Lack of therapeutic synergism between vincristine and methotrexate in L1210 murine leukemia in vivo.

In vivo studies were performed in mice bearing L1210 ascites tumor to examine the interaction of vincristine (VCR) at doses of 0.15 and 1.5 mg/kg with methotrexate (MTX) at doses of 0.5, 5, 50, and 350 mg/kg. The combination was administered on Days 2, 6, and 10 after tumor inoculation. VCR was given either concurrently with MTX or preceding it by 30, 60, or 120 minutes. VCR administered at a dose of 0.15 mg/kg achieved a peak peritoneal fluid concentration of 1.4 micron declining with a half-life (T1/2) of 33.5 minutes and produced no in vivo augmentation of MTX uptake. VCR administered at a dose of 1.5 mg/kg achieved a peak peritoneal fluid concentration of 16.5 micron declining with a T1/2 of 24.9 minutes and produced significant in vivo augmentation of MTX uptake when given concurrently with the MTX and 30 minutes prior to MTX at a dose of 350 mg/kg. No other interval was associated with augmented MTX uptake. When animal survival was evaluated, no therapeutic synergism was observed at any dose level of either drug in any schedule. In fact, VCR (0.15 and 1.5 mg/kg) and MTX at doses of greater than or equal to 50 mg/kg produced toxic synergism which adversely affected survival. Since the drug doses studied are comparable with those used in "high-dose" clinical protocols, individual tumor evaluation is indicated to support the use of these drugs in combination.