Antiangiogenic and antitumor activity of IDN 5390, a new taxane derivative.
OBJECTIVE
We previously reported that paclitaxel, a microtubule-stabilizing drug, inhibited angiogenesis, mainly by inhibiting endothelial cell motility (D. Belotti et al., Clin. Cancer Res., 2: 1843-1849, 1996). The aim of this study was to select a taxane with little cytotoxicity but with antimotility and hence antiangiogenic activity.


METHODS
Different taxanes, seco derivatives, and 14-beta-hydroxy-10-deacetyl baccatin III derivatives were tested for their effects on the proliferation and motility of human umbilical vein endothelial cells. The antiangiogenic and antineoplastic activities of the compound selected from this screening were further investigated in experimental models in vitro and in vivo.


RESULTS
From the screening of different taxanes, we selected IDN 5390, a seco derivative that showed potent antimotility activity and less cytotoxicity than paclitaxel. In comparable experimental conditions, IDN 5390 inhibited endothelial cell migration without affecting proliferation. This compound dose-dependently inhibited the capacity of human umbilical vein endothelial cells plated on Matrigel to organize into a network of cords. In vivo, IDN 5390 significantly inhibited fibroblast growth factor-2-induced angiogenesis in Matrigel implants. Daily treatment with IDN 5390 in mice bearing established lung micrometastases from the B16BL6 murine melanoma caused a reduction in the size of metastases. Finally, IDN 5390 slowed the s.c. growth of the paclitaxel-resistant human ovarian carcinoma, 1A9/PTX22, xenografted in nude mice.


CONCLUSIONS
The seco derivative IDN 5390 might represent the prototype of a new class of taxane derivatives with antiangiogenic properties.
Taraboletti
Giulia
G
Department of Oncology, Mario Negri Institute for Pharmacological Research, 24125 Bergamo, Italy. taraboletti@marionegri.it
Micheletti
Gianluca
G
Rieppi
Monica
M
Poli
Maura
M
Turatto
Michele
M
Rossi
Cosmo
C
Borsotti
Patrizia
P
Roccabianca
Paola
P
Scanziani
Eugenio
E
Nicoletti
Maria Ines
MI
Bombardelli
Ezio
E
Morazzoni
Paolo
P
Riva
Antonella
A
Giavazzi
Raffaella
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000473:pathology / Q000517:prevention & control; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology*; D043823:Taxoids; D013997:Time Factors; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; C459840:IDN 5390; D043823:Taxoids; D014404:Tubulin; D016222:Fibroblast Growth Factor 2; C080625:taxane; D017239:Paclitaxel