLASTIC SYNDROME (MDS), ACUTE MYELOGENOUS LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). A PHASE III TRIAL IN MDS SHOWED OBJECTIVE RESPONSES (COMPLETE [CR] PLUS PARTIAL [PR] REMISSION) AND LONGER MEDIAN TIME TO PROGRESSION TO AML OR DEATH WITH DECITABINE THAN WITH SUPPORTIVE CARE ALONE. THE OPTIMAL USE OF DECITABINE MAY BE IN COMBINATION WITH OTHER AGENTS THAT PROMOTE GENE EXPRESSION, NAMELY, HISTONE DEACETYLASE (HDAC) INHIBITORS. OPTIMIZED DECITABINE DOSES AND COMBINATIONS WITH OTHER EPIGENETIC THERAPIES THAT CAN BE USED AT MINIMALLY TOXIC DOSES PROVIDE POTENTIALLY SAFER THERAPEUTIC OPTIONS AND INTRODUCE NOVEL COMBINATION THERAPIES. 2005 3 6896 34 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 4 5499 44 REVIEW: RECENT CLINICAL TRIALS IN EPIGENETIC THERAPY. EPIGENETIC FACTORS SUCH AS DNA METHYLATION AND HISTONE DEACETYLATION ARE KNOWN TO CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF CELLS BY SILENCING CRITICAL GENES. DRUGS THAT INHIBIT DNA METHYLTRANSFERASES OR HISTONE DEACETYLASES WERE SHOWN TO HAVE THE POTENTIAL TO REACTIVATE SILENCED GENES AND INDUCE DIFFERENTIATION OR APOPTOSIS OF MALIGNANT CELLS. THE MOST INTENSIVELY STUDIED CLASS OF SUCH AGENTS IS DNA METHYLTRANSFERASE INHIBITORS, INCLUDING 5-AZACYTIDINE (AZACITIDINE) AND 5-AZA-2'-DEOXYCYTIDINE (DECITABINE). IN 2004, AZACITIDINE WAS APPROVED FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME ON THE BASIS OF PHASE II AND III STUDIES THAT SHOWED A RESPONSE RATE (COMPLETE AND PARTIAL RESPONSES) OF 15%. AZACITIDINE IS ALSO BEING EVALUATED IN CLINICAL TRIALS FOR OTHER MALIGNANT DISEASES. DECITABINE HAS RESPONSE RATES OF 17-49% IN MYELODYSPLASTIC SYNDROME IN MULTIPLE PHASE II AND III STUDIES AND ALSO ACTIVITY IN ACUTE AND CHRONIC MYELOGENOUS LEUKEMIA. HISTONE DEACETYLASE INHIBITORS BELONG TO ANOTHER CLASS OF EPIGENETIC MODIFYING AGENTS THAT INCLUDE DEPSIPEPTIDE, BUTYRATE DERIVATIVES, SUBEROYLANILIDE HYDROXAMIC ACID AND VALPROIC ACID. NO AGENT IN THIS CLASS HAS BEEN STUDIED IN A PHASE III TRIAL, BUT SEVERAL AGENTS HAVE BEEN OR ARE BEING STUDIED IN PHASE II TRIALS. FURTHER RESEARCH IS NEEDED TO DETERMINE THE APPROPRIATE PATIENT SELECTION AND DOSING SCHEDULES. 2006 5 834 33 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 6 1621 55 DNA METHYLTRANSFERASES AS TARGETS FOR CANCER THERAPY. METHYLATION OF DNA AT 5-POSITION OF CYTOSINE, CATALYZED BY DNA METHYLTRANSFERASES, IS THE PREDOMINANT EPIGENETIC MODIFICATION IN MAMMALS. ABERRATIONS IN METHYLATION PLAY A CAUSAL ROLE IN A VARIETY OF DISEASES, INCLUDING CANCER. RECENT STUDIES HAVE ESTABLISHED THAT LIKE MUTATION, METHYLATION-MEDIATED GENE SILENCING OFTEN LEADS TO