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.
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