Biologic agents as biochemical modulators: pharmacologic basis for the interaction of cytotoxic chemotherapeutic drugs and interferon

Biochemical modulation of cytotoxic cancer chemotherapeutic agents is one means of enhancing the activity and selectivity of antitumor drugs. Traditionally this approach has utilized detailed information regarding a particular enzymatic reaction or biochemical pathway to develop potential modulating agents. In contrast, the reported clinical therapeutic activity of IFN in combination with cytotoxic agents has prompted a reexamination of the biochemical actions of the cytokine. Interferon elicits a number of cellular actions that might contribute to its pharmacologic activity, including both direct antitumor effects and host-mediated actions. The best understood are those related to the cytotoxicity of the fluoropyrimidine antimetabolites and include enzymatic reactions involved in fluoropyrimidine metabolic activation, catabolism, and interaction with its target enzyme. However, even in this instance, a mechanistic association of a specific pharmacologic action with therapeutic activity remains to be determined. These studies demonstrate that cytokines and other biologic agents may exert specific biochemical modulations that augment (or potentially attenuate) the activity of the cytotoxic chemotherapeutic agents.