TUMORIGENESIS. PARADOXICALLY, GENOME-WIDE DNA HYPOMETHYLATION MAY ALSO PLAY A CAUSAL ROLE IN CARCINOGENESIS BY INDUCING CHROMOSOMAL INSTABILITY AND SPURIOUS GENE EXPRESSION. SINCE METHYLATION DOES NOT ALTER DNA BASE SEQUENCE, MUCH ATTENTION HAS BEEN FOCUSED RECENTLY ON DEVELOPING SMALL MOLECULE INHIBITORS OF DNA METHYLTRANSFERASES THAT CAN POTENTIALLY BE USED AS ANTICANCER AGENTS. VIDAZA (5-AZACYTIDINE), MARKETED BY PHARMION (BOULDER, CO, USA), WAS THE FIRST DNA METHYLTRANSFERASE INHIBITOR APPROVED BY THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) FOR CHEMOTHERAPY AGAINST MYELODYSPLASTIC SYNDROME (MDS), A HETEROGENEOUS BONE MARROW DISORDER. RECENTLY MGI PHARMA INC. (BLOOMINGTON, MN, USA) GOT FDA APPROVAL TO MARKET DACOGEN (5-AZA-2'-DEOXYCYTIDINE, OR DECITABINE) FOR TREATING MDS PATIENTS. THESE DRUGS WERE USED EARLIER AGAINST CERTAIN ANEMIAS TO INDUCE EXPRESSION OF FETAL GLOBIN GENES. INTEREST IN CLINICAL TRIALS OF THESE DRUGS AS ANTICANCER AGENTS HAS BEEN RENEWED ONLY RECENTLY BECAUSE OF REVERSAL OF METHYLATION-MEDIATED SILENCING OF CRITICAL GENES IN CANCER. CLINICAL TRIALS HAVE SHOWN THAT BOTH DRUGS HAVE THERAPEUTIC POTENTIAL AGAINST LEUKEMIA SUCH AS MDS, ACUTE MYELOID LEUKEMIA, CHRONIC MYELOGENOUS LEUKEMIA AND CHRONIC MYELOMONOCYTIC LEUKEMIA. IN CONTRAST, THEIR EFFECTIVENESS WITH SOLID TUMORS APPEARS TO BE LESS PROMISING, WHICH CHALLENGES RESEARCHERS TO DEVELOP INHIBITORS WITH MORE EFFICACY AND LESS TOXICITY. THE MAJOR HINDRANCE OF THEIR USAGE AS ANTICANCER AGENTS IS THEIR INSTABILITY IN VIVO AS WELL AS THE TOXICITY SECONDARY TO THEIR EXCESSIVE INCORPORATION INTO DNA, WHICH CAUSES CELL CYCLE ARREST. GENE EXPRESSION PROFILING IN CANCER CELLS REVEALED THAT ANTINEOPLASTIC PROPERTY OF THESE DRUGS IS MEDIATED THROUGH BOTH METHYLATION-DEPENDENT AND -INDEPENDENT PATHWAYS. RECENTLY, WE HAVE SHOWN THAT TREATMENT OF CANCER CELLS WITH THESE CYTIDINE ANALOGUES ALSO INDUCES PROTEASOMAL DEGRADATION OF DNA METHYLTRANSFERASE 1, THE UBIQUITOUSLY EXPRESSED ENZYME UPREGULATED IN ALMOST ALL CANCER CELLS. DEVELOPMENT OF RELATED STABLE DRUGS THAT CAN FACILITATE GENE ACTIVATION IN CANCER CELLS BY ENHANCING DEGRADATION OF DNA METHYLTRANSFERASES WITHOUT BEING INCORPORATED INTO DNA WOULD BE IDEAL FOR CHEMOTHERAPY. IN THIS MONOGRAPH WE REVIEW HISTORICAL PERSPECTIVE AND RECENT ADVANCES ON THE MOLECULAR MECHANISMS OF ACTION AND CLINICAL APPLICATIONS OF THESE DNA HYPOMETHYLATING AGENTS. 2007 7 1542 41 DNA METHYLATION IN HAEMATOLOGICAL MALIGNANCIES: THE ROLE OF DECITABINE. NORMAL CELL DEVELOPMENT AND FUNCTION IS DEPENDENT UPON CONTROLLED GENE EXPRESSION. