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Figure 20.7 Schematic relation between the dose of a drug and (a) the probability of a given measure of antineoplastic effect, and (b) the probability of a given measure of normal-tissue toxicity. Although the therapeutic index might be defined as the ratio of doses to give 50% probabilities of normal tissue damage and antineoplastic effects, when the endpoint toxicity is severe, a more appropriate definition of the therapeutic index should be at a lower probability of toxicity as noted in the box. (Adapted from Tannock, 1992, with permission of the author and publisher.)

Figure 20.7 Schematic relation between the dose of a drug and (a) the probability of a given measure of antineoplastic effect, and (b) the probability of a given measure of normal-tissue toxicity. Although the therapeutic index might be defined as the ratio of doses to give 50% probabilities of normal tissue damage and antineoplastic effects, when the endpoint toxicity is severe, a more appropriate definition of the therapeutic index should be at a lower probability of toxicity as noted in the box. (Adapted from Tannock, 1992, with permission of the author and publisher.)

neoplasms the limit of clinical and/or radiological detection is of the order of 1 g of tissue or about 109 cells. If these 109 cells are scattered throughout the organism rather than in a single locus, obviously there will be no clinical detection of the neoplastic disease. The question of how many neoplastic cells could remain in the host before a cure was effected was answered several decades ago in experiments using rodents.

The L-1210 Leukemia Model and Chemotherapy

In 1965, Howard Skipper reported investigations on the therapy of experimental leukemia in mice. Skipper demonstrated that in this system it was necessary to kill every leukemic cell in the host (regardless of the total number, their anatomical distribution, or metabolic heterogeneity) in order to effect a cure, since one single, viable L-1210 cell could grow, proliferate, and kill the mouse. Obviously, the major problem in this investigation was associated with the killing of a relatively small but persistent fraction of leukemic cells that survived the maximum tolerated therapy because of the relative efficacy of the drug, drug resistance, or anatomical compartmentalization.

A hypothetical illustration of the possible importance of drug level and schedule in attempts to achieve a total cure in experimental leukemia in animals is seen in Figure 20.8. As indicated in the figure, if one initially administers 105 leukemic cells to a mouse, one finds that the cells, after a 2-day lag, proliferate logarithmically until the mouse is killed when 109 cells are present in the body. Therefore, the time of survival is inversely related to the number of leukemic cells in the mouse at any one time. Line A in the figure represents the number of leukemic cells in untreated animals as a function of days after inoculation of the cells. Line B, representing the daily drug treatment, termed low-level, long-term (until death), is plotted to show a daily 50% "drug kill" of the leukemic cell population in the animal together with a daily quadrupling of the surviving leukemic cells. The percentage of cells killed by a given dose of a given active drug is constant or, in other words, a constant fraction of cells is killed with each dose. This phenome

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