Antineoplastics in chemotherapy

ATC CODE: 101

ALSO KNOWN AS: Chemotherapeutic agents, antitumor compounds, cytotoxic antibiotics

DEFINITION: Antineoplastics are anticancer drugs used to treat malignancies and cancerous growths.

Cancers treated: Various types of cancers

Subclasses of this group: Alkylating agents, antimetabolites, mitotic inhibitors, topoisomerase inhibitors, cytotoxic antibiotics

Delivery routes: Oral, intravenous, intramuscular, or subcutaneous injection

How these drugs work: Antineoplastics are chemicals used in chemotherapy to treat cancer and inhibit tumor cell growth. The term “neoplastic” refers to cancer cells, so the term “antineoplastic” literally means “anticancer cell.” Antineoplastic agents are used to stop tumor development, prevent cancer spread, relieve some associated symptoms, and prolong patient survival. Antineoplastics are also sometimes called chemotherapeutic agents, antitumor compounds, or cytotoxic antibiotics.

The first antineoplastic agents were used in the 1940s and either were made from synthetic chemicals or were derived from natural plants. There are several major categories of antineoplastic agents based on their origins, chemical structures, and how they work. These classifications include alkylating agents, antimetabolites, cytotoxic antibiotics, mitotic inhibitors, and topoisomerase inhibitors. Antineoplastic agents inhibit tumor cell growth using different mechanisms, with many affecting deoxyribonucleic acid (DNA) synthesis and interfering with cell division. Others work by altering immune function or affecting the hormonal status of tumors. Antineoplastic drugs are either cycle-specific or non-cycle-specific. Cycle-specific drugs act only during certain phases of the cell cycle. Non-cycle-specific drugs may act during any cell cycle phase.

The largest group of antineoplastic compounds is the alkylating agents, among the first anticancer drugs used. Alkylating agents cross-link DNA and prevent DNA bases from pairing up correctly, interfering with DNA synthesis and preventing cells from reproducing. Categories of alkylating agents include nitrogen mustards, ethylenimines, alkyl sulfonates, triazines, and nitrosoureas. Nitrogen mustards comprise the largest group of alkylating drugs and are particularly useful for treating neoplasms that increase white blood cells, such as lymphomas and leukemias, because they result in leukopenia (low levels of white blood cells). Unlike most other types of antineoplastic agents, nitrosoureas can cross the blood-brain barrier and thus are useful for treating brain tumors. Also included among the alkylating agents are the metal salts, such as carboplatin and cisplatin.

Antimetabolites work by interfering with DNA and RNA growth. Antimetabolites are analogs of normal metabolites (nucleic acids) and act by replacing natural substances. Since these compounds structurally resemble DNA base pairs, they become incorporated into DNA, thus interfering with DNA synthesis. Antimetabolites are cell-cycle specific and attack cells only during certain cell cycle phases. Most antimetabolites are preferentially effective against cells that are actively synthesizing DNA. Antimetabolites are classified by the metabolite they affect. These include folic acid, purine, and pyrimidine analogs. These compounds function by interfering with DNA synthesis. This is either by directly inhibiting important enzymes or by being converted into substances that impair DNA synthesis. Methotrexate, a folic acid analog, inhibits an enzyme necessary for the regeneration of intermediates required for DNA synthesis. Pyrimidine and purine analogs are converted into compounds that inhibit enzymes involved in DNA synthesis. 5-fluorouracil and cytarabine are examples of pyrimidine analogs. Purine analogs include 6-mercaptopurine and pentostatin.

Some antineoplastic drugs are considered antimitotics or mitotic inhibitors and bind to tubulin, preventing polymerization of microtubules necessary for mitotic spindle formation. This prevents mitosis and arrests cells during metaphase. Many of the vinca alkaloids function as mitotic inhibitors. Topoisomerase inhibitors interfere with DNA synthesis by disrupting the function of topoisomerases I and II enzymes, which are important in tubulin formation. Topoisomerases control the structure of DNA necessary for replication, and compounds that inhibit these enzymes work by preventing DNA from being unwound, a step required for DNA synthesis.

