Antimetabolites are compounds with similar structures to normal metabolites or coenzymes, and their main role is to combine with enzymes necessary for the synthesis of normal metabolites, thereby interfering with the synthesis of nucleic acids and inhibiting the growth and proliferation of tumor cells.
Some antimetabolites have a feedback inhibition effect that blocks the synthesis of metabolite precursors. Antimetabolites are primarily folic acid, purines, pyrimidines, or amino acid analogues that can act on one or more key steps in dna anabolic processes.
Antimetabolites act on different links in the process of nucleic acid synthesis, and can be divided into thymidylate synthase inhibitors, dihydrofolate reductase inhibitors, DNA polymerase inhibitors, nucleotide reductase inhibitors and purine nucleotide synthase inhibitors according to their effects.
Thymidine synthetase inhibitor
Mechanism of action: Because its metabolic activator fluorouracil deoxynucleotide interferes with the transition from deoxyuracil to deoxythymidine nucleotide, it affects the synthesis of DNA.
Fluorouracil (5-FU) is a fluoride of uracil, is currently the most widely used antipyrimidine drug, converted into 5-fluorodeoxyuracil nucleotide in vivo, inhibits thymine nucleotide synthetase, thereby inhibiting DNA synthesis, and also has a certain inhibitory effect on RNA synthesis.
Indications:
It is used for gastrointestinal malignant tumors, breast cancer, ovarian cancer, chorionic epithelial carcinoma, malignant hydatidiform mole, head and neck squamous cell carcinoma, skin cancer, bladder cancer, etc.
Disadvantages:
Adverse reactions are mainly gastrointestinal toxicity (nausea, vomiting, occasional diarrhea), bone marrow suppression, nervous system toxicity (headache, dizziness, ataxia), cardiotoxicity, etc.
Oral absorption is incomplete and requires injection administration.
Short half-life (10-20 minutes), short duration of maintenance of serum concentrations, and continuous injection of the drug.
Dihydrofolate reductase inhibitors
Mechanism of action: by inhibiting dihydrofolate reductase, the process of reducing dihydrofolate to physiologically active tetrahydrofolate is blocked, so that coenzyme metabolism is terminated and DNA synthesis is blocked. It also has an inhibitory effect on thymine synthase.
Methotrexate is the earliest folate antagonist used in clinical practice and belongs to the classical dihydrofolate reductase inhibitor. It mainly acts on the S phase of the cell cycle, is a cell cycle-specific drug, and also has a delaying effect on cells in the G1/S stage, and has a weak effect on G1 stage cells.
It is used for acute leukemia, head and neck cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, malignant mole, chorioepithelial carcinoma, testicular cancer.
Mainly gastrointestinal reactions (stomatitis, lip ulcers, pharyngitis, nausea, vomiting, gastritis and diarrhea), bone marrow suppression.
Drug-induced hepatitis, kidney damage, alopecia, dermatitis, pigmentation, and drug-induced pneumonia may occur.
Symptoms such as headache, back pain, vomiting, fever, and convulsions can occur when intrathecal or head and neck arteries are injected in large doses.
Use in the first trimester of pregnancy can cause teratogenicity, and a small number of patients have delayed menstruation and decreased reproductive function.
Tips：
Both oral and injectable therapy is acceptable.
After methotrexate, the addition of formyltetrahydrofolate calcium can directly provide the THC coenzyme to the cells, avoiding the inhibitory effect of methotrexate to alleviate the toxic effect of its cytotoxicity.
DNA polymerase inhibitors
Mechanism of action: Such drugs are converted to cytarabine triphosphate and cytarabine diphosphate after kinase phosphorylation, the former can strongly inhibit the synthesis of DNA polymerase, and the latter can inhibit the conversion of cytidine diphosphate into deoxycytidine diphosphate, thereby inhibiting cell DNA polymerization and synthesis.
Cytarabine mainly acts on the proliferation phase of cell S and can also delay the entry of G1 stage cells into phase S. Combined with other anti-tumor drugs can improve efficacy.
It is mainly used for acute leukemia, and has a certain effect on malignant lymphoma, lung cancer, gastrointestinal cancer, head and neck cancer, and also has a certain effect on viral keratitis and epidemic conjunctivitis.
Oral absorption is extremely poor, usually administered intravenously continuously.
Adverse reactions are mainly bone marrow suppression, gastrointestinal reactions, cytarabine syndrome mostly occurs 6-12 hours after medication, with bone pain or myalgia, sore throat, fever, general malaise, rash, redness of the eyes and other manifestations.
In order to prevent cytarabine from deamination and inactivation, its amino acids are acylated with chain hydrocarbon acids and made into prodrugs, so that the anti-tumor effect is strong and long-lasting. Derivatives: enotabine, cytarabine palmitoyl, azatidine.
Nucleotide reductase inhibitors
Mechanism of action: Hydroxyurea, inosine dialdehyde, adenosine dialdehyde, guanazole, etc. inhibit the reduction of cytidylates, guanylates, adenylates, and thymidines from being reduced to the corresponding deoxynucleotides by inhibiting nucleotide reductase, and ultimately preventing the synthesis of DNA.
Hydroxyurea is a representative drug of nucleotide reductase inhibitors, selectively acts on S-stage cells and can be treated orally or injectably.
It is used for malignant melanoma, stomach cancer, bowel cancer, breast cancer, bladder cancer, head and neck cancer, malignant lymphoma, primary liver cancer and acute and chronic myelogenous leukemia. It is also combined with radiotherapy and chemotherapy to treat brain tumors.
Adverse reactions are mainly bone marrow suppression, but gastrointestinal reactions can also occur, which can cause teratogenicity.
Purine nucleotide synthase inhibitor
Mechanism of action: Adenine and guanine are components of DNA, hypoxanthine is an important intermediate in their biosynthesis, and purine antagonists are mainly derivatives of hypoxanthine and guanine.
Purine antagonists are converted in vivo to thioinous inosylates under the action of hypoxanthine guanylate transferase, preventing inosylates from converting to adenylates or guanylates, interfering with purine metabolism, thereby blocking DNA synthesis. The effect on S-stage cells is more pronounced.
6-Mercaptopurine is a derivative of NH2 at the 6th position of adenine that is replaced by -SH.
It is mainly used for acute leukemia with good effect, and due to slow onset of action, it is more used as a maintenance drug. It can also be used for chorioepithelial carcinoma and malignant mole moles. In addition, it also has a certain effect on malignant lymphoma and multiple myeloma.
Adverse reactions are mainly gastrointestinal reactions and bone marrow suppression, and a few may appear jaundice and abnormal liver function, and occasionally hyperuricemia. (Tumor time)
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