title: Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models.
abstract: OBJECTIVE
  The aim of the work was to determine and characterize, in vitro and in vivo, the therapeutic activity of PHA-793887, a new potent pan-cdk inhibitor, in the context of hematopoietic neoplasms.
  
  
  METHODS
  Thirteen leukemic cell lines bearing different cytogenetic abnormalities and normal hematopoietic cells were used in cytotoxicity and colony assays. The drug activity at the molecular level was analyzed by Western blotting. PHA-793887 was also tested in vivo in several leukemia xenograft models.
  
  
  RESULTS
  PHA-793887 was cytotoxic for leukemic cell lines in vitro, with IC(50) ranging from 0.3 to 7 microM (mean: 2.9 microM), regardless of any specific chromosomal aberration. At these doses, the drug was not cytotoxic for normal unstimulated peripheral blood mononuclear cells or CD34(+) hematopoietic stem cells. Interestingly, in colony assays PHA-793887 showed very high activity against leukemia cell lines, with an IC(50) <0.1 microM (mean: 0.08 microM), indicating that it has efficient and prolonged antiproliferative activity. PHA-793887 induced cell-cycle arrest, inhibited Rb and nucleophosmin phosphorylation, and modulated cyclin E and cdc6 expression at low doses (0.2-1 microM) and induced apoptosis at the highest dose (5 microM). It was also effective in vivo in both subcutaneous xenograft and primary leukemic disseminated models that better mimic naturally occurring human disease. Interestingly, in one disseminated model derived from a relapsed Philadelphia-positive acute lymphoid leukemia patient, PHA-793887 showed strong therapeutic activity also when treatment was started after establishment of high disease burden.
  
  
  CONCLUSIONS
  We conclude that PHA-793887 has promising therapeutic activity against acute leukemias in vitro and in vivo.
authors.affiliation: Nerviano Medical Sciences Srl, Business Unit Oncology, Nerviano, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Alzani
authors.forename: Olga
authors.initials: O
authors.lastname: Pedrini
authors.forename: Clara
authors.initials: C
authors.lastname: Albanese
authors.forename: Roberta
authors.initials: R
authors.lastname: Ceruti
authors.forename: Alessia
authors.initials: A
authors.lastname: Casolaro
authors.forename: Veronica
authors.initials: V
authors.lastname: Patton
authors.forename: Francesco
authors.initials: F
authors.lastname: Colotta
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.forename: Martino
authors.initials: M
authors.lastname: Introna
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
authors.forename: Josée
authors.initials: J
authors.lastname: Golay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID
chemical_list: D000970:Antineoplastic Agents; D018844:Cyclin-Dependent Kinases