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT CAN PLAY AN IMPORTANT ROLE IN THE CONTROL OF GENE EXPRESSION. DNA METHYLATION AT CYTOSINE RESIDUES IN GENE PROMOTER CPG SEQUENCES IS KNOWN TO INHIBIT GENE TRANSCRIPTION. INAPPROPRIATE INHIBITION OF THE TRANSCRIPTION OF TUMOUR SUPPRESSOR GENES, GENES THAT INHIBIT ANGIOGENESIS AND METASTASIS AND GENES INVOLVED IN DNA REPAIR BY UNCONTROLLED METHYLATION, CAN LEAD TO UNREGULATED GROWTH AND PROLIFERATION OF A CELL AND CARCINOGENESIS. PROMOTER HYPERMETHYLATION AFFECTING THE P16 GENE, RESULTING IN GENE SILENCING, HAS BEEN SHOWN TO OCCUR IN MANY HUMAN SOLID TUMOURS AND A 'HYPERMETHYLATION PROFILE' IN SOME LEUKAEMIAS HAS BEEN DEFINED. THE MOLECULAR MECHANISMS BY WHICH ABERRANT DNA METHYLATION TAKES PLACE DURING CARCINOGENESIS ARE STILL NOT CLEAR. HOWEVER, THE LARGE NUMBER OF TARGET GENES (INVOLVED IN TUMORIGENESIS) THAT ARE SILENCED BY ABERRANT METHYLATION SUGGESTS THAT INHIBITION OF THIS PROCESS MAY HAVE POTENTIAL AS CANCER THERAPY. DECITABINE (NSC-127716, DACOGEN; SUPERGEN) IS A POTENT AND SPECIFIC HYPOMETHYLATING AGENT AND AN INHIBITOR OF THE DNA METHYLTRANSFERASE ACTIVITY THAT MEDIATES DNA METHYLATION. DECITABINE HAS BEEN SHOWN TO HAVE A BROAD RANGE OF ANTINEOPLASTIC ACTIVITY IN PRECLINICAL STUDIES. THIS AGENT HAS EXHIBITED SIGNIFICANT ACTIVITY IN THE TREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROME, CHRONIC MYELOID LEUKAEMIA AND ACUTE MYELOID LEUKAEMIA, ALTHOUGH CLINICAL PHASE I AND II STUDIES WITH SOLID TUMOURS HAVE NOT BEEN VERY PROMISING. PHASE II AND III STUDIES ARE CURRENTLY ONGOING TO EVALUATE DECITABINE, BOTH ALONE AND IN COMBINATION, IN VARIOUS STAGES OF THESE HAEMATOLOGICAL MALIGNANCIES. 2003 8 1616 33 DNA METHYLTRANSFERASE AND HISTONE DEACETYLASE INHIBITORS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROMES. THE RECENTLY APPROVED DRUGS 5-AZACITIDINE (5AC) AND 5-AZA-2'-DEOXYAZACYTIDINE (DAC) ARE IN WIDE CLINICAL USE FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME (MDS) OF ALL TYPES AND CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). THESE AGENTS WERE DEVELOPED BASED UPON AN UNDERSTANDING OF THE IMPORTANCE OF EPIGENETIC CHANGES IN MALIGNANCY, AND THEY HAVE BEEN EVALUATED IN RANDOMIZED CLINICAL TRIALS, WHICH DEMONSTRATE RESPONSE RATES BETWEEN 20% AND 40% IN PATIENTS FOR WHOM NO PREVIOUS STANDARD OF CARE WAS AVAILABLE. AS UNDERSTANDING OF THE EPIGENETIC CHANGES CHARACTERISTIC OF THE MALIGNANT PHENOTYPE IMPROVES, WE ARE ABLE TO TARGET OTHER REGULATORS OF CHROMATIN CONFORMATION THAT CONTRIBUTE TO ABERRANT GENE TRANSCRIPTION AND DYSREGULATED CELL GROWTH. THE HISTONE DEACETYLASE (HDAC) INHIBITORS BELONG TO ONE CLASS OF THERAPEUTICS DEVELOPED USING THIS PARADIGM. ALTHOUGH RESPONSES USING HDAC INHIBITORS ALONE IN MDS HAVE BEEN MODEST, ROBUST PRECLINICAL DATA DRIVE CLINICAL TRIALS IN WHICH THEY ARE UTILIZED IN COMBINATION WITH DNA METHYLTRANSFERASE (DNMT) INHIBITORS. COMBINATION THERAPY OFFERS THE POSSIBILITY OF HEMATOLOGIC IMPROVEMENT AND REMISSION TO MYELODYSPLASTIC PATIENTS WITH PREVIOUSLY UNTREATABLE DISEASE. 