The effects of vincristine (VCR) in combination with methotrexate (MTX) and other antitumor agents were evaluated by cell growth inhibition assay using a human acute lymphoblastic leukemia cell line (MOLT-3). The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity (G. G. Steel and M. J. Peckman, Int. J. Radiat. Oncol., 5: 85–91, 1979). Simultaneous exposure of VCR and MTX produced subadditive or mutually protective interactions. Sequential exposure to VCR first followed immediately by MTX produced similar interactions. When the interval of VCR exposure first and then MTX was increased from 0 to 3, 8, and 24 h, the inhibition of cell growth moved from protection and subadditivity to additivity only. The reversed order of exposure to the 2 drugs produced an entirely different picture. Thus, when the interval of MTX exposure first followed by VCR increased from 0 to 3, 8, and 24 h, the inhibitory effects of the combination changed progressively from the area of subadditivity to the area of supraadditivity. When these data were evaluated using median effect plot analyses (T-C. Chou and P. Talalay. In: New Avenues in Developmental Cancer Chemotherapy, pp. 36–64. Orlando, FL: Academic Press, 1987), strongly synergistic interaction of this sequence at space intervals was confirmed. These data show that the synergistic effects were produced only when MTX was followed 8 or 24 h later by VCR. Other schedules were only additive or even antagonistic.
Simultaneous exposure of VCR with daunorubicin, 1-β-d-arabinofuranosylcytosine, or bleomycin also had subadditive and protective effects. VCR, followed by daunorubicin with the interval of 24 h and vice versa, was again subadditive and protective. VCR, followed by 1-β-d-arabinofuranosylcytosine with the interval of 24 h and vice versa, was again subadditive or additive only. Simultaneous and continuous exposures of VCR with vinblastine or l-asparaginase were only marginally supraadditive.
Supported in part by USPHS Grant 15936 from the National Cancer Institute, Bethesda, MD; by the Iwama Memorial Sony International Fellowship; by the T. J. Martell Memorial Foundation for Cancer and Leukemia Research, Inc., New York, NY; by the United Leukemia Fund, Inc., New York, NY; and by the Chemotherapy Foundation, New York, NY.