Anticancer drugs methotrexate

Anticancer drugs Methotrexate Doxorubicin Daunorubicin Epirubicin Etoposide Vincristine Vinblastine Paclitaxel Iiinotecan... 

Inhibitors. Aside from its role in providing reduced folate coenzymes for cells, this enzyme has attracted a great deal of attention because it appears to be a site of action of the important anticancer drugs methotrexate (amethopterin) and aminopterin.293 364 365 These compounds inhibit dihydrofolate reductase in concentrations as low as 10 8 to 10 9 M. Methotrexate is also widely used as an immunosuppresant drug and in the treatment of parasitic infections. 

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5,N 10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33-2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5,N 10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 55 Cancer Chemotherapy). 

Dihydrofolate reductase (DR) is shown near the top of Figure 9.6. This enzyme catalyzes the reduction of H2folate to H4folate. DR is part of the cycle of reactions in the synthesis of thymidylic acid. The enzyme also catalyzes the reduction of folic acid to dihydrofolic acid and then to tetrahydrofolic acid. DR is the target of the anticancer drug methotrexate (MTX). MTX exerts its toxic effects more on rapidly... 

Anticancer drugs methotrexate, mitoxantrone, camptothecin analogs (SN-38, etc.), topotecan Glucuronide conjugates 4-methylumbeUiferone glucuronide, estradiol- 17-D-glucuronide... 

Pontinha, A.D.R., Jorgem S.M.A., Chiorcea-Paquim, A.-M., Diculescu, V.C., Oliveira Brett, A.M. In situ evaluation of anticancer drug methotrexate-DNA interaction using a DNA-electrochemical biosensor and AFM characterization. Phys. Chem. Chem. Phys. (PCCP) 13 (12) 5227-5234 (2011)... 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

Zerouga M, Stillwell W, Jenski LJ. Synthesis of a novel phosphatidylcholine conjugated to docosahexaenoic acid and methotrexate that inhibits cell proliferation. Anticancer Drugs 2002 13 301. 

Anticancer drugs Daunorubicin Topotecan 9-Aminocamptothecin SN-38 (iiinotecan metabolite) Epirubicin Mitoxantrone Methotrexate Imatinib Gefitinib (i)... 

Most anticancer drugs damage hair follicles and produce partial or complete alopecia. Patients should be warned of this reaction, especially if paclitaxel, cyclophosphamide, doxorubicin, vincristine, methotrexate, or dactinomycin is used. Hair usually regrows normally after completion of chemotherapy. 

Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treatment of meningeal metastases. Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced the incidence of recurrences in the CNS and has contributed to the cure rate in this disease. Daily oral doses of methotrexate are used for severe cases of the nonneoplastic skin disease psoriasis (see Chapter 41), and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis. 

Thymidylate synthase requires methylene tetrahydro-folate as a reductant and the reduction of dihydrofolate is also an important part of the process. In protozoa dihydrofolate reductase and thymidylate synthase occur as a singlechain bifunctional enzyme.f As has been pointed out in the main text, such folic acid analogs as methotrexate are among the most useful anticancer drugs. By inhibiting dihydrofolate reductase they deprive thymidylate synthase of an essential substrate. 

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