2008 9 2728 38 EXPLORING EPIGENETIC AND MICRORNA APPROACHES FOR GAMMA-GLOBIN GENE REGULATION. THERAPEUTIC INTERVENTIONS AIMED AT INDUCING FETAL HEMOGLOBIN AND REDUCING THE CONCENTRATION OF SICKLE HEMOGLOBIN IS AN EFFECTIVE APPROACH TO AMELIORATING ACUTE AND CHRONIC COMPLICATIONS OF SICKLE CELL DISEASE, EXEMPLIFIED BY THE LONG-TERM USE OF HYDROXYUREA. HOWEVER, THERE REMAINS AN UNMET NEED FOR THE DEVELOPMENT OF ADDITIONAL SAFE AND EFFECTIVE DRUGS FOR SINGLE AGENT OR COMBINATION THERAPY FOR INDIVIDUALS WITH BETA-HEMOGLOBINOPATHIES. REGULATION OF THE GAMMA-GLOBIN TO BETA-GLOBIN SWITCH IS ACHIEVED BY CHROMATIN REMODELING AT THE HBB LOCUS ON CHROMOSOME 11 AND INTERACTIONS OF MAJOR DNA BINDING PROTEINS, SUCH AS KLF1 AND BCL11A IN THE PROXIMAL PROMOTERS OF THE GLOBIN GENES. EXPERIMENTAL EVIDENCE ALSO SUPPORTS A ROLE OF EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION, HISTONE ACETYLATION/METHYLATION, AND MICRORNA EXPRESSION IN GAMMA-GLOBIN GENE SILENCING DURING DEVELOPMENT. IN THIS REVIEW, WE WILL CRITICALLY EVALUATE THE ROLE OF EPIGENETIC MECHANISMS IN GAMMA-GLOBIN GENE REGULATION AND DISCUSS DATA GENERATED IN TISSUE CULTURE, PRE-CLINICAL ANIMAL MODELS, AND CLINICAL TRIALS TO SUPPORT DRUG DEVELOPMENT TO DATE. THE QUESTION REMAINS WHETHER MODULATION OF EPIGENETIC PATHWAYS WILL PRODUCE SUFFICIENT EFFICACY AND SPECIFICITY FOR FETAL HEMOGLOBIN INDUCTION AND TO WHAT EXTENT TARGETING THESE PATHWAYS FORM THE BASIS OF PROSPECTS FOR CLINICAL THERAPY. 2021 10 358 38 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 11 6675 32 USING EPIGENETIC THERAPY TO OVERCOME CHEMOTHERAPY RESISTANCE. IT HAS BEEN KNOWN FOR DECADES THAT AS CANCER PROGRESSES, TUMORS DEVELOP GENETIC ALTERATIONS, MAKING THEM HIGHLY PRONE TO DEVELOPING RESISTANCE TO THERAPIES. CLASSICALLY, IT HAS BEEN THOUGHT THAT THESE ACQUIRED GENETIC CHANGES ARE FIXED. THIS HAS LED TO THE PARADIGM OF MOVING FROM ONE CANCER THERAPY TO THE NEXT WHILE AVOIDING PAST THERAPIES. HOWEVER, EMERGING DATA ON EPIGENETIC CHANGES DURING TUMOR PROGRESSION AND USE OF EPIGENETIC THERAPIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS LEADING TO CHEMOTHERAPY RESISTANCE HAVE THE POTENTIAL TO BE REVERSIBLE WITH EPIGENETIC THERAPY. IN FACT, PROMISING CLINICAL DATA EXIST THAT TREATMENT WITH EPIGENETIC AGENTS CAN DIMINISH