Figure 551

The cell cycle. S, G1, G2, and G0 are phases of the cell cycle.

that these proliferation-dependent but non-phase-specific agents be administered in single large doses to take advantage of their sparing effect on normal cells that may be in G0.

Unfortunately, many human cancers have a large proportion of cells in the resting phase, and these cells are also resistant to the class 3 agents, which include cyclophosphamide, dactinomycin, and fluorouracil.

This classification of anticancer drugs has inherent limitations. For instance, it may be difficult to generalize about the phase specificity of a particular drug, since this may vary among cell types. Several techniques are available to synchronize cell populations in such a way that most cells will be in the same phase of the cell cycle. After synchronization, one can treat cells in each phase and determine their relative sensitivity to drugs throughout the cell cycle.

Some drugs that exert their maximum cytotoxicity during the S-phase of the cycle also prevent cells from progressing through the cell cycle to the S-phase; this is accomplished by sublethal inhibition of RNA and protein synthesis. The antimetabolites methotrexate, fluo-rouracil, and mercaptopurine all can inhibit RNA synthesis in Gr and G2-phases and inhibit DNA synthesis during S-phase. This inhibition of cell cycle progression actually may result in reduced cytotoxicity, and such agents have been termed S-phase-specific but self-limited.

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