A new dimethyl ester bisphosphonate inhibits angiogenesis and growth of human epidermoid carcinoma xenograft in nude mice.
Bisphosphonates are extensively used in the treatment of patients with metastasis-induced osteolysis. The major drawback in the efficacy of all bisphosphonates lies in their high hydrophilic nature, which results in poor membrane permeability and low availability for soft tissues. A reasonable approach to overcome these problems consists in masking one or more ionizable groups of bisphosphonates, notably by esterification of the hydroxyl functions. We have previously shown that the novel non-nitrogen-containing bisphosphonate BP7033 inhibited angiogenesis and growth of primary tumors in nude mice. The present study focuses on the dimethyl-esterified analog of this compound (Me-BP7033). In-vitro, Me-BP7033 inhibited proliferation of human carcinoma A431 cells as well as their invasive activity based on a transwell invasion assay. in-vivo, administration of Me-BP7033 (0.3 mg/kg) twice a week for 5 weeks inhibited the tumor growth of A431 cells xenografted in nude mice by 65%. Immunostaining of endothelial cells (ECs) in tumor sections revealed that Me-BP7033 inhibited the intratumor ECs density by 60%. The in-vivo anti-angiogenic properties of Me-BP7033 were also demonstrated in an in-vivo angiogenesis assay showing that Me-BP7033 reduced the vascular endothelial growth factor-stimulated infiltration of ECs in a Matrigel plug by 70%. In summary, we demonstrated for the first time that a diesterified bisphosphonate exhibited in vivo both anti-tumoral and anti-angiogenic activities with no apparent sign of toxic effects. These new diesterified compounds, which could display enhanced bioavailability and pharmacokinetics, thus represent interesting candidates for therapeutic applications such as cancer treatment.
Ledoux
Dominique
D
EA3406, Laboratoire de Pharmacologie, Université Paris 13, Bobigny, France. dominique.ledoux@avc.ap-hop-paris.fr
Hamma-Kourbali
Yamina
Y
Di Benedetto
Mélanie
M
Foucault-Bertaud
Alexandrine
A
Oudar
Olivier
O
Sainte-Catherine
Odile
O
Lecouvey
Marc
M
Kraemer
Michel
M
D000818:Animals; D001592:Benzyl Alcohols / Q000737:chemistry / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
C479078:BP 7033; D001592:Benzyl Alcohols; D004164:Diphosphonates; C516039:Me-BP7033; D042461:Vascular Endothelial Growth Factor A