CHEMOTHERAPY RESISTANCE IN A NUMBER OF TUMOR TYPES INCLUDING CHRONIC MYELOGENOUS LEUKEMIA, COLORECTAL, OVARIAN, LUNG AND BREAST CANCER. THE POTENTIAL FOR EPIGENETIC-MODIFYING DRUGS TO ALLOW FOR TREATMENT OF RESISTANT DISEASE IS EXCITING AND CLINICAL TRIALS HAVE JUST BEGUN TO EVALUATE THIS AREA. 2016 12 5913 26 TARGETED THERAPY IN LEUKEMIA. RESEARCH CONDUCTED OVER THE LAST TWO DECADES HAS YIELDED A DETAILED UNDERSTANDING OF THE MOLECULAR LESIONS THAT CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS AND COMMITTED PROGENITORS INTO THE VARIOUS FORMS OF ACUTE AND CHRONIC LEUKEMIA. ALTHOUGH OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LEUKEMIA REMAINS INCOMPLETE, THE INFORMATION GAINED TO DATE HAS HAD A PROFOUND IMPACT ON THE WAY THESE MALIGNANCIES ARE BOTH DIAGNOSED AND MONITORED DURING THERAPY. MORE RECENTLY, TARGETED THERAPIES HAVE BEEN DEVELOPED AGAINST SOME OF THE IDENTIFIED GENETIC LESIONS. THESE THERAPIES HAVE LED TO SIGNIFICANT IMPROVEMENTS IN PATIENT OUTCOMES WHILE SIMULTANEOUSLY DECREASING THERAPY-RELATED TOXICITY. WITH THE ADVENT OF GENOME-WIDE METHODS TO DEFINE THE TOTAL COMPLEMENT OF GENETIC AND EPIGENETIC LESIONS INVOLVED IN LEUKEMOGENESIS, NEW TARGETED THERAPIES CAN BE ANTICIPATED. THIS REVIEW HIGHLIGHTS SOME OF THE TARGETED THERAPIES THAT ARE PRESENTLY BEING USED TO TREAT HEMATOPOIETIC MALIGNANCIES AND DESCRIBES SOME OF THE RECENT ADVANCES THAT SHOULD HAVE A SIGNIFICANT IMPACT ON THE DEVELOPMENT OF FUTURE TARGET THERAPIES. 2008 13 6773 28 [ADVANCES OF RESEARCH ON DEMETHYLATION THERAPY FOR HEMATOLOGIC MALIGNANCIES]. DNA METHYLATION IS AN IMPORTANT AND REVERSIBLE EPIGENETIC MODIFICATION WHICH REGULATES GENOMIC STABILITY. METHYLATION IS ESSENTIAL FOR MAMMALIAN DEVELOPMENT. GENERALLY, GENE EXPRESSION LEVEL AND DNA METHYLATION ARE NEGATIVE CORRELATION. TRANSCRIPTIONAL SILENCING VIA METHYLATION OF CPG ISLANDS IN THE PROMOTER IS IMPORTANT FOR CELL GROWTH AND DIFFERENTIATION AND PLAYS A KEY ROLE IN TUMORIGENESIS. DEMETHYLATION DRUG CAN MODIFY CHROMATIN AND RESTORE THE ABILITY OF ANTI-ONCOGENE. DEMETHYLATION THERAPY AS A NEW THERAPY MAY TREAT EFFICIENTLY HEMATOLOGICAL MALIGNANCIES WITH RESISTANCE AND RELAPSE. IN THIS REVIEW, DNA METHYLATION MECHANISM, RELATIONSHIP BETWEEN ABERRANT METHYLATION AND HEMATOLOGIC MALIGNANCIES, MECHANISM OF DEMETHYLATION THERAPY, THE ADVANCE OF RESEARCH ON THE DEMETHYLATION THERAPY OF HEMATOLOGICAL MALIGNANCIES, SUCH AS ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MYELODYSPLASTIC SYNDROME WERE SUMMARIZED. 