What is the mechanism of Capecitabine?

Capecitabine is an oral chemotherapeutic agent that is widely used in the treatment of various cancers, including colorectal cancer and breast cancer. Understanding the mechanism of Capecitabine is crucial for comprehending its therapeutic effects and the rationale behind its use.

Capecitabine itself is a prodrug, which means it is an inactive substance that is metabolized in the body to produce an active cancer-fighting compound. Specifically, Capecitabine is metabolized into 5-fluorouracil (5-FU), a well-known cytotoxic agent. The transformation of Capecitabine into 5-FU involves a multi-step enzymatic process, designed to target cancer cells more effectively.

The first step in this activation process occurs in the liver. After oral administration, Capecitabine is absorbed through the gastrointestinal tract and transported to the liver, where it undergoes enzymatic conversion by carboxylesterase to form 5'-deoxy-5-fluorocytidine (5'-DFCR). This intermediate is then converted by cytidine deaminase, which is found in both the liver and tumor tissues, into 5'-deoxy-5-fluorouridine (5'-DFUR).

The final and most crucial step in the activation of Capecitabine to 5-FU is catalyzed by the enzyme thymidine phosphorylase. This enzyme is present in higher concentrations within tumor cells compared to normal cells. Thymidine phosphorylase converts 5'-DFUR into the active chemotherapeutic agent 5-FU. This selective activation within tumor tissues is one of the key mechanisms through which Capecitabine exerts its cytotoxic effects while minimizing damage to healthy tissues.

Once formed, 5-FU functions as an antimetabolite, disrupting the synthesis of DNA and RNA within the cancer cells. 5-FU is incorporated into the RNA and DNA of rapidly dividing cells, leading to the inhibition of RNA processing and DNA synthesis. This results in cell cycle arrest and ultimately induces cell death, particularly in rapidly proliferating tumor cells.

Moreover, 5-FU inhibits the enzyme thymidylate synthase, which is essential for DNA synthesis and repair. Inhibition of this enzyme leads to a depletion of thymidine triphosphate (dTTP), one of the nucleotide building blocks required for DNA replication. The lack of dTTP causes an imbalance in the nucleotide pool, further hampering DNA synthesis and repair mechanisms, which is lethal to rapidly dividing cells.

In summary, Capecitabine is a prodrug that is converted into the active chemotherapeutic agent 5-FU through a series of enzymatic reactions, primarily occurring in the liver and tumor tissues. The selective activation of 5-FU within tumor cells allows for targeted cytotoxicity, thereby maximizing the therapeutic efficacy of the drug while minimizing systemic toxicity. The mechanism of action involves the incorporation of 5-FU into RNA and DNA, disrupting their synthesis and function, and the inhibition of thymidylate synthase, leading to cell death of rapidly dividing tumor cells.