Cancer chemotherapy remains a challenging area of pharmacology. On the one hand, use of cytotoxic anticancer drugs produces high rates of cure of a few cancers, which, without chemotherapy, result in extremely high mortality rates (eg, acute lymphocytic leukemia in children, testicular cancer, and Hodgkin’s lymphoma). On the other hand, some types of cancer are barely affected by currently available drugs. Furthermore, as a group, the cytotoxic anticancer drugs are more toxic than any other drug class and thus their benefit must be carefully weighed against their risks. Many of the available drugs are cytotoxic agents that act on all dividing cells, cancerous or normal. The ultimate goal in cancer chemotherapy is to use advances in cell biology to develop targeted therapies that selectively affect specific cancer cells. This area is one of the most rapidly expanding fields in drug development.
CANCER CELL CYCLE KINETICS
Cancer cell population kinetics and the cancer cell cycle are important determinants of the actions and clinical uses of anticancer drugs. Some anticancer drugs exert their actions selectively on cycling cells (cell cycle-specific [CCS] drugs), and others (cell cycle-nonspecific [CCNS] drugs) kill tumor cells in both cycling and resting phases of the cell cycle (although cycling cells are more sensitive). CCS drugs are usually most effective when cells are in a specific phase of the cell cycle (Figure 54–1). Both types of drugs are most effective when a large proportion of the tumor cells are proliferating (ie, when the growth fraction is high).
Phases of the cell cycle that are susceptible to the actions of cell cycle-specific (CCS) drugs. All dividing cells—normal and neoplastic—must traverse these cell cycle phases before and during cell division. Tumor cells are usually most responsive to specific drugs (or drug groups) in the phases indicated. Cell cycle-nonspecific (CCNS) drugs act on tumor cells while they are actively cycling and while they are in the resting phase (G0). (Reproduced and modified, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 54–2.)
B. The Log-Kill Hypothesis
Cytotoxic drugs act with first-order kinetics in a murine model of leukemia. In this model system, in which all the cells are actively progressing through the cell cycle, a given dose kills a constant proportion of a cell population rather than a constant number of cells. The log-kill hypothesis proposes that the magnitude of tumor cell kill by anticancer drugs is a logarithmic function. For example, a 3-log-kill dose of an effective drug reduces a cancer cell population of 1012 cells to 109 (a total kill of 999 × 109 cells); the same dose would reduce a starting population of 106 cells ...