Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model.
The proteasome is a ubiquitous and essential intracellular enzyme that degrades many proteins regulating cell cycle, apoptosis, transcription, cell adhesion,angiogenesis, and antigen presentation. We have shown recently that the proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human myeloma cells in vitro. In this study, we examined the efficacy, toxicity, and in vivo mechanism of action of PS-341 using a human plasmacytoma xenograft mouse model. One hundred immunodeficient (beige-nude-xid) mice were used in two independent experiments. The mice were injected s.c. with 3 x 10(7) RPMI-8226 myeloma cells. When tumors became measurable (9.2 days; range, 6-13 days after tumor injection), mice were assigned to treatment groups receiving PS-341 0.05 mg/kg (n = 13), 0.1 mg/kg (n = 15), 0.5 mg/kg (n = 14), or 1.0 mg/kg (n = 14) twice weekly via tail vein, or to control groups (n = 13) receiving the vehicle only. Significant inhibition of tumor growth, even with some complete tumor regression, was observed in PS-341-treated mice. The median overall survival was also significantly prolonged compared with controls (30 and 34 days for high dose-treated mice versus 14 days for controls; P < 0.0001). PS-341 was well tolerated up to 0.5 mg/kg, but some mice treated at 1.0 mg/kg became moribund and lost weight. Analysis of tumors harvested from treated animals showed that PS-341 induced apoptosis and decreased angiogenesis in vivo. These studies therefore demonstrate that PS-341 has significant in vivo antimyeloma activity at doses that are well tolerated in a murine model, confirming our in vitro data and further supporting the early clinical promise of PS-341 to overcome drug resistance and improve patient outcome.
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Richard
R
LeBlanc
Laurence P
LP
Catley
Teru
T
Hideshima
Suzanne
S
Lentzsch
Constantine S
CS
Mitsiades
Nicholas
N
Mitsiades
Donna
D
Neuberg
Olga
O
Goloubeva
Christine S
CS
Pien
Julian
J
Adams
Deepak
D
Gupta
Paul G
PG
Richardson
Nikhil C
NC
Munshi
Kenneth C
KC
Anderson
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000009:adverse effects / Q000494:pharmacology*; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011480:Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib