Drugs and the Cell Cycle

DRUGS AND THE CELL CYCLE

Various classification schemes have been proposed to describe the effects of drugs on the cell cycle. One such classification divides the anticancer drugs into three cat-egories:

·              Class 1 agents (e.g., radiation, mechloreth-amine, and carmustine) exert their cytotoxicity in a nonspecific (i.e., non–proliferation de-pendent) manner. They kill both normal and malignant cells to the same extent.

·              Class 2 agents are phase specific and reach a plateau in cell kill with increasing dosages. Only a certain proportion of cells are sensitive to the toxic effects of these drugs. For example, hydroxyurea and cytarabine kill only cells in the S-phase. Similarly, bleomycin is most toxic to cells in G₂- and early M-phases. Because they affect only a small fraction of the cell population at any one time, it has been sug-gested that these drugs should be given either by continuous infusion or in frequent small doses. Such a dosage regimen would increase the number of tumor cells exposed to the drug during the sensitive phase of their cell cycle.

·              Class 3 agents kill proliferating cells in prefer-ence to resting cells. It has been recommended 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 cy-clophosphamide, 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 cy-cle. 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 pro-tein synthesis. The antimetabolites methotrexate, fluo-rouracil, and mercaptopurine all can inhibit RNA syn-thesis in G₁- 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.