ABSTRACT

Chemotherapy combinations have been devised in order to maximize cell killing by using agents that target different points in the cell cycle, rather than combining agents that target the cells in the same phase. Combining different chemotherapeutic agents accomplishes at least three objectives: It provides overlapping and sometimes synergistic cell kill within the range of toxicity tolerated by the patient for each drug, it provides coverage for resistant tumor cell subclones in a heterogeneous tumor population, and it slows the development of new drug-resistant tumor cell subclones (4). Several general principles guide selection of agents used in combination regimens: (a) Drugs known to be active as single agents should be chosen, with preference for agents that induce complete remission. (b) Drugs with different mechanisms of action should be chosen, to allow for additive or synergistic effects on tumor cells. (c) Drugs with differing dose-limiting toxicities should be chosen, to allow for each drug to be given at the full therapeutic dosage. (d) The treatment-free interval between cycles should be the shortest time that allows for recovery of the most sensitive normal tissue. (e) Drugs with different

Table 1 Agents That Kill Tumor Cells in Specific Phases of the Cell Cycle

G1 phase S phase G2 phase M phase

Asparaginase Capecitabine Bleomycin Docetaxel Corticosteroids Cytarabine Irinotecan Etoposide

Doxorubicin Mitoxantrone Paclitaxel

Fludarabine Topotecan Teniposide

Fluorouracil Vinblastine

Gemcitabine Vincristine

Hydroxyurea Vinorelbine

Mercaptopurine

Methotrexate

Prednisone

Procarbazine

Thioguanine

patterns of resistance should be combined to maximize killing of cells that may be resistant to a single agent.