title: Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer.
abstract: OBJECTIVE
  Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma.
  
  
  METHODS
  Patients with treatment-naïve locally advanced nasopharyngeal carcinoma received seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation.
  
  
  RESULTS
  At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T.
  
  
  CONCLUSIONS
  Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.
authors.affiliation: Department of Hematology-Oncology, National University Hospital, Oncology Research Institute, School of Computing, and Department of Head and Neck Surgery, National University of Singapore, Singapore.
authors.forename: Wen-Son
authors.initials: WS
authors.lastname: Hsieh
authors.forename: Ross
authors.initials: R
authors.lastname: Soo
authors.forename: Bee-Keow
authors.initials: BK
authors.lastname: Peh
authors.forename: Thomas
authors.initials: T
authors.lastname: Loh
authors.forename: Difeng
authors.initials: D
authors.lastname: Dong
authors.forename: Donny
authors.initials: D
authors.lastname: Soh
authors.forename: Lim-Soon
authors.initials: LS
authors.lastname: Wong
authors.forename: Simon
authors.initials: S
authors.lastname: Green
authors.forename: Judy
authors.initials: J
authors.lastname: Chiao
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Cui
authors.forename: Yoke-Fong
authors.initials: YF
authors.lastname: Lai
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mow
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D019938:Cyclin D1 / Q000032:analysis; D004279:DNA, Viral / Q000097:blood; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011687:Purines / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000077546:Roscovitine
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; D004279:DNA, Viral; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D000077546:Roscovitine; D019938:Cyclin D1