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Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases
Author(s) -
Dive Vincent,
Andarawewa Kumari L.,
Boulay Anne,
Matziari Magdalini,
Beau Fabrice,
Guerin Eric,
Rousseau Bernard,
Yiotakis Athanasios,
Rio MarieChristine
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20459
Subject(s) - matrix metalloproteinase , in vivo , pharmacokinetics , medicine , pharmacology , excretion , endocrinology , chemistry , biology , microbiology and biotechnology
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 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 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 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.