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.