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Categories of Chemotherapeutic Agents
Most chemotherapy agents and medications work by interfering with DNA synthesis or function. Each chemotherapy drug works during different phases of the cell cycle. Based on their action, 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
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. Majority of alkaline agents are active or dormant nitrogen
mustards, which are poisonous compound initially used for certain military
purposes. Chlorambucil, Cyclophosphamide, CCNU, Melphalan, Procarbazine,
Thiotepa, BCNU, and Busulfan are some of the commonly used alkylating
agents.
Although they might differ in their clinical activity, action mechanism
of all alkylating agents is the same. These agents work directly on the
DNA and prevent the cell division process by cross-linking and breaking
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
dies eventually.
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.
Antimetabolites
Structure of antimetabolites (antineoplastic agents) is similar to certain compounds such as 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 tumor cells. These agents get incorporated in the DNA or RNA to interfere with the process of division of cancer cells.
Antimetabolites were first discovered in the year 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 new agents that could inhibit biological enzymatic reactions.
Antimetabolites are 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 a commonly used antimetabolites chemotherapy agent, is effective in the S-phase of the cell cycle. It works by inhibiting 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. Gemcitabine, and Fludarabine.
Anthracyclines
Anthracyclines were developed between 1970s and 1990s and are daunosamine and tetra-hydronaphthacenedione-based chemotherapy agents. These 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. For instance, daunorubicin is developed by isolating it from soil-dwelling fungus Streptomyces. Similarly, Doxorubicin, which is another commonly used anthracycline chemotherapy agent, is isolated from mutated strain of Streptomyces. Although both the drugs have similar clinical action mechanisms, doxorubicin is more effective in treating solid tumors. Idarubicin, Epirubicin, and Mitoxantrone are few of the other commonly used anthracycline chemotherapy drugs.
Anthracyclines work by forming free oxygen radicals that breaks DNA strands thereby inhibiting DNA synthesis and function. These chemotherapeutic agents form a complex with DNA and enzyme to inhibit the topoisomerase enzyme. Topoisomerase is an enzyme class that causes the supercoiling of DNA, allowing DNA repair, transcription, and replication.
One of the main side effects of anthracyclines is that it can damage cells of heart muscle along with the DNA of cancer cell leading to cardiac toxicity.
Antitumor antibiotics
Antitumor antibiotics are also 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 oxygen radicals that result in DNA strand breaks, killing the growth of cancer cells. In most of the cases, these drugs are used in combination with other chemotherapy agents.
Bleomycin is one of the commonly used antitumor antibiotic used to treat testicular cancer and hodgkin’s lymphoma.
The most serious side effect of this drug is lung toxicity that occurs when the oxygen radical formed by the antitumor antibiotics damages lung cells along with the cancer cells.
Monoclonal antibodies
Monoclonal antibodies are one of the newer chemotherapy agents 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 chemotherapeutic cancer treatments.
The treatment is known to be useful in treating colon, lung, head, neck, and breast cancers. Some of the monoclonal drugs are 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 by the host’s immune system. They also prevent growth of cancer cells by blocking the cell receptors to which chemicals called ‘growth factors’ attach promoting cell growth.
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.
Platinums
Platinum-based natural metal derivatives were found to be useful for cancer treatments around 150 years ago with the synthesis of cisplatin. However, there clinical use did not commence until 30 years ago. Platinum-based chemotherapy agents work by cross-linking subunits of DNA. These agents act during any part of cell cycle and help in treating cancer by impairing 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 of the patient. Second generation platinum-complex carboplatin is found to be much less toxic in comparison to cisplatin and has fewer kidney-related side effects. Oxaliplatin, which is third generation platinum-based complex, is found to be helpful in treating colon cancer. Although, oxaliplatin does not cause any toxicity in kidney it can lead to severe neuropathies.
Plant alkaloids
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.
Topoisomerase Inhibitors
Topoisomerase inhibitors are chemotherapy agents are categorized into Type I and Type II Topoisomerases inhibitors and they 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
Vinca alkaloids are derived from the periwinkle plant, Vinca rosea (Catharanthus roseus) and are known to be 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
Taxanes are plant alkaloids that were first developed in 1963 by isolating it from first isolated from the bark of the Pacific yew tree, Taxus brevifolia 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
Epipodophyllotoxins chemotherapy agents are extracted from the American May Apple tree (Podophyllum peltatum). Recently, it has been found in more quantities 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.
Non phase-specific cancer drugs
Dose-dense chemotherapy
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