Just a little article I wrote in my Spare time.

How do chemotherapy drugs work?

The object of all chemotherapy drugs is to kill the cancerous cells and not harm the adjacent healthy cells. To that end, scientists tried to identify characteristics that are unique to cancer cells and are not found on normal tissue. A distinct cancer trait could serve as a potential target for a chemotherapy drugs and thereby fulfill the above goal. One feature that is truly unique for most cancer cells is that they grow at a rate faster than normal cells. Therefore targeting some aspect of the cell growth cycle seems reasonable. Fast growing cells would be affected the most and slow growing cells would be least disturbed. In fact, that is the basis for many chemotherapeutics. This seems obvious when considering the side effect profiles of most chemotherapy drugs. Hair follicles, skin, and the cells that line the gastrointestinal tract are some of the fastest growing cells in the human body, and therefore are most sensitive to the effects of chemotherapy. It is for this reason that patients may experience hair loss, diarrhea, and rashes.

The human body processes and excretes all drugs through either the liver or the kidneys. Therefore, when a patient has kidney or liver damage, giving chemotherapy becomes precarious. Administering the recommended amount of drug may prove to be too toxic in a patient unable to metabolize and excrete it. The pharmacokinetics for cancer patients are very complex and chemotherapy pharmacology is a subspecialty on its own. Unfortunately, kidney and liver damage often result due to cancer invasion, limiting the patient's chemotherapy options.
Pharmacokinetics is further complicated in the cancer patient, as they are often taking multiple medications, some of which have overlapping metabolic pathways and side effect profiles. An example of this difficult situation is in the brain cancer patient. Because brain tumors often present as seizures, many of these patients take anti-seizure medications. Anti-seizure medications are metabolized by the liver and affect the metabolism of many chemotherapy drugs. Dose adjustments are an absolute necessity to avoid toxicities or sub-therapeutic dosing.

The cell cycle

The cell cycle is broken up into four phases the G1, S, G2, and M phases. The G1 phase is the phase most active in protein synthesis. The cellular DNA at this phase is tightly coiled and is not actively being transcribed. Few chemotherapy agents are active at this phase of the cell cycle. By contrast, the S phase is the synthetic phase of the cell cycle. DNA replication is most active and many chemotherapeutic agents are most active in this phase. G2 represent a time when mostly RNA, but some protein, is actively produced. Mitosis, actual cell division, occurs during the M phase. There are two major classes of chemotherapy drugs that are most active during this phase of the cell cycle.

The remainder of this article includes a summary of the major classes of chemotherapy drugs.
Alkylating agents

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 attack the negatively charged sites on the DNA -- the oxygen, nitrogen, phosphorous and sulfur atoms. By binding to the DNA, replication, transcription and even base pairing are significantly altered. Alkylation of the DNA also leads to DNA strand breaks and DNA strand cross- linking. By altering DNA in this manner, cellular activity is effectively stopped and the cell will die. Chemotherapy drugs in this class are active in every stage of the cell cycle. As a consequence, this class of anticancer drugs is very powerful and is used in most every type of cancer both solid tumors and leukemia.

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 are 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 leukemia (Acute Myeloid Leukemia) that can occur years after therapy.
Some of the more common alkylating agents include: Cyclophosphamide, Ifosphamide, Melphalan, Chlorambucil, BCNU, CCNU, Decarbazine, Procarbazine, Busulfan, and Thiotepa.

Antimetabolites

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.

