Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases.
The in vivo disposition and antitumor efficacy of a newly developed phosphinic matrix metalloproteinase inhibitor (RXP03) were examined. RXP03 potently inhibits MMP-11, MMP-8 and MMP-13, but not MMP-1 and MMP-7. Twenty-four hours after i.p. injection into mice, most of the RXP03 was recovered intact in plasma, feces (biliary excretion) and tumor tissue. Pharmacokinetic parameters indicated that, after an i.p. dose of 100 microg/day, the plasma concentration of RXP03 over 24 hr remained higher than the Ki values determined for MMP-11, MMP-8 and MMP-13. Efficacy of RXP03 on the growth of primary tumors induced by s.c. injection of C(26) colon carcinoma cells in mice was observed to depend both on RXP03 doses and treatment schedules. Tumor volumes in mice treated for 18 days with 50, 100 and 150 microg/day of RXP03 were decreased compared with control tumor volumes, 100 microg/day being the most effective dose. Treatment at higher dose (600 microg/day) did not significantly reduce the tumor size as compared to control. Short treatments with RXP03 100 microg/day, 3 to 7 days after C(26) inoculation, were more effective on tumor growth than continuous treatment over 18 days. Strikingly, RXP03 treatment started 6 days after the C(26) injection and continued until day 18 led to stimulation of tumor growth, as compared to control. These paradoxical effects, depending on the RXP03 treatment schedule, underline the need to define carefully the spatiotemporal function of each MMP at various stages of tumor growth to achieve optimal therapeutic effects by MMP inhibitor treatment.
Dive
Vincent
V
CEA, Département d'Ingénierie et d'Etudes des Protéines, Gif/Yvette, France. vincent.dive@cea.fr <vincent.dive@cea.fr>
Andarawewa
Kumari L
KL
Boulay
Anne
A
Matziari
Magdalini
M
Beau
Fabrice
F
Guerin
Eric
E
Rousseau
Bernard
B
Yiotakis
Athanasios
A
Rio
Marie-Christine
MC
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D016246:Lymphocytes, Tumor-Infiltrating; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009605:Nitrosomethylurethane / Q000633:toxicity; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*
D000477:Alkylating Agents; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; C423682:RXP03; D009605:Nitrosomethylurethane; D020782:Matrix Metalloproteinases