Cytarabine, also known as cytosine arabinoside or Ara-C, is a chemotherapy medication used primarily in the treatment of certain blood cancers. It is a foundational drug in the management of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML). It interferes with the growth and division of rapidly multiplying cells, a hallmark of cancer. It is typically administered through injection into a vein, under the skin, or directly into the cerebrospinal fluid.
Cytarabine’s Entry and Activation in Cells
For cytarabine to be effective, it must enter target cells and transform. The drug primarily enters cells through nucleoside transporters, specialized proteins embedded in the cell membrane. Once inside, cytarabine is inactive and must be converted to its active form.
This activation process involves phosphorylation, where phosphate groups are added to the cytarabine molecule. The enzyme deoxycytidine kinase (dCK) plays a significant role in this initial phosphorylation step, converting cytarabine into cytarabine monophosphate (ara-CMP). Subsequent enzymatic reactions further phosphorylate ara-CMP, eventually leading to the formation of cytarabine triphosphate (ara-CTP), which is the active metabolite responsible for the drug’s anticancer effects.
Disrupting DNA Replication: The Core Mechanism
Ara-CTP primarily disrupts DNA replication, a process essential for cell division. Ara-CTP functions as a “mimic” of deoxycytidine triphosphate (dCTP), a natural building block of DNA. Because of its structural similarity, ara-CTP can be mistakenly incorporated into the growing DNA strand by DNA polymerase enzymes.
Once ara-CTP is incorporated, it acts as a chain terminator. Unlike natural dCTP, ara-CTP lacks the necessary hydroxyl group at the 3′ position of its sugar component, which is required for the addition of subsequent nucleotides. This structural difference prevents further elongation of the DNA strand, effectively halting DNA synthesis. This interference is most pronounced during the S-phase of the cell cycle, the period when cells actively synthesize new DNA in preparation for division.
Why Cytarabine Targets Cancer Cells
Cytarabine’s effectiveness against cancer cells stems from its selective targeting of rapidly dividing cells. Cancer cells are characterized by uncontrolled and fast proliferation, meaning they spend more time in the S-phase of the cell cycle compared to most healthy cells. This increased rate of DNA synthesis in cancer cells makes them more susceptible to the disruptive effects of ara-CTP. While some healthy cells also divide, such as those in the bone marrow or gastrointestinal lining, the higher proportion of cancer cells undergoing DNA synthesis means they accumulate more of the damaging ara-CTP, leading to their death. This difference in replication rates contributes to the drug’s therapeutic window.
Understanding Side Effects Through Its Action
Despite its targeted action against rapidly dividing cancer cells, cytarabine can also affect healthy cells that have high rates of turnover. This non-selective impact on fast-growing normal tissues accounts for many of the drug’s common side effects.
For instance, the bone marrow, responsible for producing blood cells, is highly susceptible because its cells are constantly dividing. The suppression of bone marrow activity can lead to a reduction in white blood cells, increasing the risk of infection, and a decrease in platelets, potentially causing bleeding. Similarly, cells lining the gastrointestinal tract divide quickly, making them vulnerable to damage, which can result in nausea, vomiting, and mouth sores. Hair follicles, also containing rapidly dividing cells, can be affected, leading to hair loss.