title: The future of epigenetic therapy in solid tumours--lessons from the past.
abstract: The promise of targeting epigenetic abnormalities for cancer therapy has not been realized for solid tumours, although increasing evidence is demonstrating its worth in haematological malignancies. In fact, true clinical efficacy in haematopoietic-related neoplasms has only become evident at low doses of epigenetic-targeting drugs (namely, inhibitors of histone deacetylase and DNA methyltransferases). Describing data from preclinical studies and early clinical trial results, we hypothesize that in using low-dose epigenetic-modulating agents, tumour cells can be reprogrammed, which overrides any immediate cytotoxic and off-target effect observed at high dose. We suggest that such optimization of drug dosing and scheduling of currently available agents could give these agents a prominent place in cancer management--when used alone or in combination with other therapies. If so, optimal use of these known agents might also pave the way for the introduction of other agents that target the epigenome.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
authors.forename: Nilofer
authors.initials: N
authors.lastname: Azad
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Zahnow
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000187:drug effects; D005544:Forecasting; D015316:Genetic Therapy / Q000379:methods / Q000639:trends*; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends*; D015337:Multicenter Studies as Topic; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D004248:DNA (Cytosine-5-)-Methyltransferases
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