2009 14 2083 36 EPIGENETIC DRUGS: A LONGSTANDING STORY. IN THIS CHAPTER, THE DEVELOPMENT OF DECITABINE FROM ITS SYNTHESIS IN 1964 TO THE SUBMISSION OF A REGISTRATION FILE IN 2004 IS REVIEWED. THE PROPER APPLICATION OF THE UNIQUE PROPERTIES OF DECITABINE TOOK QUITE SOME TIME TO ELUCIDATE. IN ADDITION, THE PRACTICAL HANDLING IN THE CLINIC WAS NOT EASY AS THE PROLONGED MYELOSUPPRESSION OF DECITABINE MADE IT DIFFICULT TO DETERMINE THE PREFERRED DOSE AND SCHEDULE. LABORATORY STUDIES ON DNA METHYLATION AND CELL DIFFERENTIATION SHOWED POSSIBLE APPLICATIONS IN SOLID AND HEMATOLOGIC MALIGNANCIES. HOWEVER, DESPITE MANY ATTEMPTS, RESULTS IN SOLID TUMORS HAVE BEEN DISAPPOINTING THUS FAR. AFTER THOROUGH INVESTIGATION, DECITABINE ACHIEVED THERAPEUTIC APPLICATION IN MYELODYSPLASTIC SYNDROME (MDS), IN PARTICULAR IN PATIENTS WITH A POOR PROGNOSIS. FURTHER INDICATIONS MAY INCLUDE ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOGENOUS LEUKEMIA (CML), HEMATOPOIETIC STEM CELL TRANSPLANTATION, SICKLE CELL ANEMIA, AND THALASSEMIA. WHEREAS MOST DRUGS ARE ALREADY AT THE END OF THEIR LIFE CYCLE AFTER 40 YEARS, DECITABINE IS ONLY AT THE BEGINNING. ITS APPLICATION WILL BROADEN WITH THE INCREASE IN KNOWLEDGE OF EPIGENETIC MECHANISMS AND THEIR RELATIONSHIP TO DRUG THERAPY. 2005 15 3571 28 IMPACT OF LOCAL ANESTHETICS ON EPIGENETICS IN CANCER. DEFECTIVE SILENCING OF TUMOR SUPPRESSOR GENES THROUGH EPIGENETIC ALTERATIONS CONTRIBUTES TO ONCOGENESIS BY PERTURBING CELL CYCLE REGULATION, DNA REPAIR OR CELL DEATH MECHANISMS. REVERSAL OF SUCH EPIGENETIC CHANGES INCLUDING DNA HYPERMETHYLATION PROVIDES A PROMISING ANTICANCER STRATEGY. UNTIL NOW, THE NUCLEOSIDE DERIVATIVES 5-AZACYTIDINE AND DECITABINE ARE THE SOLE DNA METHYLTRANSFERASE (DNMT) INHIBITORS APPROVED BY THE FDA FOR THE TREATMENT OF SPECIFIC HEMATOLOGICAL CANCERS. NEVERTHELESS, DUE TO THEIR NUCLEOSIDE STRUCTURE, THESE INHIBITORS DIRECTLY INCORPORATE INTO DNA, WHICH LEADS TO SEVERE SIDE EFFECTS AND COMPROMISES GENOMIC STABILITY. MUCH EMPHASIS HAS BEEN PLACED ON THE DEVELOPMENT OF LESS TOXIC EPIGENETIC MODIFIERS. RECENTLY, SEVERAL PRECLINICAL STUDIES DEMONSTRATED THE POTENT EPIGENETIC EFFECTS OF LOCAL ANESTHETICS, WHICH ARE ROUTINELY USED DURING PRIMARY TUMOR RESECTION TO RELIEF SURGICAL PAIN. THESE NON-NUCLEOSIDE MOLECULES INHIBIT DNMT ACTIVITY, AFFECT THE EXPRESSION OF MICRO-RNAS AND REPRESS HISTONE ACETYLATION, THUS EXERTING CYTOTOXIC EFFECTS ON MALIGNANT CELLS. THE IN-DEPTH MECHANISTIC COMPREHENSION OF THESE EPIGENETIC EFFECTS MIGHT PROMOTE THE USE OF LOCAL ANESTHETICS AS ANTICANCER DRUGS. 