A methodology for investigating the therapeutic efficacy of 3-way drug combinations has been presented and illustrated by 2 applications using an experimental mouse tumor system, L1210. The experimental design involves testing drugs individually, in all possible pairs but with varying ratios between the 2 drugs involved, and, all 3 drugs simultaneously but in varying percentage composition for the combined treatment. Any particular design is equivalent to the selection of a set of points at the vertices, along the edges, and in the interior of an equilateral triangle, each such point identifying the relative proportion in which the 3 drugs are to be used. Moreover, for each such relative proportion a range of dose levels is employed with the intention of bracketing the optimal dose for that combination.
In the present applications there was no clear evidence of therapeutic synergism. What was illustrated was the feasibility for evaluating 3-way drug combinations and the usefulness of the design triangle in such studies. The design triangle permits ready visualization of both the experimental design involved and any patterns of synergism indicated by the resulting experimental data. This is illustrated in the interpretation of the present data.
Various related problems are discussed.
Partly supported by Contract PH43-64-911 from the Cancer Chemotherapy National Service Center, NIH, to Microbiological Associates, Inc.