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Chapter: Modern Pharmacology with Clinical Applications: The Rational Basis for Cancer Chemotherapy

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The Log Cell Kill Hypothesis

Cytotoxic drugs act by first-order kinetics; that is, at a given dose, they kill a constant fraction of the tumor cells rather than a fixed number of cells.

THE LOG CELL KILL HYPOTHESIS

 

Cytotoxic drugs act by first-order kinetics; that is, at a given dose, they kill a constant fraction of the tumor cells rather than a fixed number of cells. For example, a drug dose that would result in a three-log cell kill (i.e., 99.9% cytotoxicity) would reduce the tumor burden of an animal that has 108 leukemic cells to 105 cells. This killing of a fraction of cells rather than an absolute number per dose is called the log cell kill hypothesis.

 

The earliest detectable human cancers usually have a volume of at least 1 cc and contain 109 (1 billion) cells. This number reflects the result of at least 30 cycles of cell division, or cell doublings, and represents a kineti-cally advanced stage in the tumor’s growth. Most pa-tients actually have tumor burdens that are greater than 109. Since the major limiting factor in chemotherapy is cytotoxicity to normal tissues, only a limited log cell kill can be expected with each individual treatment.

 

Even in the absence of tumor regrowth, several cy-cles of therapy would be required for eradication of the tumor, assuming it was sensitive to the drugs employed. When a tumor has decreased in size to approximately 108 cells, it is generally no longer detectable clinically and is considered a clinically complete remission. Regrowth of residual cells is the obvious cause of re-lapse in patients who have achieved clinically complete remissions.

 

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