The Cell Cycle

Using cytotoxic agents to treat cancer is based on understanding several important concepts, including the cell life cycle, cell cycle time, growth fraction, and tumor burden. All the tissues in our bodies are comprised of cells that grow and reproduce, to replace cells that are lost during injury or normal wear and tear. The cell cycle is a five-step process, that both normal cells and abnormal cancer cells go through, in order to grow and reproduce to form new cells.

Phase 1 - Resting Phase (G-O) – In this phase, cells are not dividing and are temporarily out of the cell cycle. Depending on the type of cell, this phase can last for a few hours to several years. When the cell is signaled to reproduce, it moves into the G1 phase.

Phase 2 - Post-mitotic phase or interphase (G-1) – In this phase, the cell starts making more proteins in preparation for cell division. Enzymes needed for deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis are produced. DNA is an essential nucleic acid comprised of deoxyribose, a phosphate, and 4 nitrogenous bases – adenine, guanine, cytosine, and thymine. Chemical reactions occur between the bases, leading to the formation of the double-stranded DNA helix, which serves as the genetic template for cell division. The duration of the G-1 phase can last from hours to days.

Phase 3 - Synthesis (S) – In this phase, the proteins containing the genetic code (DNA) are copied so that both of the new cells formed will have the right amount of DNA. The S phase lasts approximately 10 to 20 hours.

Phase 4 - Premitotic phase (G-2) - This phase occurs just before the cell starts splitting into two cells. Additional protein and RNA synthesis occurs. The G-2 phase lasts from 2 to 10 hours.

Phase 5 - Mitosis (M) – Cellular division occurs in this phase. When mitosis occurs, the cell then divides, creating two identical cells. The M phase lasts from one-half hour to one hour. (At this DNA Animations website, there are excellent graphics to be explored. Click here for a movie showing mitosis (it takes a long time to load, but it's worth it) and/or click here for a smaller mitosis animation. )

Check out 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?
G-O
 G-1
 S
 G-2
 M

Understanding the concept of the cell cycle is important, because many chemotherapy drugs work only on actively reproducing cells. Knowing how specific drugs kill cancer cells helps oncologists predict which drugs are likely to work well together. Cell-cycle specific drugs exert their major killing effect on cells that are actively dividing at specific phases during the cell cycle. Cell destruction occurs when cancer cells attempt to divide. Cell-cycle specific agents are not active against cells in the resting state (G-O). Cell-cycle specific agents are most effective when given in divided doses or by continuous infusion. Continuous infusion of cell cycle-specific agents results in exposure of a greater number of cells to cytotoxic drugs and in a higher rate of cell destruction in tumors that are dividing rapidly. Cell-cycle nonspecific drugs act against cancer cells at any phase of the cell cycle, including the G-O or resting phase. Cell-cycle nonspecific drugs are most effective when given in bolus doses.
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% 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.

The body has a sophisticated system for maintaining normal cell repair and growth. It is thought that the body responds to a feedback system that signals a cell to enter the G-1 phase of the cell life cycle in response to cell death. In persons who have cancer, this feedback system doesn’t work normally and cancer cells enter the cell cycle independently of the body’s feedback system. Cancer is a disease in which cells don’t respond to the normal mechanisms that control normal cell birth 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
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 G-O or resting phase is the major factor in the cell cycle time. The growth fraction of tumor refers to the percentage of cells actively dividing at a given point in time. A higher growth fraction causes more cancer cells to be killed when they are exposed to cell-cycle specific drugs. Tumors with a greater fraction of cells in G-O are more sensitive to cell-cycle nonspecific agents. 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.
INSTANT FEEDBACK:
Cancers with a small tumor burden are more sensitive to cytotoxic drugs than tumors with a large number of cells.
True
 False