An Analysis of 5 Commonly Used Antimetabolite Antitumor Drugs

In the clinical treatment of malignant tumors, antimetabolite agents have become one of the core components of chemotherapy regimens due to their strong targeting properties and well-defined mechanisms of action. These drugs mimic endogenous metabolic substances, interfere with nucleic acid synthesis in tumor cells, inhibit tumor cell proliferation and differentiation, and ultimately achieve tumor cell death or control of tumor progression.

Drawing on its long-standing professional expertise and clinical insight in the pharmaceutical field, DengyueMed provides a systematic analysis of five commonly used antimetabolite anticancer agents—pemetrexed, raltitrexed, fluorouracil, capecitabine, and Teysuno (tegafur/gimeracil/oteracil)—focusing on their pharmacological mechanisms of action, clinical indications, dosing and administration standards, and key safety management considerations, to facilitate a comprehensive understanding of their characteristics and appropriate clinical use.

1.Pemetrexed: A Broad-Spectrum Anticancer Agent with Multi-Target Antimetabolite Activity

Pemetrexed is a multi-target antifolate agent with a unique mechanism of action. It simultaneously inhibits several key enzymes involved in tumor cell nucleic acid synthesis, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT).

This “multi-target inhibition” strategy makes it difficult for tumor cells to escape drug activity through single-enzyme compensation, thereby significantly enhancing antitumor efficacy while relatively sparing normal cells.Clinically, pemetrexed is primarily used for the treatment of locally advanced or metastatic non-squamous non–small cell lung cancer (NSCLC). It is an important drug for first-line chemotherapy, maintenance therapy, and second-line treatment, often used in combination with cisplatin or carboplatin, and has been shown to significantly prolong patient survival.

In addition, pemetrexed is also indicated for malignant pleural mesothelioma, particularly in patients who are not eligible for surgical resection, and is currently one of the cornerstone therapies for this disease.

When using pemetrexed, supplementation with folic acid and vitamin B12 is essential. Regular supplementation before and during treatment helps reduce hematologic and gastrointestinal toxicities, including leukopenia and oral mucositis.

Pemetrexed is contraindicated in patients with hypersensitivity to the drug or its components, as well as in those with severe hepatic or renal impairment.

2.Raltitrexed: A Highly Targeted and Efficient Antifolate Chemotherapy Agent

Raltitrexed is a selective thymidylate synthase inhibitor belonging to the antifolate class. Compared with pemetrexed, it has a more specific mechanism of action, selectively inhibiting thymidylate synthase and blocking the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). This results in inhibition of DNA synthesis and suppression of tumor cell proliferation.

Due to its precise target, raltitrexed exerts strong antitumor effects with relatively limited interference in normal cellular metabolism.Clinically, raltitrexed is mainly used for the treatment of advanced colorectal cancer, particularly in patients who are unable to tolerate fluorouracil-based therapy. It may be administered as monotherapy or in combination with other chemotherapeutic agents.

In addition, raltitrexed has been used in the treatment of advanced gastric cancer and pancreatic cancer, showing therapeutic benefits in certain refractory cases.

The main adverse reactions associated with raltitrexed include gastrointestinal toxicity and myelosuppression, such as nausea, vomiting, diarrhea, and leukopenia. These effects are generally mild and manageable with supportive care.

Raltitrexed is contraindicated in pregnant and lactating women and should be used with caution in patients with severe hepatic or renal dysfunction. Routine monitoring of blood counts and liver and kidney function is required during treatment.

3.Fluorouracil: A Classic and Foundational Anticancer Agent

Fluorouracil (5-FU) is one of the most classic and widely used antimetabolite antitumor drugs. Since its introduction, it has remained a cornerstone of chemotherapy for gastrointestinal malignancies, breast cancer, and other solid tumors.

Its mechanism of action involves structural mimicry of uracil. After entering tumor cells, fluorouracil is converted into active metabolites that interfere with DNA and RNA synthesis, thereby inhibiting tumor cell proliferation and inducing apoptosis.

Fluorouracil has a broad range of clinical applications, particularly in the treatment of colorectal cancer, gastric cancer, esophageal cancer, and pancreatic cancer, and is often combined with agents such as oxaliplatin or cisplatin as part of first-line chemotherapy regimens. It is also used in breast cancer, cervical cancer, ovarian cancer, as well as skin cancers and head and neck tumors.