Another widely used antimetabolite that thwarts DNA synthesis by interfering with the nucleotide (DNA components) production is 5-Fluorouracil. 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. A unique and interesting aspect of this drug is its toxicity profile. 5-Fluorouracil is metabolized by a naturally occurring enzyme called dihydropyrimidine dehydrogenase, DPD. There is a small population of people who may be deficient of this particular enzyme. Lacking DPD does not interfere with normal body biochemistry and thus the phenotype is silent. However, when these patients are challenged with this chemotherapy drug, they are unable to metabolize it and therefore get acute and sever toxicity. 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 provide the patient with Thymidine as an antidote. A drug called Capecitabine is an oral pro-5-Fluorouracil compound that has similar side effect potentials.
Other antimetabolites that inhibit DNA synthesis and DNA repair include: Cytarabine, Gemcitabine (Gemzar®), 6-mercaptopurine, 6-thioguanine, Fludarabine, and Cladribine.

Anthracyclines

Many of the currently effective anti-cancer drugs are 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 carcinomas. 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.

Antibiotic

Another small peptide 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 to other chemotherapies. Bleomycin is an active agent in the regimen for testicular cancer as well as Hodgkin's lymphoma. The most concerning side effect of this drug is lung toxicities due to oxygen free radical formation.

Camptothecins

The drugs in this class of chemotherapeutics act by forming a complex with Topoisomerase and DNA resulting in the inhibition and function of this enzyme. The presence of Topoisomerase is required for on-going DNA synthesis. These drugs are used in many solid and liquid tumors and the side effect profile of this class of drugs is agent specific. Camptothecins include both irinotecan and topotecan. The parent compound, first identified in the late 1950's, is a naturally occurring alkaloid found in the bark and wood of the Chinese tree Camptotheca accuminata.
Etoposide, a chemotherapeutic that works by the same mechanism, is a natural product isolated from the mandrake plant and is not considered a camptothecin but rather an epipodophyllotoxin.

Vinca Alkaloids The leaves of a periwinkle plant, Vinca rosea, were used to make tea that reportedly improved diabetes. Early research showed that aqueous extract of this plant administered by injection into rats resulted in their death within a week. Further investigation showed that the rats die of sepsis due to bone marrow suppression caused by this extract. Isolation and chemical characterization lead to the currently used drugs: vincristine, vinblastine, and vinorelbine. These chemotherapeutics bind to the tubulin and lead to the disruption of the mitotic spindle apparatus. The disruption of mitosis implies that these drugs are active specifically during the M phase of the cell cycle. They have a wide application to many different malignancies and cause neurotoxicity as the most prominent and dose limiting side effect.

Taxanes
Another class of chemotherapeutics that are specific for the M phase of the cell cycle is the Taxanes. The taxanes include paclitaxel and docetaxel. They bind with high affinity to the microtubules and inhibit their normal function. This class of drugs has a broad range of clinical activity including breast cancer, lung cancer, head and neck cancer, ovarian cancer, bladder cancer, esophageal cancer, gastric cancer and prostate cancer. The most common side effect of these drugs is the lowering of the blood cells. These compounds were first isolated for the bark of the Pacific yew tree Taxus brevifolia in 1963. It was not until 1971 that paclitaxel was identified as the active component.

Platinums

Natural metal derivatives were also shown to have some activity in the fight against cancer. These agents work by cross-linking DNA subunits. (The cross linking can happen either between two strands or within one strand of DNA.) The resultant cross-link acts to inhibit DNA synthesis, transcription and function. The platinum compounds can act in any cell cycle. Cisplatin is used most often in lung cancer and testicular cancer. The most significant toxicity of cisplatin is kidney damage. Second-generation platinum, called carboplatin, has fewer kidney side effects, and at times may be an appropriate substitute for regiments containing cisplatinum. Oxaliplatin is a third-generation platinum that is active in colon cancer and has no renal toxicities, however, its major side effect is neuropathies.

Conclusion

There are other drugs now being used as effective therapies for malignancy. These include hormones for breast, prostate and endometrial cancers, monoclonal antibodies, immunotherapy with IL-2 and TNF alpha, and small molecule inhibitors. The process of drug discovery involves much time, effort and resources. New approaches are constantly being developed and modified. The process of testing a new agent in clinical trials begins with the discovery of new compounds, new ideas, new pathways, and new principles.



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