Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma.
Aplidin is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC(50) of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 microg kg(-1) daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (P<0.001), while BM invasion with myeloma cells was decreased by 35% (P<0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.
Laboratory of Hematology and Immunology, Vrije Universiteit Brussel, Laarbeeklaan 103, Jette, Brussels 1090, Belgium.
J
J
Caers
E
E
Menu
H
H
De Raeve
D
D
Lepage
E
E
Van Valckenborgh
B
B
Van Camp
E
E
Alvarez
K
K
Vanderkerken
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D002453:Cell Cycle; D004261:DNA Replication / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010456:Peptides, Cyclic; D051381:Rats
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C098980:plitidepsin