Figure 4.

Combinatorial (positive/negative) selectivity of a regimen that utilizes interference/codominance and antiinhibitor. The diagram tabulates the relative toxicities of the compound abi in the setting of a two-compound treatment of cells that either lack or contain the macromolecular targets A, B, and C. The inhibitor-containing compound abi is described in the main text and Figs. 1, 2, and 3C. The antiinhibitor-containing compound ci* is described in the main text and Fig. 3. A and B are negative targets, in that they reduce, through the binding to the moieties a and b of abi, the inhibition of an essential enzyme I by abi. C is a positive target, in that it reduces, through the binding to the c moiety of ci*, the binding of ci* to enzyme I. This results in a larger fraction of enzyme I available for the inhibition by abi. It is assumed that the concentrations of A, B, and C in cells that contain them significantly exceed the concentration of I (see the main text). In all of the cell types except A⁻ B⁻ C⁺, the enzyme I would be at most partially inhibited by the i moiety of abi, because of the competing interactions of abi with A and/or B, and also because in C⁻ cells a fraction of enzyme I would be protected from the inhibition by abi through the interaction of I with the antiinhibitor moiety i* of ci*. By contrast, in A⁻ B⁻ C⁺ cells, the antiinhibitor-containing ci* would be sequestered by C, whereas abi would not be sequestered by A or B, which are absent from these cells. As a result, a larger fraction of the inhibitor-containing abi molecules would be available for the interaction with I, resulting in the selective toxicity of abi to A⁻ B⁻ C⁺ cells. The selectivity pattern of abi requires that certain pharmacokinetic conditions are met as well (see the main text). Note that the physiological effects and the uses of abi-type compounds are not confined to cytotoxic regimens.