Anticancer Res. 2004 May-Jun;24(3a):1759-63.
Antiangiogenic potency of various chemotherapeutic drugs for metronomic chemotherapy.
Drevs J, Fakler J, Eisele S, Medinger M, Bing G, Esser N, Marmé D, Unger C.
Department of Medical Oncology, Tumor Biology Center, Freiburg, Germany.
previous preclinical findings continuous low dose (metronomic)
chemotherapy is thought to inhibit tumor angiogenesis. This suggests
that activated endothelial cells may be more sensitive to
chemotherapeutic drugs than tumor cells. Therefore, we assessed the
IC50 for several relevant chemotherapeutic drugs in different
endothelial and tumor cell lines to identify optimal compounds to be
used for metronomic therapy in a murine renal cell carcinoma model.
Adriamycin, idarubicin, 5-fluorouracil, paclitaxel and etoposide were
chosen for our studies because of their oral availability in patients
or previous reports on metronomic potential. IC50s were determined by
BrdU cell growth assay after short time as well as long term exposure
of the following cell lines: human endothelial cells (HdmVEC/HUVEC),
human breast cancer (Mcf-7), melanoma (Skmel), liver cancer
(Huh7/Alexander), lung cancer (A549/LXFL), colon cancer (Dld) and
murine renal cell carcinoma (RENCA). In addition, FACS analysis was
performed to determine the effect on cell cycle. In vivo, doses of 2x12
mg/kg, 2x1.2 mg/kg and 10x0.24 mg/kg adriamycin were applied to 12
RENCA mice each and antitumor as well as antiangiogenic effects were
assessed 21 days after tumor cell application. Independent of the
exposure time, all chemotherapeutic drugs were more active against the
endothelial cell lines. IC50s were significantly lower in endothelial
cells (4.02E-06 to 6.16E-14 M) as compared to tumor cells (7.44E-02 to
1.9E-11 M). Cell cycle analysis of all chemotherapeutic drugs revealed
a G1-arrest in endothelial cells. Adriamycin applied in metronomic
doses of 10x0.24 mg/kg showed significant antiangiogenic activity
whereas, in contrast, the application of 2x12 mg/kg significantly
increased the vessel density in primary tumors. In summary, all
chemotherapeutic agents were more active against endothelial cells in
comparison to tumor cells. The hypothesis of an antiangiogenic active
metronomic therapy could be confirmed in vivo by the use of adriamycin