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oncology Oncology is a branch of medicine that deals with the study, treatment, diagnosis and prevention of cancer. A medical professional who practices oncology is an ''oncologist''. The name's etymological origin is the Greek word ὄγκος (''ó ...
, the fact that one round of
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
does not kill all the
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
s in a
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
is a poorly understood phenomenon called fractional kill, or fractional cell kill. The fractional kill hypothesis states that a defined chemotherapy concentration, applied for a defined time period, will kill a constant fraction of the cells in a population, independent of the absolute number of cells.Chabner, B. and D. L. Longo (2006). Cancer Chemotherapy and Biotherapy: Principles and Practice. Philadelphia, Lippincott Willians & Wilkins. In solid tumors, poor access of the tumor to the drug can limit the fraction of tumor cells killed, but the validity of the fractional kill hypothesis has also been established in animal models of leukemia, as well as in human leukemia and lymphoma, where drug access is less of an issue. Because only a fraction of the cells die with each treatment, repeated doses must be administered to continue to reduce the size of the tumor. Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity to the patient. The goal is to reduce the tumor population to zero with successive fractional kills. For example, assuming a 99% kill per cycle of chemotherapy, a tumor of 1011 cells would be reduced to less than one cell with six treatment cycles: 1011 * 0.016 < 1. However, the tumor can also re-grow during the intervals between treatments, limiting the net reduction of each fractional kill.Skeel, R. T. (2003). Handbook of Cancer Chemotherapy, Lippincott Williams & Wilkins.


Cited cause of fractional killing: cell cycle effects

The fractional killing of tumors in response to treatment is assumed to be due to the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
specificity of chemotherapy drugs.
Cytarabine Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by i ...
, a DNA-synthesis inhibitor also known as ara-C, is cited as the classic cell cycle phase-specific agent. Chemotherapy dosing schedules have been optimized based on the fact that cytarabine is only expected to be effective in the DNA synthesis (S) phase of the cell cycle. Consistent with this, leukemia patients respond better to cytarabine treatments given every 12 hours rather than every 24 hours. This finding that can be explained by the fact that S-phase in these leukemia cells lasts 18–20 hours, allowing some cells to escape the cytotoxic effect of the drug if it is given every 24 hours. However, alternative explanations are possible, as described below.


Lack of cell cycle effect in drugs documented to be cell cycle phase specific

Very little direct information is available on whether cells undergo
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
from a certain point in the cell cycle.Cotter, T. G., J. M. Glynn, et al. (1992). "The induction of apoptosis by chemotherapeutic agents occurs in all phases of the cell cycle." Anticancer Res 12(3): 773-9. One study which did address this topic used
flow cytometry Flow cytometry (FC) is a technique used to detect and measure physical and chemical characteristics of a population of cells or particles. In this process, a sample containing cells or particles is suspended in a fluid and injected into the flow ...
or elutriation of synchronized cells treated with actinomycin D1,
camptothecin Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of '' Camptotheca acuminata'' (Campt ...
, or
aphidicolin Aphidicolin is a tetracyclic diterpene antibiotic isolated from the fungus '' Cephalosporum aphidicola'' with antiviral and antimitotic properties. Aphidicolin is a reversible inhibitor of eukaryotic nuclear DNA replication. It blocks the cell c ...
, each of which had been documented to exert its effects in a particular phase of the cell cycle. Surprisingly, the authors found that each of the agents was able to induce apoptosis in all phases of the cell cycle, suggesting that the mechanism through which the drugs induce apoptosis may be independent of the drugs’ biochemical targets. In fact, a trace through the literature on the S-phase specificity of cytarabine leads to studies that simply assume S-phase specificity based on cytarabine's reported site of biochemical action, which the later papers reference. The lack of a cell cycle effect for camptothecin has also been reported recently in a live-cell microscopy study.Cohen, A. A., N. Geva-Zatorsky, et al. (2008). "Dynamic proteomics of individual cancer cells in response to a drug." Science 322(5907): 1511-6.


Cell-to-cell variation in protein levels

A recent paper by Spencer et al.Spencer, S. L., S. Gaudet, et al. (2009). "Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis." Nature. http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08012.html. raises the possibility that cell-to-cell variability in protein concentrations may contribute to fractional killing in the case of treatment with
TRAIL A trail, also known as a path or track, is an unpaved lane or small road usually passing through a natural area. In the United Kingdom and the Republic of Ireland, a path or footpath is the preferred term for a pedestrian or hiking trail. ...
(TNF-related apoptosis inducing ligand). TRAIL is a ligand native to the human body that is currently being developed as a cancer treatment. Spencer et al. observed fractional killing at a single cell level in several cell lines, even in genetically identical populations grown in homogeneous environments. This paper ruled out the conventional explanation (cell cycle effects) in two of these cell lines, and provided evidence supporting the hypothesis that random variation in cellular initial conditions causes some cells to die while allowing others to survive.


References

{{Reflist Oncology Cell biology