title: Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies.
abstract: OBJECTIVE
  Palbociclib (PD-0332991) is the first selective cyclin-dependent kinase (CDK) 4/6 inhibitor approved for metastatic breast cancer. Hematologic effects, especially neutropenia, are dose-limiting adverse events for palbociclib in humans.
  
  
  METHODS
  Reversible hematologic effects and bone marrow hypocellularity have been identified in toxicology studies in rats and dogs after palbociclib treatment. To understand the mechanism by which the hematologic toxicity occurs, and to further differentiate it from the myelotoxicity caused by cytotoxic chemotherapeutic agents, anin vitroassay using human bone marrow mononuclear cells (hBMNC) was utilized.
  
  
  RESULTS
  This work demonstrated that palbociclib-induced bone marrow suppression occurred through cell-cycle arrest, with no apoptosis at clinically relevant concentrations, was not lineage-specific, and was reversible upon palbociclib withdrawal. In contrast, treatment with chemotherapeutic agents (paclitaxel and doxorubicin) resulted in DNA damage and apoptotic cell death in hBMNCs. In the presence or absence of the antiestrogen, palbociclib-treated hBMNCs did not become senescent and resumed proliferation following palbociclib withdrawal, consistent with pharmacologic quiescence. The breast cancer cells, MCF-7, conversely, became senescent following palbociclib or antiestrogen treatment with additive effects in combination and remained arrested in the presence of antiestrogen.
  
  
  CONCLUSIONS
  Palbociclib causes reversible bone marrow suppression, clearly differentiating it from apoptotic cell death caused by cytotoxic chemotherapeutic agents. This study also distinguished the cell-cycle arresting action of palbociclib on normal bone marrow cells from the senescent effects observed in breast cancer cells. These results shed light on the mechanism and support risk management of palbociclib-induced bone marrow toxicity in the clinic.
authors.affiliation: Drug Safety Research and Development, Pfizer Inc. San Diego, California. wenyue.hu@pfizer.com.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Hu
authors.affiliation: Drug Safety Research and Development, Pfizer Inc. San Diego, California.
authors.forename: Tae
authors.initials: T
authors.lastname: Sung
authors.affiliation: Drug Safety Research and Development, Pfizer Inc. San Diego, California.
authors.forename: Bart A
authors.initials: BA
authors.lastname: Jessen
authors.affiliation: Drug Safety Research and Development, Pfizer Inc. San Diego, California.
authors.forename: Stephane
authors.initials: S
authors.lastname: Thibault
authors.affiliation: Drug Safety Research and Development, Pfizer Inc. Pearl River, New York.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Finkelstein
authors.affiliation: Drug Safety Research and Development, Pfizer Inc. Groton, Connecticut.
authors.forename: Nasir K
authors.initials: NK
authors.lastname: Khan
authors.affiliation: Drug Safety Research and Development, Pfizer Inc. San Diego, California.
authors.forename: Aida I
authors.initials: AI
authors.lastname: Sacaan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001772:Blood Cell Count; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004285:Dogs; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D023421:Models, Animal; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077267:Fulvestrant; D004958:Estradiol; C500026:palbociclib