Asbestos Cancer Update 2010

Another chemotherapy isolated form the fungus Streptomyces verticullus is Bleomycin. Its mechanism of action is similar to that of the anthracyclines, in that free oxygen radicals are formed that result in DNA breaks leading to cancer cell death. This drug is rarely used by itself rather in conjunction with other chemotherapies. Bleomycin is an active agent in regimens for testicular cancer and Hodgkin’s lymphoma. The most concerning side effect of this drug is lung toxicities due to oxygen free radical formation.

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Many of the currently effective anti-cancer drugs are developed from natural sources. The drug daunorubicin was isolated from Streptomyces, a soil-dwelling fungus. Doxorubicin, another anthracycline drug, was isolated from a mutated strain of the same fungus. Both of these drugs have a similar mechanism of action, but the latter is more effective in the treatment of solid tumors. This class of chemotherapeutics works by the formation of free oxygen radicals. These radicals result in DNA strand breaks and subsequent inhibition of DNA synthesis and function. Anthracyclines also inhibit the enzyme topoisomerase by forming a complex with the enzyme and DNA. Topoisomerases are a class of enzymes that serve to unwind the DNA double strand helix to allow for DNA repair, replication and transcription. This class of chemotherapeutics is also not cell cycle specific. The most important side effect of this group of drugs is cardiac toxicity. The same free radicals that serve to damage the DNA of the cancer cell may damage the cells of the heart muscle. Oncologists monitor heart function very carefully when patients are on these medications. Other commonly used anthracyclines include Idarubicin, Epirubicin, and Mitoxantrone.

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In 1948, Dr. Sidney Farber showed that a folic acid analog could induce remission in childhood leukemia. Approximately 10 out of the 16 patients treated demonstrated evidence of hematologic improvement. This experience provided the foundation for scientists to synthesize a number of other agents that either target naturally occurring compounds or inhibit key enzymatic reactions in their biochemical pathways. In general, all antimetabolites interfere with normal metabolic pathways, including those necessary for making new DNA. The most widely used antifolate in cancer therapy, with activity against leukemia, lymphoma, breast cancer, head and neck cancer, sarcomas, colon cancer, bladder cancer and choriocarcinomas, is Methotraxate. Methotraxate inhibits a crucial enzyme required for DNA synthesis and therefore exerts its effect on the S phase of the cell cycle.

5-Fluorouracil (5-FU), another widely used antimetabolite, prevents DNA synthesis by interfering with the nucleotide ( DNA components) production. It, too, has a wide range of activity including colon cancer, breast cancer, head and neck cancer, pancreatic cancer, gastric cancer, anal cancer, esophageal cancer and hepatomas (primary liver tumor). A unique and interesting aspect of this drug is its toxicity profile. 5-Fluorouracil is metabolized by a naturally occurring enzyme in the body called dihydropyrimidine dehydrogenase, or DPD. There is a small population of people who are deficient of this particular enzyme. Lacking DPD does not interfere with normal body function and thus people are not aware that they are lacking it. However, when these patients are given this chemotherapy drug, they are unable to metabolize it and therefore get acute and severe toxicities (side effects). The most often seen toxicities include bone marrow suppression, severe GI toxicities, and neurotoxicities which may include seizures and even coma. It is important for the oncologist to recognize this early and give the patient Thymidine as an antidote. A drug called Capecitabine is an oral type of 5-Fluorouracil compound that has similar side effect potentials.

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Alkylating agents are the oldest class of anticancer drugs. Almost all of these drugs are active or latent nitrogen mustards. Nitrogen mustards are various poisonous compounds originally developed for military use. Alkylating agents all share a common mechanism of action, but differ in their clinical activity. They work by attacking the negatively charged sites on the DNA (oxygen, nitrogen, phosphorous and sulfur atoms). By binding to the DNA, steps (replication, transcription, and base pairing) leading to duplication of the cell’s genetic material are significantly altered. In addition, alkylation of DNA leads to DNA strand breaks and DNA strand cross-linking. By altering DNA in this manner, cellular activity is stopped and the cell dies. Chemotherapy drugs in this class are active in every phase of the cell cycle. As a result, this class of anticancer drugs is very powerful and is used in many types of cancer, including both solid tumors and leukemias.

In general, prolonged use of these drugs will lead decreased sperm production, cessation of menstruation, and possibly cause permanent infertility. This class of chemotherapeutics should never be used in the first trimester of pregnancy as they have been shown to increase fetal malformations. Use in the second or third trimester does not seem to carry the same risk. All alkylating agents can cause secondary cancers although not all agents are equal in their carcinogenic potential. The most common secondary cancer is a type of leukemia (AML, or Acute Myeloid Leukemia) that can occur years after therapy with an alkylating agent.

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Most chemotherapy agents kill cancer cells by affecting DNA synthesis or function, a process that occurs through the cell cycle. Each drug varies in the way this occurs within the cell cycle.

The major categories of chemotherapy agents are alkylating agents, antimetabolites, anthracyclines, plant alkaloids, antitumor antibiotics, taxanes, and platinums. Let’s review the characteristics of these groups.

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