Drugs: How Chemotherapy Works

Most chemotherapy drugs are cytotoxic (kill cells), and their action is some sort of interference with cell division. The cancer cell starts to divide, is affected by the drug, and dies. Most normal cells in our bodies rarely divide, but cancer cells divide often. Thus, drugs that prevent cell division kill more cancer cells than they do normal cells. At least one monoclonal antibody is used in pediatric cancers, and one drug that is a targeted therapy. These drugs are not cytotoxic, instead, they find and kill only cancer cells. One chemotherapy agent is an enzyme that depletes a necessary amino acid and affects cancer cells more than normal cells.

Each cytotoxic chemotherapy drug has a different method for killing cancer cells. They fall into several mechanistic classes: Alkylating agents, heavy metals, antimetabolites, anthracycline antibiotics, epipodophyllotoxins, plant alkaloids, and antitumor antibiotics. These are useful classifications with which to become familiar, since the COG Survivorship Guidelines list the chemotherapy drugs according to these classifications.

Alkylating agents. These drugs alkylate the DNA, causing it to be defective, and interfering with cell division. To alkylate means to put a methyl or other small alkyl group onto the DNA molecule. Cytoxin, ifosfamide, and busulfan are alkylating agents. In general, these are fairly aggressive chemotherapy agents.

Non-Classical Alkylators. Dacarbazine and Temozolomide.

Heavy metals. Two chemotherapy agents contain the heavy metal platinum. These agents cause crosslinking in DNA, making it impossible for the dividing cell to duplicate its DNA, leading eventually to cell death. Carboplatin and cisplatin are the heavy metal chemotherapy drugs. (These drugs are sometimes classified as alkylating agents.)

Antimetabolites. These drugs prevent the cell from getting something that it needs to divide. Sometimes they mimic some sort of molecule that a cell needs to grow, bind to an enzyme that is used in growth processes, and then inhibit that enzyme from working. Or, they mimic a building block of DNA, are incorporated into growing strands, and prevent the DNA from functioning. Methotrexate, Clofarabine, Fludarabine, mercaptopurine, thioguanine, cytarabine, and fluorouricil are antimetabolites.

Anthracycline antibiotics. Anthracyclines were originally isolated from microorganisms and tried as antibiotics, a task at which they excelled, although they were too toxic for use in infections. In the 1960s they were found to be useful against cancer cells. Anthracyclines prevent DNA replication by interfering with an enzyme called topoisomerase II. Daunorubicin, Doxorubicin, and Idarubicin are anthracyclines.

Epipodophyllotoxins. Topoisomerase inhibitors (see anthracycline antibiotics) derived from a toxin found in the American Mayapple. Topotecan, Irinotecan, Etoposide, and Teniposide are epipodophyllotoxins.

Plant alkaloids. Plant alkaloids prevent cell division, or mitosis, by binding to tubulin, a structural protein involved in the formation of microtubular fibers necessary for cell division. Vincristine and vinblastine are plant alkaloids.

Antitumor antibiotics. Antitumor antibiotics bind to DNA duplexes, interfering with replication and transcription of DNA, eventually leading to cell death. Originally tried as antibiotics (but found too cytotoxic for this use), these drugs are some of the older chemotherapy agents. Dactinomycin and bleomycin are antitumor antibiotics.

Monoclonal antibodies. Monoclonal antibodies are created to bind to specific substances, such as specific types of cancer cells. Rituximab is an example of a monoclonal antibody.

Enzyme. Asparaginase is an enzyme that depletes a compound necessary for the growth of certain cancer cells.