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| 25 years ago, at about this time of year, while anxious over finishing my Ph.D, I found out that I had cancer and it would take three weeks for the specialists at Dana Farber to see me. While I had time on my hands I learned about cancer. While we are waiting for the time that I will describe the staging and treatment of my cancer, allow me to give a description of cancer and its treatment in a greatly over-simplified form. |
| CANCER IN A NUTSHELL - PART FIVE MECHANISM OF ACTION OF CLASSES OF CANCER CHEMOTHERAPY DRUGS - - |
| This is my last "in a nutshell" post. After this post, I will return to the narrative of the my cancer staging and treatment. I will be discussing in this post the chemical mechanism of how various cancer drugs work. I am only going to discuss the main types of drugs including three of those that were used to treat me. This was the most interesting part to me of what I learned about cancer treatment. I still am amazed that researchers can describe how drugs work on a molecular level. I really need pictures to illustrate the molecules, but I hope you can get the main idea. I will be referring back to material from my previous posts on DNA structure and function and the one on the cell cycle. You may wish to review those documents. |
| I am going to use warfare analogies to describe the way the different drugs work. As I said in an earlier post, cancer chemotherapy is selective poisoning. It is a brutal process, and it usually involves an attack on DNA, so I think combat comparisons are apt. Either the DNA is attacked chemically, a mistake is introduced into the DNA, or the functioning of DNA is inhibited. The classes of drugs and their corresponding analogy are: |
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Class of drug Warfare analogy ------------------ ---------------------- Alkylating Agents Bomb orf machine gun Antimetabolites Spy or industrial espionage Plant alkaloids Communication and control sabotage Anti-cancer antibiotics Cutting off supply lines |
| The first analogy is pretty good, and they get fuzzier as one goes down. There are other drugs but these are the main classes used. I received one in each of these classes except for the antimetabolites. |
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**** Alkylating Agents **** Alkylating agents are extremely reactive molecules that react with just about any molecule with reactive sites. DNA has many such sites where these compounds can add an extra bond to DNA, or react with the DNA to damage it, or react and break the DNA chain. All of these forms of damage will prevent DNA from being read to produce proteins or replicate properly. Alkylating agents are the crudest form of treatment. They do not discriminate in their reactions. They tend to attack cells at all stages of the cell cycle. Using an alkylating agent is a lot like rushing into a bank that is under a hostage situation and tossing in a bomb or strafing the place with a machine gun. In all likelihood the robbers will be killed, but a lot of hostages will also be hurt. DNA has enzymes that roam the structure and can repair minor damage similar to a cowboy riding fences and repairing breaks in the barbed wire. To circumvent these repair mechanism, many alkylating agents are bifunctional so they can cause damage in two nearby spots that are harder to repair. Mustard gas that was in the boat that was bombed in WW II (see the last update) and related a nitrogen mustard that was given to me act in this way. Platinum drugs such as Cisplatin have similar effect as alkylating agents even though they are chemically very different. |
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**** Antimetabolites **** These drugs are more subtle. They are similar in shape to the DNA bases. In the phase of the cell cycle where DNA is being synthesized, an antimetabolite slips in as an imposter and incorporates into DNA. This corrupted DNA will not function properly. Another way these drugs can function is to bind very strongly to the proteins that syntesize the DNA bases an shut down the supply of these vital components. This is like bombing an factory and cutting off the crucial supply of components like bullets, tanks, jeeps, food and bombs. . |
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**** Plant alkaloids **** Plant alkaloids are natural products (for example a drug given to me , vincristine, is isolated from the periwinkle plant) that are only active in the step in the cell cycle called mitosis. This means this class of drugs only affects cells that are actively dividing. Microtubules, the structures that draw chromosomes to opposite sides of the cell, are actually polymers of many identical copies of a small protein called tubulin. The tublin proteins stick to each other and form long cylindrical hollow "wires". The alkaloids bind strongly to the tubulin protein and prevent the formation of the miocrotubules. Without microubules, the chromosomes can not migrate to each side of the cell, and the cell will not divide. |
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**** Anti-cancer antibiotics **** One of the most distinguishing characteristics of DNA is it double helix shape often described as a twisted ladder. The sides of the ladder are sugar and phosphate molecules, and the steps of the ladder are made up of flat paired DNA bases. Unlike a regular ladder, there is no space between the steps. The shape of DNA is very consistent and the molecules that interact with it recognize and are designed to bind to the specific shapes of DNA molecule. Anti-cancer antibiotics are drugs that were first used to treat bacterial infections. These molecules all have in common that they are flat molecules that are shaped like the flat steps of the DNA bases. This flatness allows the antibiotics to insert between to adjacent steps of the DNA. This process is called intercalation. The insertion causes the DNA to unwind (or lengthen the helix) a bit. This causes a small kink in the structure of the DNA which alters the local shape. When the proteins that read DNA to form RNA to make proteins get to this kink, they do not recognize the shape and they can not get past the kink. In a like manner, the molecules that open DNA to start replication are stopped by the kink. Shutting down these two processes prevents formation of the proteins the cell needs and the division of cells necessary for growth of tissue. |
| Those are the ways that the four major classes of anti-cancer drugs attack and shut down DNA. Thank you for your patience during this series of technical posts. |
| Stay tuned for more of the story. |
| (Cancer Chronicles is a series of status updates that account the events of 25 years ago when I went through a bout with cancer. Its purposes are multi-fold: catharsis, education, information, celebration, etc. ) |
| This originally was posted to facebook October 18, 2012. |
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