2022 16 1686 33 DRUGGING THE PAIN EPIGENOME. MORE THAN 20% OF ADULTS WORLDWIDE EXPERIENCE DIFFERENT TYPES OF CHRONIC PAIN, WHICH ARE FREQUENTLY ASSOCIATED WITH SEVERAL COMORBIDITIES AND A DECREASE IN QUALITY OF LIFE. SEVERAL APPROVED PAINKILLERS ARE AVAILABLE, BUT CURRENT ANALGESICS ARE OFTEN HAMPERED BY INSUFFICIENT EFFICACY AND/OR SEVERE ADVERSE EFFECTS. CONSEQUENTLY, NOVEL STRATEGIES FOR SAFE, HIGHLY EFFICACIOUS TREATMENTS ARE HIGHLY DESIRABLE, PARTICULARLY FOR CHRONIC PAIN. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNAS (MIRNAS) STRONGLY AFFECT THE REGULATION OF GENE EXPRESSION, POTENTIALLY FOR LONG PERIODS OVER YEARS OR EVEN GENERATIONS, AND HAVE BEEN ASSOCIATED WITH PATHOPHYSIOLOGICAL PAIN. SEVERAL STUDIES, MOSTLY IN ANIMALS, REVEALED THAT INHIBITORS OF DNA METHYLATION, ACTIVATORS AND INHIBITORS OF HISTONE MODIFICATION AND MODULATORS OF MIRNAS REVERSE A NUMBER OF PATHOLOGICAL CHANGES IN THE PAIN EPIGENOME, WHICH ARE ASSOCIATED WITH ALTERED EXPRESSION OF PAIN-RELEVANT GENES. THIS EPIGENETIC MODULATION MIGHT THEN REDUCE THE NOCICEPTIVE RESPONSE AND PROVIDE NOVEL THERAPEUTIC OPTIONS FOR ANALGESIC THERAPY OF CHRONIC PAIN STATES. HOWEVER, A NUMBER OF CHALLENGES, SUCH AS NONSPECIFIC EFFECTS AND POOR DELIVERY TO TARGET CELLS AND TISSUES, HINDER THE RAPID DEVELOPMENT OF SUCH ANALGESICS. IN THIS REVIEW, WE CRITICALLY SUMMARIZE DATA ON EPIGENETICS AND PAIN, FOCUSING ON CHALLENGES IN CLINICAL DEVELOPMENT AS WELL AS POSSIBLE NEW APPROACHES TO THE DRUG MODULATION OF THE PAIN EPIGENOME. 2017 17 2535 30 EPIGENETICS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ENORMOUS EVIDENCE HAS ACCUMULATED IN THE PAST DECADES THAT ESTABLISHES THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CANCER AND HAS RESULTED IN SHIFTING THE FOCUS FROM ENTIRELY GENETIC-BASED STUDIES TO INTEGRATED STUDIES INVOLVING BOTH GENETIC AND EPIGENETIC ALTERATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS ONE SUCH EXAMPLE WHERE STUDIES INVOLVING EPIGENETIC ABERRATIONS HAVE ACCELERATED THE SEARCH FOR AFFECTED GENES, WHICH WAS INITIALLY RESTRICTED TO COMMONLY DELETED CHROMOSOMAL REGIONS. MANY NOVEL GENES THAT ARE EPIGENETICALLY SILENCED IN CLL HAVE BEEN IDENTIFIED. ADVANCES IN THE UNDERSTANDING OF POST-TRANSLATIONAL HISTONE MODIFICATIONS AND DNA METHYLATION IN NORMAL AND IN CLL CELLS HAVE PROVEN TO BE EXTREMELY BENEFICIAL IN FINDING POWERFUL DIAGNOSTIC MARKERS, AS WELL AS IN EXPLORING NOVEL THERAPIES. AT PRESENT, THE FIELD OF EPIGENETICS IS AT AN EVOLVING STAGE, BUT THERE IS NO DOUBT THAT FURTHER UNRAVELING OF ITS CAUSE AND EFFECTS IN TRANSFORMED CELLS WILL BRING A NEW REVOLUTION IN CANCER THERAPEUTICS. 