Chemotherapy: 101.

Chemotherapy is the use of chemicals to destroy cancer cells and works by interfering with the cancer cell's ability to grow. Radiation therapy and surgery are also employed; both of which may be used in conjunction with chemotherapy. What makes chemotherapy very effective, is that it has the ability to treat widespread (metastatic) cancer, that is in more than one location in your body. There are many different types of drugs that qualify as chemotherapy agents, and the drug that is chosen depends on the type of cancer. Antineoplastic drugs are classified into five major categories based on the way the drugs affect cell chemistry, and which stage of the cells life cycle the drugs effect.

Cell Cycles.

Each cell goes through a four phase cycle in order to replicate itself. The first phase called G1 and it is when the cell prepares to replicate its chromosomes. The second stage is called S, and in this phase DNA synthesis occurs and the DNA is duplicated. The next phase is the G2 phase, when the RNA and protein duplicate. The final stage is the M stage, which is the stage of actual cell division. In this final stage, the duplicated DNA and RNA split and move to separate ends of the cell, and the cell actually divides into two identical, functional cells.

Depending on the drug chosen, chemotherapy will affect malignant cells in one of three ways:

  • Damage the DNA of the cancer cells so they can no longer reproduce. This is done by altering the DNA structure in the nucleus of the cell preventing replication.
  • During the S phase of cell life, inhibit the synthesis of new DNA strands so that no cell replication is possible. This occurs when the drugs block the formation of nucleotides that are necessary for new DNA to be created.
  • Stop the mitotic processes of the cell so that the cancer cell cannot divide into two cells. The formation of mitotic spindles is necessary to move the original DNA and the replicated DNA to opposite sides of the cell so the cell can divide into two cells.

Current chemotherapy drugs will act in one of these ways to achieve the ultimate goal of killing the cancer cells in the body.

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The drugs used in chemotherapy are divided into five broad categories. They are placed in these categories depending on their role in the destruction of cancer cells. More specifically, the drugs are classified into a specific category depending on what part of the cell cycle the drug interrupts. These categories are Alkylating Agents, Nitrosoureas, Antimetabolites, Antitumor Antibiotics, Plant Alkaloids, and Steroid Hormones.

ALKYLATING AGENTS are drugs that work by directly attacking the DNA of a cell. These drugs can work at any time of the cell cycle, but are most effective during DNA synthesis. They are used to treat Hodgkin's disease, lymphomas, chronic leukemias, and certain carcinomas of the lung, breast, prostrate, and ovary. Alkylating agents are administered either orally or intravenously. Examples of drugs in this category are Cyclophosphamide and Mechlorethamine, Cisplatin (Platinol).

Because these drugs damage DNA, they can cause long term-damage to the bone marrow. In rare cases, this can lead to acute leukemia. The risk of leukemia from alkylating agents is “dose-dependent,” meaning that the risk is small with lower doses, but goes up as the total amount of the drug used gets higher. The risk of leukemia after getting alkylating agents is highest about 5 to 10 years after treatment.

Alkylating agents are divided into different classes, including:

Nitrogen mustards: such as mechlorethamine (nitrogen mustard), chlorambucil, cyclosphosphamide, ifosfamied and melphalan

Nitrosoureas: are similar to alkylating agents, and work by inhibiting the changes necessary for DNA repair. A very important feature of this class of drugs is that they can cross the blood-brain barrier which makes them very useful for treating brain tumors. They can also be used to treat lymphomas and melanomas. Nitrosoureas are administered either orally or intravenously. Examples of drugs in this category are Carmustine and Lomustine.

Alkyl sulfonates: busulfan

Triazines: dacarbazine and temozolomide

Ethylenimines: thiotepa and altretamine

The platinum drugs (such as cistaplin, carboplatin and oxalaplatin) are sometimes grouped with alkylating agents because they kill cells in a similar way. These drugs are less likely than the alkylating agents to cause leukemia later.

ANTIMETABOLITES block cell growth by interfering with DNA synthesis. These drugs work by mimicking a substance involved in DNA synthesis, inhibiting production of an acid necessary for DNA to be synthesized. These drugs affect the "S" phase of the cell cycle. They are administered either orally or intravenously. Examples of these drugs are 6-mercaptopurine, capecitabine, floxuridine, methotrexate 5-fluorouracil and gemcitabine.

ANTITUMOR ANTIBIOTICS.These drugs are not like the antibiotics used to treat infections. They work by binding with DNA (altering DNA inside cancer cells to keep them from growing and multiplying) to prevent RNA synthesis. These also prevent cell growth by preventing DNA replication. Antitumor antibiotics prevent the DNA from reattaching itself together which causes the cell to die. Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. These drugs work in all phases of the cell cycle. They are widely used for a variety of cancers. Antitumor antibiotic drugs are administered intravenously. Some examples of this category are Doxorubicin and Epirubicin.

Anti-tumor antibiotics that are not anthracyclines include:

Actinomycin-D, Bleomycin, Mitomycin-C and Mitoxantrone (also acts as a topoisonmerase II inhibitor)

A major concern when giving these drugs is that they can permanently damage the heart if given in high doses. For this reason, lifetime dose limits are often placed on these drugs.

PLANT(VINCA) ALKALOIDS. Mitotic inhibitors are often plant alkaloids and other compounds derived from natural products. They work by stopping mitosis in the M phase of the cell cycle but can damage cells in all phases by keeping enzymes from making proteins needed for cell reproduction. During metaphase, mitotic spindles hold the two sets of DNA the cell needs to divide. The spindles are formed using a protein called tubulin. Plant alkaloids bind to tubulin, which prevents the formation of mitotic spindles. Without mitotic spindles, the cell cannot divide. Plant alkaloids are administered intravenously. Some examples of this category are Paclitaxel, Docetaxel, Vincristine and Vinblastine.

STEROID HORMONES. These drugs modify the growth of hormone dependant cancers. Corticosteroids, often simply called steroids, are natural hormones and hormone-like drugs that are useful in the treatment of many types of cancer, as well as other illnesses.They induce a change in the three dimensional shape of the receptor on a cell preventing the cell's binding to the needed estrogen response element on the DNA. These drugs are most commonly used in treating breast cancer. The hormones are administered orally. Examples of corticosteroids include: Prednisone, Methylprednisone and Dexamethasone.

NOTE: Some chemotherapy drugs act in slightly different ways and do not fit well into any of the other categories. Examples include drugs lke L-asparaginase, which is an enzyme, and the proteasome inhibitor bortezomib.