Dosing and sequencing for antineoplastic synergism in combination chemotherapy.

The success that has been achieved in combination drug chemotherapy of neoplasia is attributable to the attention that has been focused on factors pertaining to dosing and sequencing. These factors take into account both the tumor and the host on treatment with two or more drugs and are discussed under the following headings: (a) drug toxicity for the host; (b) drug ratios; (c) drug scheduling and sequencing; (d) body burden and scheduling; (e) host protection and scheduling; (f) synchronization and scheduling; and (g) prevention and treatment of tumor cell infiltration, sequestration, resistance, and metastasis. In relation to the factors that may influence therapeutic outcome, examples are provided for combination chemotherapy in which therapeutic synergism has been achieved in experimental tumor models. The importance of further studies on dosing and sequencing in order to maximize therapeutic response is discussed.