2006 18 3565 33 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS. 2022 19 6326 25 THE ROLE OF BCL-2 FAMILY PROTEINS IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BCL-2 FAMILY PROTEINS HAVE LONG BEEN IMPLICATED IN THE PATHOLOGY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). INDEED, A NUMBER OF THESE PROTEINS HAVE BEEN SHOWN TO HAVE PROGNOSTIC IMPORTANCE IN THIS DISEASE. THE PRECISE WAYS IN WHICH THESE PROTEINS IMPACT UPON CLL AND THE WAYS IN WHICH THEY ARE REGULATED REMAIN INCOMPLETELY RESOLVED. HOWEVER, SIGNIFICANT ADVANCES HAVE BEEN RECENTLY MADE IN OUR UNDERSTANDING OF HOW THESE PROTEINS ARE CONTROLLED BY GENETIC, EPIGENETIC AND MICROENVIRONMENTAL CUES. FURTHERMORE, MAJOR PROGRESS HAS BEEN MADE IN TRYING TO TARGET THESE PROTEINS THERAPEUTICALLY. HERE WE REVIEW THE CURRENT KNOWLEDGE ABOUT THIS FAMILY OF APOPTOSIS-REGULATING PROTEINS AND HOW THEY IMPACT UPON DRUG RESISTANCE AND DISEASE PROGRESSION. WE ALSO SUMMARISE EVOLUTION IN THE DEVELOPMENT OF BCL-2 FAMILY INHIBITORS FOR THE TREATMENT OF CLL AND OTHER CANCERS. 2010 20 2551 30 EPIGENETICS IN PAIN AND ANALGESIA: AN IMMINENT RESEARCH FIELD. HERITABLE PHENOTYPES RESULTING FROM ENVIRONMENT-CAUSED CHANGES IN A CHROMOSOME WITHOUT ALTERATIONS IN THE DNA SEQUENCE ARE INCREASINGLY RECOGNIZED AS A BASIS OF PERSONALIZED THERAPY. EPIGENETIC MECHANISMS INCLUDE COVALENT MODIFICATIONS OF THE DNA (METHYLATION) OR OF THE DNA-PACKAGING HISTONES (E.G., DEACETYLATION OR PHOSPHORYLATION). IN ADDITION, REGULATORY NON-CODING RNA MOLECULES (MICRO-RNAS) EXERT EPIGENETIC ACTIONS. THIS LEADS TO DISRUPTION OR OTHERWISE MODIFIED EXPRESSION OF GENES. ENVIRONMENTAL INFLUENCES SUCH AS NUTRITIONAL FACTORS, EXPOSURE TO CHEMICALS OR DRUGS, BUT ALSO SOCIAL FACTORS APPEAR TO EXERT EPIGENETIC ACTIONS. HISTONE MODIFICATIONS AND DNA METHYLATION ARE ASSOCIATED WITH THE SUBJECT'S AGE. EPIGENETIC MECHANISMS CAN SILENCE THE EXPRESSION OF PRO- OR ANTINOCICEPTIVE GENES. TO THE EPIGENETIC CONTROL OF NOCICEPTION ADDS ITS CONTROL OF THE PHARMACODYNAMICS OR PHARMACOKINETICS OF ANALGESICS BY EPIGENETIC CONTROL OF DRUG TARGETS AND ANALGESICS METABOLIZING ENZYMES. ALTHOUGH EPIGENETICS-BASED STRATEGIES FOR PAIN THERAPY ARE NOT YET AVAILABLE, EXPERIMENTS IN RODENTS SUGGEST THAT RNA INTERFERENCE MAY BECOME A NEW THERAPY APPROACH FOR NEUROPATHIC AND OTHER PAIN. ANOTHER EPIGENETIC APPROACH TO ANALGESIC TREATMENT EMPLOYS INHIBITORS OF HISTONE DEACETYLASE THAT ACT ON THE EPIGENOME BY INDIRECTLY REMODELING THE SPATIAL CONFORMATION OF THE CHROMATIN. FINALLY, EPIGENETIC TECHNIQUES SUCH AS RNA INTERFERENCE HAVE BEEN EMPLOYED IN PAIN RESEARCH TO PROOF THE CONTRIBUTION OF CERTAIN PROTEINS TO NOCICEPTION. THUS, THE NEW FIELD OF EPIGENETICS BECOMES INCREASINGLY USED IN RESEARCH AND MANAGEMENT OF PAIN AND WILL COMPLEMENT GENETICS. THIS ARTICLE INTRODUCES EPIGENETICS TO PAIN AND SUMMARIZES THE CURRENT AND FUTURE UTILITY. 2011