Log cell kill

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The English term log cell kill , often also called fractional cell kill or fractional kill , describes a hypothesis in oncology . There is currently no adequate German-language name for the hypothesis that says that the same proportion, but not the same absolute number, of cancer cells are killed in each cycle of chemotherapy or radiation therapy .

Explanation

The exponential increase in cancer cells in leukemia.

The log cell kill hypothesis was set up in experiments with leukemic mice in 1964 by Howard E. Skipper and colleagues. In leukemia, the cancer cells multiply exponentially, i.e. the time it takes for the cancer cells to double is constant. In the semi-logarithmic tumor cell number / time diagram, this corresponds to a straight line (see diagram 1). When these mice were treated with chemotherapy drugs , it was found that at the same dose the number of cancer cells decreased logarithmically ( log ). If 99% of the cancer cells are killed with the first administration of the chemotherapeutic agent, the number of cancer cells decreases, for example, from 10 9 to 10 7 , which corresponds to two orders of magnitude (log steps). The second dose again kills 99% of the cancer cells. The number of cancer cells decreases from 10 7 to 10 5 . However, compared to the first cycle, considerably fewer cancer cells were killed in absolute terms; one billion in the first cycle versus 10 million in the second. In this idealized model, the percentage of cancer cells killed remains constant (99%), but the absolute number of cancer cells killed is decreasing.

Representation of the log-cell kill hypothesis (idealized course in the case of a solid tumor).
The blue curve shows the course after surgical tumor removal with adjuvant chemotherapy. The red curve shows the course for an inoperable tumor and chemotherapy.
About 30 cell division cycles are required from the first degenerate cell to the detectable tumor (= 10 9 cancer cells with a mass of 1 g). From this point to the normally fatal tumor mass of around 1 kg (= 10 12 cancer cells) only 10 more cycles of division are required.

This fact is the reason why the dose of chemotherapy should not be reduced in the course of the treatment cycles, even if no tumor can be diagnosed. The diagnostic limit is around 10 9 cells, which corresponds to a tumor mass of around 1 gram. In diagram 2, this limit is indicated by the lower horizontal dashed line. A dose that is too low would also select the most resistant tumor cells, which would then continue to multiply and respond significantly more poorly to a subsequent therapy cycle. The treatment protocols currently mainly used therefore provide for chemotherapy to be used as early as possible, with the highest possible doses and short regeneration phases between treatment cycles. The log cell kill hypothesis is the theoretical basis for ensuring that a patient will continue to be treated intensively even after a complete remission .

The more realistic course of chemotherapy.

In clinical reality, however, the idealized model does not exist for most human tumors. The log cell kill hypothesis can in part also be transferred to fast-growing solid tumors - even if these do not show exponential growth - but the cell killing kinetics in most cases proceed as shown in Diagram 3.
The tumor growth proceeds according to the so-called Gompertz kinetics (named after Benjamin Gompertz ). This means that tumor growth slows down as it grows in size. In the semi-logarithmic diagram this is shown by the flattening curve. Many cells leave the cell cycle with increasing tumor growth and go into the so-called G 0 phase (resting phase). Tumor growth depends on the surrounding vascular system, which supplies it with oxygen and nutrients. In many cases, the formation of new vessels cannot keep up with tumor growth. Therefore, many cells go into the resting phase or die (tumor necrosis). At this stage, sensitivity to chemotherapy drugs is significantly reduced. For this reason, only a small part of the tumor cells is killed at the start of chemotherapy (see diagram 3). As a result of the first therapy cycle, the tumor mass decreases and many of the dormant cancer cells take part in the cell cycle again. These cells can then be killed in the second cycle. Chemotherapy is therefore more effective with the second cycle than with the first therapy cycle, since a higher percentage (but not a higher absolute number) of cancer cells is destroyed. With further therapy cycles, the number of resistant cancer cells increases, which in turn reduces the percentage of cancer cells killed.

literature

Individual evidence

  1. ^ A b H. E. Skipper: Perspectives in Cancer Chemotherapy: Therapeutic Design. In: Cancer Res 24, 1964, pp. 1295-1302. PMID 14221786
  2. ↑ a b c J. R. Siewert and V. Schumpelick: Practice of visceral surgery. Verlag Springer, 2005, ISBN 3-540-21914-5
  3. ↑ M. Friedkin and A. Goldin: The use of dihydrofolate reductase in studies of mixed populations of sensitive and resistant leukemic cells. In: Cancer Res 22, 1962, pp. 607-616. PMID 13895220
  4. ^ Chemotherapy ( Memento from June 5, 2008 in the Internet Archive ) - University of Jena
  5. ^ OA Adam: Antineoplastic chemotherapy.  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. (PDF; 1.6 MB) LMU Munich@1@ 2Template: Toter Link / wsi1.med.lmu.de  
  6. ↑ a b H. D. Bruhn (editor) among others: Oncological therapy. Verlag Schattauer, 2003, ISBN 3-794-52165-X , pp. 89-92. limited preview in Google Book search