Antitumoral and antiangiogenic efficacy of bisphosphonates in vitro and in a murine RENCA model.
BACKGROUND
Bisphosphonates have shown direct antitumoral activity in vitro, in vivo and even in clinical studies, but the exact mechanism for this has not yet been elucidated. In this study the antiangiogenic potency of zoledronic acid and clodronate were evaluated.


METHODS
The effects of zoledronic acid and clodronate on the proliferation of endothelial cells and different tumor cells, and on the activity of protein kinases were investigated. Furthermore in vitro experiments were performed to evaluate the underlying antiangiogenic mechanism of action. Both bisphosphonates were examined in vivo at different doses and in daily subcutaneous application in a murine renal cell carcinoma model (RENCA). The antiangiogenic activity was evaluated by immunohistochemical staining (CD31) and by determination of mouse vascular endothelial growth factor (VEGF) serum concentration.


RESULTS
Zoledronic acid and clodronate inhibited proliferation of endothelial cells at lower concentrations than the different tumor cell lines did. This effect was more pronounced for zoledronic acid. The activity of almost all tested kinases was inhibited by zoledronic acid, whereas clodronate showed no effect. In the RENCA model, a significant effect of zoledronic acid on the primary tumor in a bell-shaped dose response curve with the highest efficacy between 100 Bg/kg 2xd and 200 Bg/kg 1xd, was observed. The mean vessel density (MVD) was significantly reduced by both bisphosphonates at different concentrations. This is the first report on increased mouse VEGF serum concentrations in the RENCA model.


CONCLUSIONS
The results indicate that these bisphosphonates, particularly zoledronic acid, possess antitumoral and antiangiogenic activity.
Cancer Hospital Sanafontis, Freiburg, Federal Republic of Germany.
Jens
J
Soltau
Ute
U
Zirrgiebel
Norbert
N
Esser
Christoph
C
Schächtele
Frank
F
Totzke
Clemens
C
Unger
Irmgard
I
Merfort
Joachim
J
Drevs
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004002:Clodronic Acid / Q000627:therapeutic use*; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011494:Protein Kinases / Q000378:metabolism; D000077211:Zoledronic Acid
D020533:Angiogenesis Inhibitors; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D004002:Clodronic Acid; D000077211:Zoledronic Acid; D011494:Protein Kinases