Chemotherapy folic acid antagonists

The most critical one-carbon transfer involved in DNA synthesis requires A, /V" -methylcne-THFA as the methylating coenzyme responsible for converting uridylic acid to Ihymidylic acid. Interestingly, some folic acid antagonists useful in cancer chemotherapy (c.g.. methotrexate (.see Chapter I2 ) interfere with DNA synthesis by inhibiting this methylaiion step. ... 

Indications Antidote for folic acid antagonists, various cancersin combination with other medications Category Antidote Chemotherapy modulating agent Half-life 4-8 hours... 

Folic Acid Antagonists - Methotrexate (MTX), folinic acid and ara-C were used sequentially with positive results in patients who had become resistant to conventional chemotherapy.18 The AT-3000 MTX resistant line of S-180 cells were found to have at least 150 times more dihydrofolate reductase than MTX sensitive cells.28 Similar data were obtained with MTX resistant hamster cells.21... 

Pemetrexed is a folic-acid antagonist that disrupts folate-dependent metabolic processes essential for cell replication. It is indicated in combination with cisplatin for the treatment of malignant pleural mesothelioma in patients whose disease is unresectable or who are otherwise not candidates for curative surgery and as a single agent for the treatment of locally advanced or metastatic non-small-cell lung cancer after prior chemotherapy. 

Pteridines are also used as pharmaceuticals. Triamterene 15 is a diuretic that promotes excretion of Na" and retains K+. The folic acid antagonist methotrexate 16 (amethopterin) is of considerable importance as an antineoplastic agent in cancer chemotherapy. 

One of the earliest known folic acid antagonists that proved to be useful in the chemotherapy of cancer, was aminopterin (4-aminofolic acid) and a closely related derivative, methotrexate (Fig. 6). now used as a highly effective agent in the treatment of at least two varieties of cancer. 

Possibly the most significant discovery in the metabolism of aromatic azo compounds had implications that heralded the age of modem chemotherapy. It was shown that the bactericidal effect of the azo dye Prontosil in vivo was in fact due to the action of its transformation product, sulfanilamide, which is an antagonist of 4-aminobenzoate that is required for the synthesis of the vitamin folic acid. Indeed, this reduction is the typical reaction involved in the first stage of the biodegradation of aromatic azo compounds. 

Antimetabolites compete with normal endogenous substrates and cause inhibition of the processes that require those substrates. Examples include purine and pyrimidine antagonists, which prevent nucleic acid replication and cellular division in cancer chemotherapy. Another example is methotrexate, which can inhibit folic acid metabolism. 

Since folic acid is critical to the formation of purines, antagonists of folic acid metabolism are used as chemotherapy drugs to inhibit nucleic acid synthesis and cell growth. Rapidly dividing cells, such as those found in cancer and tumors, are more susceptible to these antagonists. 

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