Cancer is a disease that involves uncontrolled cell divisions that infiltrate and subsequently damage the normal body tissue. These uncontrolled cell divisions occur due to acquired or inherited mutation or damage to the DNA within the cells.
DNA controls normal cell growths and divisions. DNA mutations are common in normal cells, however, these cells can easily repair majority of these mutations. The cells that are unable to repair themselves die. If these mutated cells, neither repair themselves nor die, they can grow abnormally and become cancerous. Additionally, DNA mutations can increase the life of cancer cells causing them to accumulate in the affected part of the body.
Over the years a large number of different treatments such as radiation therapy and surgical processes have been developed to treat different types of cancers. Chemotherapy is the field of medicine that involves using different types of medication to treat a large number of cancers. It is often combined with other cancer treatments to make cancer treatment more effective.
The main objective of all chemotherapy agents and drugs is to destroy the cancerous cells while minimizing any damage to the healthy cells. To achieve this, various studies have been done to identify the characteristics that are unique in cancerous cells and non existent in normal cells. Therefore, one of the main features that chemotherapy agents usually target is the fast growing nature of the cancer cells.
Understanding the Cell Cycle
For better understanding of how chemotherapy works, it is important to have a basic idea of the cell cycle. Cell cycle basically involves a sequence of events that occur when a cell duplicates itself and divides into two new cells. The cycle occurs in fours phases- G1, S (Synthesis), G2, and M (Mitosis).
DNA replication occurs during the S phase. RNA and small amount of protein is developed during the G2 phase. Actual nuclear and cytoplasmic cell division occurs during the M phase. Most of the protein synthesis occurs during the G1 phase and because during this phase DNA is coiled tightly, it is not actively transcribed or copied.
Categories of Chemotherapeutic Agents
Most of the chemotherapy agents and medication 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 were one of the earliest and most common chemotherapy agents used for cancer treatments. Their use in cancer treatments started in early 1940s. The 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.
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 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 nature. 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 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 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 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.
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 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 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 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 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.
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.
Side effects of Chemotherapy
Due to their nature of action chemotherapy agents can also affect healthy cells of the body. Although, most of the side effects are temporary, a few can last for much longer period and even become permanent problems.
Some of temporary side effects of chemotherapy are hair loss, nausea, vomiting, fatigues, infertility, liver damage, bleeding, diarrhea, and constipation. Long-term and sometimes permanent side effects include hemorrhagic cystitis, problems in heart, lungs and kidneys and damage to nervous system. Some chemotherapy treatments can also cause secondary cancers in patients.
Chemotherapy agents are commonly used to treat different types of cancer in humans. Alkylating agents, antimetabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinums, or plant alkaloids are main categories of chemotherapy agents.
Although starting a chemotherapy treatment can be frightening, with the help of your physician, you can watch for signs and symptoms after each treatment. Better knowledge about the side-effects can help keep healthy for a long time post treatment. Many chemotherapy drugs developed today have much fewer side effects and are developed to assure you a healthy post-cancer life.