Most chemotherapy agents and medications work by interfering with DNA synthesis or function. Based on their chemical action at a cellular level, chemotherapy agents can be classified as cell-cycle specific agents (effective during certain phases of cell cycle) and cell-cycle nonspecific agents (effective during all phases of cell cycle).
Depending on their characteristics and nature of treatment, chemotherapy agents can be categorized as alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinums, or plant alkaloids. Here, we discuss the main features of each of these categories.
Alkylating agents are one of the earliest and most commonly used chemotherapy agents used for cancer treatments. Their use in cancer treatments started in early 1940s with nitrogen mustards similar to those used in World War I chemical warfare. Chlorambucil, Cyclophosphamide, CCNU, Melphalan, Procarbazine, Thiotepa, BCNU, and Busulfan are among the alkylating agents.
Although they might differ in their clinical activity, all alkylating agents share the same biochemical mechanism. These agents work directly on the DNA and prevent the cell division process by cross-linking the DNA strands and causing abnormal base pairing. When a DNA is altered in this manner, undesired cellular activity comes to a halt and the cell cannot multiply.
Alkylating chemotherapy drugs are effective during all phases of cell cycle. Therefore, they are used to treat a large number of cancers. However, they are more effective in treating slow-growing cancers such as solid tumors and leukemia.
Long term use of alkylating agents can lead to permanent infertility by decreasing sperm production in males, and causing menstruation cessation in females. Many alkylating agents can also lead to secondary cancers such as Acute Myeloid Leukemia, years after the therapy.
The structures of antimetabolites are similar to those of vitamins, amino acids, and precursors of DNA or RNA found naturally in human body. Antimetabolites help in treatment cancer by inhibiting cell division thereby hindering the growth of tumors. The agents are incorporated in the DNA or RNA of the cancerous cells and interfere with the cell division process.
The efficacy of antimetabolites for cancer treatment was discovered in 1948, when Dr. Sidney Farber found that folic acid analog can reduce childhood leukemia. Out of 16 patients he tested, 10 displayed hematologic improvement. This discovery laid the foundation that enabled scientist to synthesize many agents that could inhibit enzymatic reactions.
Antimetabolites were found to be useful in treating chronic and acute cases of leukemia and various tumors. They are commonly used to treat gastrointestinal tract, breast, and ovary tumors.
Methotraxate, which is one of the most commonly used chemotherapy agents, works on the S-phase of the cell cycle. It inhibits an enzyme that is essential for DNA synthesis.
6-mercaptopurine and 5-fluorouracil (5FU) are two other commonly used antimetabolites. 5-Fluorouracil (5-FU) works by interfering with the DNA components, nucleotide, to stop DNA synthesis. This drug is used to treat many different types of cancers including breast, esophageal, head, neck, and gastric cancers. 6-mercaptopurine is an analogue of hypoxanthine and is commonly used to treat Acute Lymphoblastic Leukemia (ALL).
Other popular antimetabolite chemotherapy drugs are Thioguanine, Cytarabine, Cladribine. Alimta, Gemcitabine, and Fludarabine.
Anthracyclines were developed between 1970s and 1990s. These daunosamine and tetra-hydronaphthacenedione-based compounds are cell-cycle nonspecific and are used to treat a large number of cancers including lymphomas, leukemia, and uterine, ovarian, lung and breast cancers.
Anthracyclines drugs are developed from natural resources. Daunorubicin was discovered by isolating it from soil-dwelling fungus Streptomyces. Doxorubicin, which is another commonly used anthracycline chemotherapy agent, is isolated from mutated strain of Streptomyces. Although both the drugs have similar mechanisms, doxorubicin is more effective in treating solid tumors. Idarubicin, Epirubicin, and Mitoxantrone are other commonly used anthracycline chemotherapy drugs.
Anthracyclines work by forming free radicals that break DNA strands thereby inhibiting DNA synthesis and function. These chemotherapeutic agents form a complex with DNA and enzyme to inhibit the topoisomerase enzyme. Topoisomerases are enzymes that causes the supercoiling of DNA, allowing DNA repair, transcription, and replication.
Cardiac toxicity is a serious side effect of anthracyclines as heart muscle can be damaged.
Antitumor antibiotics were first developed from the soil fungus Streptomyces. These drugs are widely used to treat and suppress development of tumors in the body. Similar to anthracyclines, antitumor antibiotics drugs also form free radicals that break DNA strands, s1topping the multiplication of cancer cells. Treating oncologists usually combine antitumor antibiotics with other chemotherapy agents in a combination regimen.
Bleomycin is one of the commonly used antitumor antibiotic used to treat testicular cancer and Hodgkin’s lymphoma.
The limiting toxicity for antitumor antibiotics tends to be in the lungs; free radicals formed by the antitumor antibiotics damage lung cells along with the cancer cells.