Due to its proven efficacy and relatively low cost, fluorouracil remains indispensable in modern oncology practice.Common adverse reactions include:

● Gastrointestinal toxicity (nausea, vomiting, stomatitis, diarrhea);

● Myelosuppression (leukopenia, thrombocytopenia);

● Hand–foot syndrome;

● Hyperpigmentation.

Strict control of dosage and infusion rate is required, along with regular monitoring of hematologic and hepatic/renal function. Fluorouracil is contraindicated in patients with hypersensitivity to the drug, as well as in pregnant and lactating women.

4. Capecitabine: A Convenient Oral Prodrug of Fluorouracil

Capecitabine is an oral fluorouracil prodrug that is itself non-cytotoxic. After administration, it is selectively converted into fluorouracil by tumor-associated enzymes within tumor tissues.

This tumor-targeted activation allows higher concentrations of active drug within tumor tissue while minimizing exposure in normal tissues, thereby reducing systemic toxicity and significantly improving patient convenience and treatment adherence.

Clinically, capecitabine is widely used in advanced colorectal cancer, either as monotherapy or in combination with agents such as oxaliplatin or paclitaxel. It is also indicated for advanced breast cancer (particularly in patients who have failed taxane-based therapy), as well as gastric and esophageal cancers.

Additionally, capecitabine is commonly used as adjuvant chemotherapy after surgery to reduce the risk of recurrence.

The most common adverse reactions include:

1.  Hand–foot syndrome, characterized by numbness, pain, erythema, swelling, and desquamation of the palms and soles, which can usually be alleviated by dose adjustment and local care;

2.  Mild gastrointestinal toxicity and myelosuppression.

During treatment, patients should keep their hands and feet clean and dry and avoid friction or irritation. Capecitabine is contraindicated in patients allergic to capecitabine or fluorouracil, and in those with severe hepatic or renal impairment.

5. Teysuno: A Synergistic Oral Combination Antimetabolite Agent

Teysuno is an oral combination antimetabolite antitumor drug composed of tegafur, gimeracil, and oteracil potassium in a fixed ratio.

Tegafur is a prodrug of fluorouracil and is converted into 5-FU in vivo. Gimeracil inhibits the degradation of fluorouracil, prolonging its activity and enhancing efficacy. Oteracil potassium selectively inhibits fluorouracil activation in the gastrointestinal tract, thereby reducing gastrointestinal toxicity.

The synergistic action of these three components achieves an optimal balance of enhanced efficacy and reduced toxicity.

Teysuno is primarily used in gastrointestinal malignancies, particularly advanced gastric cancer, where it serves as a common option for first-line chemotherapy and postoperative adjuvant therapy, either alone or in combination with cisplatin. It has been shown to significantly improve patient survival and quality of life.

Teysuno is also used in the treatment of advanced colorectal cancer and pancreatic cancer, demonstrating broad clinical potential.

Adverse reactions associated with Teysuno are similar to those of fluorouracil but are generally milder and include:

● Gastrointestinal reactions;

● Myelosuppression;

● Hand–foot syndrome.

Dosage should be adjusted according to body surface area, and routine monitoring of blood counts and liver and kidney function is required. Teysuno is contraindicated in patients allergic to any of its components, as well as in pregnant and lactating women.

Conclusion

Pemetrexed, raltitrexed, fluorouracil, capecitabine, and Teysuno are all antimetabolite antitumor agents that exert their effects by interfering with tumor cell nucleic acid synthesis. However, each drug has distinct molecular targets, clinical indications, and safety profiles.

Fluorouracil remains a widely used foundational agent but is associated with more pronounced adverse effects. Capecitabine and Teysuno offer improved convenience and tolerability as oral formulations, making them suitable for long-term maintenance therapy. Pemetrexed, with its multi-target mechanism, is particularly effective in non–small cell lung cancer and malignant pleural mesothelioma, while raltitrexed provides a targeted option for advanced colorectal cancer patients who cannot tolerate fluorouracil.In clinical practice, physicians should tailor chemotherapy regimens based on tumor type, disease stage, patient condition, and drug tolerability, while closely monitoring adverse reactions and adjusting treatment strategies as needed to achieve optimal therapeutic outcomes and preserve patient quality of life. Patients should strictly follow medical advice, avoid unauthorized dose adjustments or discontinuation, and promptly report any adverse reactions to ensure safe and effective treatment.

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