Chemotherapy - Drug Classification I

Drugs used for chemotherapy can be classified in several ways. From my perspective, the two most useful ways are: (1) Chemical basis; and (2) Mechanism of Action. In the post, I’ll discuss the former in this post; subsequently, the latter.

There are seven major classes of chemotherapy drugs, two of which are most active during the M phase of the cell cycle. For each, I will summarize the chemical source and main side effects. For additional information on this topic, select the link for each class. A more detailed version from which this post is abstracted can be found here.

1. Alkylating Agents

The oldest class of anticancer drugs is nitrogen mustards originally developed for military uses (poison gas). They bind to the negatively charged oxygen, nitrogen, phosphorus and sulfur atoms in DNA. By doing so, cellular activity is stopped and the cell will die. Alkylating agents are effective at all stages of the cell cycle and are used for most types of cancer. All alkylating agents can cause secondary cancers, the most common of which is Acute Myeloid Leukemia, even long after treatment is completed.

2. Antimetabolites

Based on work with folic acid by Dr. Sydney Farber in 1948, antimetabolites are synthesized to target naturally occurring compounds or key enzyme reactions during metabolism. Nearly all antimetabolites interrupt metabolic pathways, including those necessary for DNA formation. Antimetabolites are most effective during the S phase when DNA formation is most active. Patients with certain natural enzyme deficiencies may suffer severe toxicities when treated with antimetabolites which target enzyme reactions.

3. Anthracyclines

Anthracyclines are derived from naturally occurring sources (fungi). They work through the formation of free oxygen radicals, which cause DNA strand breaks and enzyme (topoisomerase) action, both of which inhibit DNA formation, replication, and transcription. They are not cell cycle specific agents. Since the free radicals created also attack the heart muscle, cardiac toxicity is a major concern.

4. Antibiotics

Everybody has probably used an antibiotic, such as streptomycin or neomycin. Guess what, bleomycin is a small peptide synthesized from Streptomyces verticullus fungus and is used in chemotherapy. It action is similar to that of the Anthracyclines – free oxygen radical formation. It is an active agent used in testicular cancer and Hodgkin’s lymphoma. Lung toxicity due to free radicals is of greatest concern.

5. Camptothecins

The enzyme Topoisomerase is required for ongoing DNA formation (cf Anthracyclines). Camptothecins act by forming a complex with topoisomerase and DNA which disrupts mitosis in the M phase of the cell cycle. They are synthesized from a naturally occurring alkoloid found in plants such as the Chinese Happy Tree, Camptotheca acuminata. Other chemotherapeutics, although not classed as Camptothecins, are derived from the mandrake plant and Vinca rosea (periwinkle) and function similarly. The main toxic side effect is neurotoxicity (nerve damage, loss of feeling).

6. Taxanes

Taxanes such as paclitaxel and docetaxel were first derived from the bark if the Pacific yew tree, Taxus brevifolia . Paclitaxel was identified as the active component in 1971. Taxanes are M phase specific agents. They bind to the microtubules, which support DNA movement during cell division (mitosis), where disrupt the microtubule function. The most common side effect is anemia.

7. Platinums

Metal derivatives used in the treatment of cancer create cross-links between two DNA strands or within one strand which inhibit DNA synthesis, transcription, and function in any cell cycle phase. Cisplatin, used in lung and testicular cancer, is a first generation platinum derivative significant kidney toxicity. Carboplatin, a second generation derivative, has less effect on the kidneys. Oxaliplatic, a third generation derivative, has not kidney toxicity, but may result in nerve damage (neuropathies).

The long a short of it is that all these chemotherapeutics function by inhibiting normal DNA function leading to suspension of cellular activity (senescence) or cell death - apoptosis or necrosis. The former is “normal” cell death by which cells commit “suicide” when they are no longer useful and are absorbed into surrounding tissue or shed, Cancer cells do not do this and will continue to multiply unless apoptosis can be induced by use of chemotherapeutics or other treatments. The latter, necrosis, is cell death from injury, disease or other pathologic state, including some chemotherapies. Necrotic cells do not send the same signals to the immune system as do apoptotic cells, so they are not removed from the body by a natural process, which leads to a build up of dead tissue and cell debris – not a happy prospect.