Many antineoplastic compounds are derived from plants and are known as natural products. They vary mechanistically, with some functioning as alkylating agents, some inhibiting mitosis, and some affecting enzymes important in DNA synthesis. The vinca alkaloids, made from the periwinkle plant (Catharanthus rosea), and the taxanes, made from the Pacific yew tree (Taxus), work as mitotic inhibitors by disrupting microtubule formation. Podophyllotoxins are derived from the mayapple plant (Podophyllum peltatum). Camptothecans are distilled from the Asian “Happy Tree” (Camptotheca acuminate). Both function as topoisomerase inhibitors. These compounds are primarily effective against tumor cells during various cell cycle phases.

Another category of antineoplastics includes the antitumor or cytotoxic antibiotics. Many are produced by species of the soil fungus Streptomyces. There are several cytotoxic antibiotics, such as Dactinomycin (actinomycin D), bleomycin, and doxorubicin. Cytotoxic antibiotics generally act during various phases of the cell cycle. Dactinomycin works by binding to DNA and preventing ribonucleic acid (RNA) synthesis, an important step in making proteins. Doxorubicin works by causing DNA to uncoil, which prevents the cell from reproducing. Bleomycin acts by fragmenting DNA.

Many compounds do not fit into these categories but are still useful antineoplastic agents. These include hormones, enzymes, and reagents used in immunotherapy. Hormones such as corticosteroids alter the cellular environment, making it unfavorable for tumor growth. Enzymes, such as L-asparaginase, break down substances such as asparagine that tumor cells need for survival. Mitotane is a chemical related to the insecticide dichloro-diphenyl-trichloroethane (DDT) and interferes with the formation of adrenocortical steroids, with selective cyototoxic effects toward cells of the adrenal cortex.

Side effects: Antineoplastic compounds can destroy normal and neoplastic cells, although generally, antineoplastic agents have more significant effects on tumor cells because they divide rapidly. Many side effects associated with antineoplastic agents occur because of their impact on normal cells, especially those that divide quickly, such as the cells of hair follicles, ovaries, testes, and blood-forming organs. Hair loss is common as a result of effects on hair follicles. Anemia, immune system impairment, and clotting problems result from adverse effects on blood-forming organs, leading to decreased red blood cells, white blood cells, and platelet numbers. Nausea and vomiting are among the most common adverse side effects. Other side effects may include hematuria (blood in the urine), diarrhea, fever or chills, cough, wheezing, shortness of breath, unusual bruising, problems with urination, dizziness, irregular heartbeat, skin rash, fatigue, loss of taste, headache, swelling, allergic reactions, or body aches.

Because of the tremendous impacts of chemotherapy on the physical and mental health of patients, research efforts are becoming more focused on targeted strategies. Other promising areas of research involve the combination of drugs and treatments, personalized medicine, and immunotherapies.

Bibliography

Chu, Edward, and Vincent T. Devita, Jr. Physicians' Cancer Chemotherapy Drug Manual 2014. Burlington, Jones, 2014.

Clark, Michelle A., et al. Pharmacology. 5th ed. Philadelphia, Elsevier Health Sciences, 2011.

Dicato, Mario A. Side Effects of Medical Cancer Therapy: Prevention and Treatment. London, Springer, 2013.

Lindsay, Todd. "What to Know about Antineoplastic Chemotherapy Drugs." Medical News Today, 30 Sept. 2021, www.medicalnewstoday.com/articles/antineoplastic-chemotherapy. Accessed 20 June 2024.

Niederhuber, John E., et al. Abeloff's Clinical Oncology. 5th ed. Philadelphia, Elsevier, 2014.

Portable Pathophysiology. Philadelphia, Lippincott, 2007.

Skidmore-Roth, Linda. Mosby’s 2015 Nursing Drug Reference. 28th ed. St. Louis, Mosby, 2014.

Vardanyan, Ruben, and Victor Hruby. Synthesis of Essential Drugs. Philadelphia, Elsevier, 2006.

Uttpal, Anand. "Cancer Chemotherapy and Beyond: Current Status, Drug Candidates, Associated Risks and Progress in Targeted Therapeutics." Genes & Diseases, 18 Mar. 2022, doi: 10.1016/j.gendis.2022.02.007. Accessed 20 June 2024.

Yetman, Daniel. "Antineoplastic Chemotherapy." Healthline, 25 June 2021, www.healthline.com/health/cancer/antineoplastic-chemotherapy. Accessed 20 June 2024.