Efficacy of sequential treatment of HCT116 colon cancer monolayers and xenografts with docetaxel, flavopiridol, and 5-fluorouracil.
OBJECTIVE
Clinical treatment of solid tumors with docetaxel, flavopiridol, or 5-fluorouracil (5-FU) often encounters undesirable side effects and drug resistance. This study aims to evaluate the potential role of combination therapy with docetaxel, flavopiridol, or 5-FU in modulating chemosensitivity and better understand how they might be used clinically.


METHODS
HCT116 colon cancer cells were treated with docetaxel, flavopiridol, and 5-FU in several different administrative schedules in vitro, either sequentially or simultaneously. Cell survival was measured by MTT assay. The activity of caspase-3 was determined by caspase-3 assays and the soft agar colony assay was used to test the colony formation of HCT116 cells in soft agar. We also established xenograft models to extend in vitro observations to an in vivo system.


RESULTS
The maximum cytotoxicity was found when human colon cancer HCT116 cells were treated with docetaxel for 1 h followed by flavopiridol for 24 h and 5-FU for another 24 h. This sequential combination therapy not only inhibits tumor cell growth more strongly compared to other combination therapies but also significantly reduces colony formation in soft agar and augments apoptosis of HCT116 cells. Sequencing of docetaxel followed 1 h later by flavopiridol, followed 24 h later by 5-FU in xenograft models, also resulted in delayed tumor growth and higher survival rate.


CONCLUSIONS
These results highlight the importance of an administrative schedule when combining docetaxel with flavopiridol and 5-FU, providing a rationale explanation for its development in clinical trials.
Guo
Jun
J
Harold C. Simmons Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Zhou
An-wu
AW
Fu
Yu-cai
YC
Verma
Udit N
UN
Tripathy
Debu
D
Frenkel
Eugene P
EP
Becerra
Carlos R
CR
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D000077143:Docetaxel; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage
D005419:Flavonoids; D010880:Piperidines; D043823:Taxoids; D000077143:Docetaxel; C077990:alvocidib; D005472:Fluorouracil