Eur J Pharmacol. 2009 Aug 17.
Metronomic 5-fluorouracil, oxaliplatin and irinotecan in colorectal cancer.
Fioravanti A, Canu B, Alì G, Orlandi P, Allegrini G, Di Desidero T, Emmenegger U, Fontanini G, Danesi R, Del Tacca M, Falcone A, Bocci G.
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa.
chemotherapy (the frequent, long term, low dose administration of
chemotherapeutic drugs) is a promising therapy because it enhances the
anti-endothelial activity of conventional chemotherapeutics, but with
lower or no toxic effects compared to maximum tolerated dose
administration. The aims of the present study were to compare, in vitro
and in vivo, the antiangiogenic and antitumor activities of metronomic
irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in
colorectal cancer and to investigate the metronomic combination of
In vitro cell proliferation, combination studies and
vascular endothelial growth factor (VEGF) secretion analyses were
performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells
exposed for 144h to metronomic concentrations of SN-38, the active
metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer
xenograft model was used and tumour growth, microvessel density and
VEGF quantification were performed in tumours after the administration
of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination.
Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially
inhibited endothelial cell proliferation. Simultaneous and continuous
exposure of HT-29 and HMVEC-d cells to low concentrations
SN-38+L-OHP+5-FU for 144h showed a strong antagonism and an unfavorable
dose-reduction index. Moreover, the ternary combination resulted in a
significant increase of VEGF secretion in HT-29 cancer cells. In a
xenograft model metronomic CPT-11, but not 5-FU and L-OHP,
significantly inhibits HT-29 tumor growth and microvessel density in
the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11
therapy did not affect the microvascular count.
The metronomic concept
might not universally apply to every cytotoxic drug in colorectal
cancer and metronomic combination regimens should be used with caution.