General concepts / Cell kill hypothesis CELL KILL HYPOTHESIS
The CELL KILL HYPOTHESIS proposes that actions of CCS drugs follow first order kinetics: a given dose kills a constant PROPORTION of a tumor cell population (rather than a constant NUMBER of cells). |
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- most applicable to use of CCS drugs to treat acute leukemias and aggressive high-grade lymphomas
- for most other (esp. solid) tumours, the growth rate is not constant, due to blood supply limitations etc.
- i.e., growth rate slows (and may actually decrease) as a tumour increases in size, which can be modeled using Gompertzian kinetics
- growth rates also vary significantly among tumour types
- for most other (esp. solid) tumours, the growth rate is not constant, due to blood supply limitations etc.
- tumour cell burden and the population kinetics of the cancer cells are important determinants of the success of antineoplastic chemotherapy, and directly determine the dosing schedule
- magnitude of a tumour cell kill is a logarithmic function
i.e., a 3-log-kill dose of an effective drug will reduce the cancer cell load from 1012 cells to 109, or from 106 to 103
The example shows the effects of tumour burden, scheduling, dosing, and initiation/duration of treatment on patient survival. |
Modified from Katzung Basic and Clinical Pharmacology
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The tumour burden in an untreated patient would progress along the path described by the RED LINE - the tumour is detected (using conventional techniques) when the tumour burden reaches 109 cells; the patient is symptomatic at 1010-1011 cells, and dies at 1012 cells. |
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3 treatment options are shown:
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- there are several critical points:
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early start to the treatment is (obviously!) helpful
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treatment must continue past the time when cancer cells can't be detected using conventional techniques
- appropriate scheduling of treatment courses and care to ensure that a sufficient log-kill is obtained are also crucial factors that enable success