Figure 1.

The pathway of drug administration to the tumor response is affected by tumor drug penetration at four levels: (1) the systemic level (the concentration of the drug in the blood pool, which determines how much of the drug is available for tumor penetration), (2) the tissue level (e.g., is the drug able to distribute throughout the tumor tissue, as influenced by the tumor microenvironment), (3) the cellular or molecular engagement level (where the drug is able to engage and interact with its target at the cellular/molecular level, a proximal or direct measure of drug mechanism of action), and (4) the expression of pharmacological activity following target engagement (a distal or indirect measure of drug pharmacodynamics). All these levels will be affected by responses to treatment (bottom).