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Chapter 7. 2. Antimetabolites ( 抗代谢药物 )

An antimetabolite is a chemical with a similar structure to a substance (a metabolite ) required for normal biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division .

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Chapter 7. 2. Antimetabolites ( 抗代谢药物 )

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  1. An antimetabolite is a chemical with a similar structure to a substance (a metabolite) required for normal biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division. Antimetabolites can be used in cancer treatment, as they interfere with DNA production and therefore cell division and the growth of tumors. Because cancer cells spend more time dividing than other cells, inhibiting cell division harms tumor cells more than other cells. Chapter 7. 2. Antimetabolites (抗代谢药物)

  2. Purine Adenine Guanine Pyrimidine Cytosine Thymine

  3. 5-Fluoro-2, 4 (1H, 3H)-pyrimidinedione (5-氟-2, 4 (1H, 3H)-嘧啶二酮) Fluorouracil (5-FU) is used in the treatment of cancer. It is a pyrimidine analog. 5-FU has been in use against cancer for about 40 years, acting principally as a thymidylate synthase inhibitor. Thymidylate synthase is an enzyme important in the synthesis of pyrimidine for DNA replication. 5-FU is the first choice for the treatment of colon cancer 5-Fluorouracil (5-FU), 5-氟尿嘧啶　

  4. Fluorouracil is converted into a 'fraudulent' nucleotide, fluorodeoxyuridine monophosphate (FDUMP). Activation of 5-FU FUDMP FUDR

  5. Conversion of uridylate into thymidylate DUMP 5,10-methylene- tetrahydrofolate Thymidylate synthetase (TS) Thymidylate

  6. 5-FU prodrugs Capecitabine (Xeloda), given po, used for breast cancer. pentyl[1-(3,4-dihydroxy-5-methyl-tetrahydrofuran-2-yl)- 5-fluoro-2-oxo-1H-pyrimidin- 4-yl]aminomethanoate

  7. 5-FU Synthesis

  8. Antifolates-Another leap forward in cancer chemotherapy Shortly after World War II, a second approach to drug therapy of cancer began. Sidney Farber, a pathologist at Harvard Medical School, studied the effects of folic acid on leukemia patients. Folic acid, a vitamin crucial for DNA metabolism, had been discovered by Lucy Wills in 1937. It seemed to stimulate the proliferation of acute lymphoblastic leukaemia (ALL) cells when administered to children with this cancer. In one of the first examples of rational drug design (rather than accidental discovery), in collaboration with Harriett Kilte and Lederle Laboratories chemists, Farber synthesized folate analogues. These analogues — first aminopterin and then amethopterin (now methotrexate) were antagonistic to folic acid, and blocked the function of folate-requiring enzymes. When administered to children with ALL in the late 1940s, these agents became the first drugs to induce remission in children with ALL. Remissions were brief, but the principle was clear — antifolates could suppress proliferation of malignant cells, and could thereby re-establish normal bone-marrow function. It is worth noting that Farber met resistance to conducting his studies at a time when the commonly held medical belief was that leukemia was incurable, and that the children should be allowed to die in peace. Afterwards, Farber's 1948 report in the New England Journal of Medicine was met with incredulity and ridicule. Remarkably, a decade later at the National Cancer Institute, Roy Hertz and Min Chiu Li discovered that methotrexate treatment alone could cure choriocarcinoma (1958), a germ-cell malignancy that originates in trophoblastic cells of the placenta. This was the first solid tumour to be cured by chemotherapy.

  9. Methotrexate (MTX), 甲氨蝶呤 Mechanism of action: Blocks DNA synthesis through inhibition of the enzyme dihydrofolate reductase

  10. Inhibition of dihydrofolate reductase by MTX MTX

  11. The actions of methotrexate and fluorouracil on thymidylate synthesis.Tetrahydrofolate polyglutamate FH4 (glu)n functions as a carrier of a one-carbon unit, providing the methyl group necessary for the conversion of 2´-deoxyuridylate (DUMP) to 2´-deoxythymidylate (DTMP) by thymidylate synthetase. This one-carbon transfer results in the oxidation of FH4 (glu)n to FH2 (glu)n. Fluorouracil is converted to FDUMP, which inhibits thymidylate synthetase. DHFR, dihydrofolate reductase

  12. Cytarabine (Ara-C) was discovered in Europe in the 1960s. It gained FDA approval in June 1969. Cytosine arabinoside is an antimetabolic agent with the chemical name of 1β-arabinofuranosylcytosine. Its mode of action is due to its rapid conversion into cytosine arabinoside triphosphosphate, which damages DNA when the cell cycle holds in the S phase. Gemcitabine (Gemzar). As with fluorouracil and other analogues of pyrimidines, the drug replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. It is given iv, and is the first line treatment for small lung cancer

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