Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases

Vincent Dive*, Kumari L. Andarawewa, Anne Boulay, Magdalini Matziari, Fabrice Beau, Eric Guerin, Bernard Rousseau, Athanasios Yiotakis, Marie Christine Rio

*Corresponding author for this work

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27 Citations (Scopus)


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 μg/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 C26 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 μg/day of RXP03 were decreased compared with control tumor volumes, 100 μg/day being the most effective dose. Treatment at higher dose (600 μg/day) did not significantly reduce the tumor size as compared to control. Short treatments with RXP03 100 μg/day, 3 to 7 days after C26 inoculation, were more effective on tumor growth than continuous treatment over 18 days. Strikingly, RXP03 treatment started 6 days after the C26 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.

Original languageEnglish
Pages (from-to)775-781
Number of pages7
JournalInternational Journal of Cancer
Issue number5
Publication statusPublished - 20 Feb 2005
Externally publishedYes


  • Matrix metalloproteinase
  • Phosphinic peptides

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