The Cell Cycle


Normal cells and abnormal (cancer) cells must complete the cell cycle in order to replicate. The cell cycle is an ordered sequence of cellular events regulated by chemical signals produced by genes. Some genes (proto-oncogenes) are responsible for stimulating cellular growth and division. Other genes (tumor suppressor genes) restrict cell cycle progression.

In many cases, genetic damage causes cancer cells to lose their ability to produce or respond to the products of tumor suppressor genes. Such cells may embark on an uninhibited cycle of cell replication. Improved understanding of the cell cycle has allowed researchers to develop treatments that can inhibit each specific phase in the cycle and in some cases cause cells to self-destruct (apoptosis).

The CELL CYCLE diagram on the right depicts major landmarks on a cells journey to replication. Traditionally the eukaryotic cell cycle is divided into two alternating states; interphase and Mitosis. Shortly after mitosis, internal and external factors determine one of two outcomes for each daughter cell: rest or proliferation (replication).

Interphase is the part of the cell cycle that produces the intracellular elements necessary for mitosis. During interphase (G1, S, G2), progression from one phase to another is regulated by phase specific expression of pro-proliferative cyclins and their cyclin-dependent kinases (CDK) and anti-proliferative tumor suppressor proteins that inhibit the cell cycle.

Interphase contains several checkpoints that ensure that the cell is competent to complete mitosis. If the cell does not meet the molecular and biologic requirements of a checkpoint, it may not progress beyond the checkpoint. Cells that are blocked at a checkpoint may be triggered to enter apoptosis.

Mitosis (M) – Mitosis is the biological sum of four phases: Prophase, Metaphase, Anaphase and Telophase. When mitosis is complete, genetically equivalent chromosomes exists at opposing poles of the cell. Cytokenisis divides the mother cell into two daughter cells. The M phase usually lasts about one hour.

Many chemotherapy agents are cell cycle specific (CCS) drugs that exert their major cytotoxic effect during a specific phase of proliferation. Typically CCS drugs have less effect on cells in the resting state (GO). CCS drugs are administered in the minimum effective concentration via continuous dosing methods rather bolus to maximize the time exposure of cells within the continuum of the targeted phase.

Cell cycle non-specific (CCNS) drugs like cyclophosphamide or platinum based cisplatin act against cells in all phase of the cell cycle, including the GO or resting phase. CCNS drugs are dose dependent (>dose = >kill rate). They are most effective and least toxic when given in high dose bolus. Large solid tumors with a greater fraction of cells in resting cells may be treated more effectively by CCNS agents.


Leave RnCeus.com to check out this YouTube video The Cell Cycle for in depth explanations, and a graphic showing the relationship of the phases to one another.


INSTANT FEEDBACK:
During which phase is DNA replicated?
GO
G1
S
G2
M


Cell kill theory proposes that a set percentage of cells are killed with each dose of chemotherapy. The percentage of cells killed depends on the specific drugs used. For example, if a tumor has 1,000,000 cells and is exposed to a drug that has a 80% tumor cell kill rate, the first chemotherapy dose will kill 80% or 800,000 of the cancer cells. The second dose will kill another 80% of the cells remaining. Because only a percentage of cells die with each exposure to a cytotoxic agent, additional doses of chemotherapy must be repeated to reduce the cancer cells to just a few remaining cells. When only a few cancer cells remain, it is hoped that the body’s immune response will then kill the final cells.

Cell cycle time refers to the amount of time required for a cell to move from one mitosis or cell division to another mitosis. The length of the total cell cycle varies with the specific type of cell. How long a cell is in the GO or resting phase is the major factor in the cell cycle time.

The growth fraction of tumor refers to the percentage of cells engaged in proliferation versus G0 phases at any given point in time.

Tumor burden refers to the number of cancer cells present in the tumor. Cancers with a small tumor burden are usually more sensitive to cytotoxic therapy because they have a high number of cells reproducing. As the tumor burden increases, the growth rate slows, and the numbers of cells actively dividing slows down.


The body has a sophisticated system for maintaining normal tissue repair and growth. It is thought that the body responds to a feedback system that signals a G0 (stem cell) to enter the G-1 phase of the cell cycle in response to tissue damage. In cancer, this feedback system doesn’t work normally and cancer cells enter the cell cycle independent of the body’s feedback system. Cancer is a disease in which cells don’t respond to the normal mechanisms that control normal cell replication and death. Four characteristics of cancer cells that are not found in normal cells include:


INSTANT FEEDBACK:

The cell kill theory proposes that a set percentage of cells are killed with each dose of chemotherapy.

True
False


INSTANT FEEDBACK:
Cancers with a small tumor burden are more sensitive to cytotoxic drugs than tumors with a large number of cells.
True
False


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