Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and pharmacodynamic end-points.
Flavopiridol downregulates anti-apoptotic regulators including Mcl-1, upregulates p53, globally attenuates transcription through inhibition of P-TEFb, binds to DNA, and inhibits angiogenesis. Eighteen myeloma patients were treated with 1-hour flavopiridol infusions for 3 consecutive days every 21 days. Immunoblotting for Mcl-1, Bcl-2, p53, cyclin D, phosphoRNA polymerase II and phosphoSTAT 3 was conducted on myeloma cells. Ex vivo flavopiridol treatment of cells resulted in cytotoxicity, but only after longer exposure times at higher flavopiridol concentrations than were anticipated to be achieved in vivo. No anti-myeloma activity was observed in vivo. As administered, flavopiridol has disappointing activity as a single agent in advanced myeloma.
Dispenzieri
Angela
A
Mayo Clinic Rochester, MN 55905, USA. angela@mayo.edu
Gertz
Morie A
MA
Lacy
Martha Q
MQ
Geyer
Susan M
SM
Fitch
Tom R
TR
Fenton
Robert G
RG
Fonseca
Rafael
R
Isham
Crescent R
CR
Ziesmer
Steven C
SC
Erlichman
Charles
C
Bible
Keith C
KC
D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000517:prevention & control*; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome
D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib