What Are Antimetabolites?

Table of Contents
View All
Table of Contents

When you hear the word "chemotherapy," cancer-killing drugs and side effects like mouth sores and hair loss probably come to mind. The drugs you're thinking of are probably antimetabolites—the oldest form of cancer-halting chemotherapy medication in the cancer treatment toolkit.

Antimetabolites are a class of chemotherapy drugs that cut off DNA or RNA replication by taking the place of natural molecules (metabolites) essential to cellular division.

Person undergoing chemotherapy with antimetabolites consults with healthcare provider

FatCamera / Getty Images

What It Is

Antimetabolites (also known as nucleotide synthesis inhibitors) are structurally similar to but not exactly the same as naturally occurring molecules essential for DNA and RNA replication in cellular division.

When these small molecules enter the nucleus of a cell, they interfere with cellular replication (when a single-celled organism turns into a multicelled organism) pathways by serving as mimickers (analogs) of natural metabolites needed for replication.

Antimetabolites focus on rapidly dividing cells, making them extremely effective chemotherapeutic agents against fast-growing tumors.

How It Works

An antimetabolite works by displacing a natural metabolite needed for DNA or RNA synthesis, thereby halting cellular metabolism. These false metabolites are so similar to the real building blocks needed for normal metabolism that they are mistakenly taken up by the cell.

When they attach to the enzymes along the cellular pathway, a complex that is unusable and even toxic to the cell forms. As a result, essential enzymes involved in replicating DNA are blocked, halting cell division. 


Antimetabolites are used in a myriad of cancers ranging from cervical and breast cancer to blood and colorectal cancer. Some of the commonly used antimetabolites in cancer treatment include:

Antimetabolites are so effective at disrupting nucleic acid pathways that they are used in the treatment of a number of rheumatological and autoimmune conditions, such as multiple sclerosis and rheumatoid arthritis. They work by interrupting the inflammatory cascade, lessening pain, swelling, and other symptoms. 

Of note, methotrexate—an antifolate drug—is one of the most widely used antimetabolites. Folate and folate cofactors are essential for cellular division.

Folate is so important to cellular metabolism that people are encouraged to take folate supplements during their first trimester of pregnancy to stave off spinal cord deformities and promote the overall healthy development of the embryo and fetus.

Methotrexate blocks folate cofactors from binding to enzymes involved in cellular replication. As a result, cell division is halted.  Methotrexate's uses range from stopping cell division in early pregnancy to interfering with the inflammatory pathways involved in rheumatoid and psoriatic arthritis.

Methotrexate is a disease-modifying antirheumatic drug (DMARD). It is used off-label (meaning it is an unapproved use of an FDA-approved drug) to treat a number of autoimmune conditions.


The three main types of antimetabolites based on the type of molecule that it mimics are:

  • Folic acid analogs, such as methotrexate and pemetrexed
  • Pyrimidine analogs, such 5-FU and capecitabine
  • Purine analogs such as 6-MP


The structure of an antimetabolite is close, but not exactly the same as a naturally occurring molecule in your body. Antimetabolites are analogs of forerunners of purine, pyrimidines, and folate cofactors that are essential for DNA and RNA synthesis. 


Antimetabolites have been on the market for over 70 years, since the discovery of aminopterin, an anticancer drug that was the first to show evidence of leukemia (blood cancer) remission. Antimetabolites have been shown to not only kill cancer cells but also induce long-term remission in some cases, increasing life expectancy and quality of life.


Generally, the longer you take antimetabolites, the more likely you are to develop side effects. Antimetabolites are nonspecific, damaging both normal and abnormal cells. As a result, other rapidly dividing cells, such as those in your hair, gastrointestinal tract, and bone marrow, may be affected.

Some people have minor side effects, while others have severe side effects that can happen together or one after another. Common side effects include:

  • Fatigue
  • Nausea
  • Vomiting
  • Diarrhea
  • Hair loss (alopecia)
  • Low numbers of healthy red blood cells (anemia)
  • Mouth sores
  • Low white blood cell levels, leading to being immunocompromised and therefore open to infections (neutropenia)
  • Damage to nerves that can cause numbness and tingling, particularly in the hands and feet (neuropathy)

It is impossible to predict the type and severity of your side effects. Before you start taking these medications, you and your healthcare provider must weigh the risk vs. the benefits of treatment.

Your age, general health, and the type, location, and stage of your cancer are some factors that will determine if antimetabolite chemotherapy is right for you. Generally, the rule of thumb is to use these drugs' lowest, most effective dose. 


Since 1948, antimetabolites have served as a valuable component of cancer treatment. Antimetabolites are a class of chemotherapy drugs, in which analogs that mimic natural metabolites insert into the nucleus of rapidly dividing cells, disrupting DNA or RNA replication and cell division.

A Word From Verywell

Antimetabolites have been a staple of cancer treatment for over half a century but you should always weigh the risks and the benefits before using these drugs. Not only is the effectiveness of these medications highly variable (they do not work in every one) but long-term use also increases the likelihood of experiencing side effects. 

Antimetabolites were once the gold standard drug treatment for a variety of cancers, but long gone are the days of using a single therapy to treat cancer.

New treatment regimens are more comprehensive in nature. They may include surgery, radiation, stem cell transplantation, targeted drug therapy, immunotherapy, and polypharmacy (the use of a combination of chemotherapy drugs from different classes, such as alkylating agents, anthracyclines, and tyrosine kinase inhibitors).

If you have cancer, check with your oncologist (cancer specialist) and other healthcare providers on your cancer management team to determine what treatments are best for you.

5 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Cancer Australia. Antimetabolites.

  2. American Cancer Society. How chemotherapy drugs work.

  3. John Hopkins Arthritis Center. Rheumatoid arthritis treatment options.

  4. Falzone L, Salomone S, Libra M. Evolution of cancer pharmacological treatments at the turn of the third millennium. Front Pharmacol. 2018;9:1300. doi:10.3389/fphar.2018.01300

  5. Osmosis from Elsevier. Antimetabolites: nursing pharmacology.

By Shamard Charles, MD, MPH
Shamard Charles, MD, MPH is a public health physician and journalist. He has held positions with major news networks like NBC reporting on health policy, public health initiatives, diversity in medicine, and new developments in health care research and medical treatments.