A2.2 Cytotoxic chemotherapy

Topic

Cytotoxic chemotherapy agents act on all cells within the body that are actively dividing at any given moment, without distinguishing between tumor cells and healthy tissue; these agents function by damaging the genetic material of dividing cells or by blocking the machinery those cells use to replicate.

Regarding this replication machinery, cytotoxic agents act at different points depending on the specific agent: some directly damage genetic material while the cell is copying it; others specifically block mitosis—the stage of the cell cycle where the duplicated cell divides into two daughter cells; and others inhibit the synthesis of nucleotides, the building blocks the cell needs to copy its genetic material during the synthesis phase. The greater the proportion of cells in a tissue that are in the genetic material synthesis phase at any given time, the more vulnerable that tissue is to these three mechanisms of cytotoxic damage.

Tumors typically have a high proportion of cells in the genetic material synthesis phase, resulting in a high net growth rate and making them, in principle, prime targets for cytotoxic agents. However, this same high proportion of cells in the synthesis phase is also found in various rapidly renewing healthy tissues—such as the intestinal lining, the bone marrow (which produces blood cells), and hair follicles. Consequently, these rapidly renewing healthy tissues are just as sensitive to cytotoxic agents as the tumor itself, and this shared sensitivity is the root cause of the classic adverse effects associated with cytotoxic chemotherapy. The physics describing how these cytotoxic agents act within the body involves the same combination of pharmacokinetics and pharmacodynamics governing any drug—applied here to agents that damage genetic material, block mitosis, or inhibit nucleotide synthesis. Within this framework, treatment efficacy is modeled as a reduction in the net tumor growth rate; this reduction is greater the higher the drug concentration reaching the tumor and the longer that concentration remains above the level required to produce an effect. Overall, the reduction in the net tumor growth rate increases in proportion to the product of the intratumoral drug concentration and the effective exposure time.

However, this reduction in the net tumor growth rate does not affect all tumor cells equally. By preferentially killing the most sensitive cells, cytotoxic agents exert selective pressure on the surviving tumor population; this selective pressure drives the tumor's clonal evolution toward subpopulations that are increasingly less sensitive to cytotoxic agents—the root cause of resistance to cytotoxic chemotherapy. Thus, the very mechanism that enables cytotoxic agents to destroy actively dividing cells is, over time, what ultimately selects for the cells within the tumor capable of resisting them.

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