Log cell-kill

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 10 leukemic cells to 10 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 10 (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 patients actually have tumor burdens that are greater than 10 . 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. 

Drugs that act by different mechanisms may have additive or synergistic therapeutic effects. Tumors may contain heterogeneous clones of cells that differ in their susceptibility to drugs. Combination therapy will thus increase log cell kill and diminish the probability of emergence of resistant clones of tumor cells. 

It has been well-defined that the efficiency of anitneoplastic drugs may be characterized by their inherent log cell-kill index. In other words, the negative log of the fraction of the cancerous tumor cell population which essentially survives a single-course of treatment. 

However, the log cell-kill index represents a very thin (tenuous) number, but it definitely serves a tremendous usefulness in rightly predicting the effects of combinations which essentially fulfil criteria (a) and (/>) above (Section 1.1.5). Thus, the very close predicted effect of a combination is usually accomplished by the simple addition of the various indices obtained from the component drugs. 

Simulated effect of dose-dense therapy vs. conventional scheduling on log-cell kill in Gompertzian growth. The initial lime zero may represent the lime of initial diagnosis at the time of surgery with subsequent treatment. (Adapted from Norton, L., Theoretical Concepts and the emerging role of taxanes in adjuvant therapy. The Oncologist, 6(3), 30,2001. With permission.)... 

The cell-kill hypothesis states that the effects of antitumor drugs on tumor cell populations follow first-order kinetics. This means that the number of cells killed is proportional to the dose. Thus, chemotherapy follows an exponential or log-kill model in which a constant proportion, not a constant number, of cancer cells are killed. Ilieoretically. the fractional reductions possible with cancer chemotherapy can never reduce tumor populations to zero. Complete er ica-tion requires another effect, such as the immune response. A modified form of the first-order log-kill hypothesis holds that tumor regressions produced by chemotherapy are de-.scribed by the relative growth fraction present in the tumor at the lime of treatment This idea is consistent with the finding that very small and very large tumors are less responsive than tumors of intermediate size. ... 

Under certain conditions, the Gompertzian tumor model provides an accurate barometer for tumor growth in vivo. However, deviations occur over time due to selection and expansion sub-clones that are chemo-resistant. Skipper s Cell Kill Hypothesis is based on the notion that chemotherapy will lead first-order cell kill kinetics. Therefore, each administration of chemotherapy will produce tiie same fraction of tumor cell death. In theory, it is believed that a log-cell drop of 9 to 11 orders of magnitude is required for tumor eradication. Clinically this scenario is complicated by the chemosen-sitivity of normal tissue and tumor, pharmacokinetic hetereogeneity of patients, and tumor heterogeneity. 

Methotrexate acts by inhibition of dihydrofolate reductase, the enzyme requisite for the reduction of dihydrofolic acid (3) to 5,6,7,8-tetrahydrofolic acid (4). In turn, (4) is a precursor to a series of enzyme cofactors (5-7) essential for the transfer of one carbon unit necessary for the biosynthesis of purines and pyrimidines and hence, ultimately, DNA. As an inhibitor of dihydrofolate reductase, methotrexate kills cells during the S phase of the cell cycle, when the cells are in the log phase of growth. Unfortunately, this cytotoxicity is non-selective, and rapidly proliferating normal cells, e.g., gastrointestinal epithelium cells and bone marrow, are dramatically affected as well. In addition, recent use of high dose methotrexate therapy with leucovorin rescue has led to additional clinical problems arising from a dose-related nephrotoxic metabolite, 7-hydroxy methotrexate (8). Finally, the very polar nature of methotrexate renders it virtually impenetrable to the blood-brain barrier, which can necessitate direct intrathecal injection in order to achieve therapeutic doses for the treatment of CNS tumours. 

ROS into more vital regions of the bacterial cells (note that S. aureus has no outer cell membrane). In recent research, it was demonstrated by Wilson that the photosensitizer methylene blue is more active on gold particles and kills even MRSA (with 2 log reductions after 10 min irradiation with green light) without degrading a polysiloxane or a polyurethane matrix and with only 10% photobleaching after 6 months [128]. 

The "log-kill" hypothesis states that cytotoxic anticancer agents kill a certain percentage, not a fixed number, of cells. 

Log-kill hypothesis A concept used in cancer chemotherapy to mean that anticancer drugs kill a fixed proportion of a tumor cell population, not a fixed number of tumor cells. For example, a 1-log-kill will decrease a tumor cell population by one order of magnitude, ie, 90% of the cells will be eradicated... 

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