title: Second generation hybrid polar compounds are potent inducers of transformed cell differentiation.
abstract: Hybrid polar compounds, of which hexamethylenebisacetamide (HMBA) is the prototype, are potent inducers of differentiation of murine erythroleukemia (MEL) cells and a wide variety of other transformed cells. HMBA has been shown to induce differentiation of neoplastic cells in patients, but is not an adequate therapeutic agent because of dose-limiting toxicity. We report on a group of three potent second generation hybrid polar compounds, diethyl bis-(pentamethylene-N,N-dimethylcarboxamide) malonate (EMBA), suberoylanilide hydroxamic acid (SAHA), and m-carboxycinnamic acid bis-hydroxamide (CBHA) with optimal concentrations for inducing MEL cells of 0.4 mM, 2 microM, and 4 microM, respectively, compared to 5 mM for HMBA. All three agents induce accumulation of underphosphorylated pRB; increased levels of p2l protein, a prolongation of the initial G1 phase of the cell cycle; and accumulation of hemoglobin. However, based upon their effective concentrations, the cross-resistance or sensitivity of an HMBA-resistant MEL cell variant, and differences in c-myb expression during induction, these differentiation-inducing hybrid polar compounds can be grouped into two subsets, HMBA/EMBA and SAHA/CBHA. This classification may prove of value in selecting and planning prospective preclinical and clinical studies toward the treatment of cancer by differentiation therapy.
authors.affiliation: Program of Cell Biology and Genetics, DeWitt Wallace Research Laboratories, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Richon
authors.forename: Y
authors.initials: Y
authors.lastname: Webb
authors.forename: R
authors.initials: R
authors.lastname: Merger
authors.forename: T
authors.initials: T
authors.lastname: Sheppard
authors.forename: B
authors.initials: B
authors.lastname: Jursic
authors.forename: L
authors.initials: L
authors.lastname: Ngo
authors.forename: F
authors.initials: F
authors.lastname: Civoli
authors.forename: R
authors.initials: R
authors.lastname: Breslow
authors.forename: R A
authors.initials: RA
authors.lastname: Rifkind
authors.forename: P A
authors.initials: PA
authors.lastname: Marks
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects*; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; C014026:hexamethylene bisacetamide