Several of the newer chemotherapy agents are monoclonal antibodies. The first one was approved for cancer treatment by the Food and Drug Administration (FDA) in 1997. Alemtuzumab (Campath), Bevacizumab (Avastin), Cetuximab (Erbitux), Gemtuzumab (Mylotarg), Ibritumomab (Zevalin), Panitumumab (Vectibix), Rituximab (Rituxan), Tositumomab (Bexxar), and Trastuzumab (Herceptin) are some of the FDA-approved monoclonal drugs used in cancer treatments.
Monoclonal antibodies (abbreviated MAbs) are useful in treating colon, lung, head, neck, and breast cancers. Monoclonal drugs are also used to treat chronic lymphocytic leukemia, acute myelogenous leukemia, and non-Hodgkin’s lymphoma.
Monoclonal antibodies work by attaching to certain parts of the tumor-specific antigens and make them easily recognizable to the body’s immune system. Some prevent growth of cancer tumors by blocking the cell receptors to the body’s “growth factors”.
Monoclonal antibodies can be combined with radioactive particles and other powerful anticancer drugs to deliver them directly to cancer cells. Using this method, long term radioactive treatment and anticancer drugs can be given to patients without causing any serious harm to other healthy cells of the body.
Cisplatin was first syntheized in the nineteenth century, but clinical use of platinum compounds for cancer treatment did not commence until the 1970s. Platinum-based chemotherapy agents work by cross-linking subunits of DNA. These agents act during all parts of the cell cycle and impair DNA synthesis, transcription, and function.
Cisplatin, although found to be useful in treating testicular and lung cancer, is highly toxic and can severely damage the kidneys. Second generation platinum-complex carboplatin are much less toxic in comparison and have fewer kidney-related side effects. Oxaliplatin, which is third generation platinum-based complex, is used to treat colon cancer. Oxaliplatin is easier on the kidneys but it can lead to severe neuropathies. Platinum-based drugs are often used for treatment of mesothelioma.
Plant alkaloid chemotherapy agents, as the name suggests, are plant derivatives. They are cell-specific chemotherapy agents. However, the cycle affected is based on the drug used for the treatment. They are primarily categorized into four groups: topoisomerase inhibitors, vinca alkaloids, taxanes, and epipodophyllotoxins. Plant alkaloids are cell-cycle specific, but the cycle affected varies from drug to drug. Vincristine (Oncovin) is a plant alkaloid of interest in mesothelioma treatment.
Both Type I and Type II Topoisomerases inhibitors work by interfering with DNA transcription, replication, and function to prevent DNA supercoiling.
- Type I Topoisomerase inhibitors: These chemotherapy agents are extracted from the bark and wood of the Chinese tree Camptotheca accuminata. They work by forming a complex with topoisomerase DNA. This in turn suppresses the function of topoisomerase.
Camptothecins which includes irinotecan and topotecan are commonly used type I topoisomerase inhibitors, first discovered in the late 1950s.
- Type II Topoisomerase inhibitors: These are extracted from the alkaloids found in the roots of May Apple plants. They work in the in the work in the late S and G2 phases of the cell cycle.
Amsacrine, etoposide, etoposide phosphate, and teniposide are some of the examples of type II topoisomerase inhibitors.
Vinca alkaloids are derived from the periwinkle plant, Vinca rosea (Catharanthus roseus) which has traditionally been used by the natives of Madagascar to treat diabetes.
Although not useful in controlling diabetes, vinca alkaloids, are useful in treating leukemias. They are effective in the M phase of the cell cycle and work by inhibiting tubulin assembly in microtubules.
Vincristine, Vinblastine, Vinorelbine, and Vindesine are some of the popularly used vinca alkaloid chemotherapy agents used today. Major side effect of vinca alkaloids is that they can cause neurotoxicity in patients.
Taxanes are plant alkaloids that were first developed for therapeutic use in 1963. Paclitaxel, which is the active components of taxanes was first discovered in 1971 and was made available for clinical use in the year 1993.
Taxanes also work in the M-phase of the cell cycle and inhibit the function of microtubules by binding with them. Paclitaxel and docetaxel are commonly used taxanes. Taxanes chemotherapy agents are used to treat a large array of cancers including breast, ovarian, lung, head and neck, gastric, esophageal, prostrate and gastric cancers. The main side effect of taxanes is that they lower the blood counts in patients. Spindle inhibitors.
Epipodophyllotoxins chemotherapy agents are extracted from the American May Apple tree (Podophyllum peltatum). It has also been found in the endangered Himalayan May Apple tree.
Etoposide and Teniposide are commonly used epipodophyllotoxins chemotherapy agents which are effective in the G1 and S phases of the cell cycle. They prevent DNA replication by stopping the cell from entering the G1 phase and stop DNA replication in the S phase.