Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer.
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.
Hsieh
Wen-Son
WS
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.
Soo
Ross
R
Peh
Bee-Keow
BK
Loh
Thomas
T
Dong
Difeng
D
Soh
Donny
D
Wong
Lim-Soon
LS
Green
Simon
S
Chiao
Judy
J
Cui
Chun-Ying
CY
Lai
Yoke-Fong
YF
Lee
Soo-Chin
SC
Mow
Benjamin
B
Soong
Richie
R
Salto-Tellez
Manuel
M
Goh
Boon-Cher
BC
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
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