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Antineoplastic agents, analogs of pyrimidine bases

The analogs of pyrimidine bases used as antineoplastic are 5-fluoro-uracil, cytarabine and gemcitabine.

Fluorouracil or 5-FU

In 5-FU the fluorine atom, which replaces an hydrogen atom of the pyrimidine nucleus, has a volume close to that of hydrogen, but a very different chemical reactivity, which induces metabolic disturbances in the biosynthesis of DNA and RNA.

5-FU is converted into active metabolites which are incorporated in the biosynthesis of nucleic acids and disturb it. It is metabolized into:

  • 5-fluorodeoxyuridine monophosphate, 5-FdUMP, which, by constituting a ternary complex with the N-methylene-tetrahydrofolate (folinic acid) and thymidylate synthase, blocks the synthesis of thymidine and consequently that of DNA, impairing cell multiplication. The formation of this ternary complex 5-FdUMP- folinic acid-enzyme explains why the combination of folinic acid and 5-FU potentiates the inhibition of thymidylate synthase.
  • FU-monophosphate, FUMP, then into FU-triphosphate, FUTP, which, incorporated in the place of uracil in RNA, elicits misreadings of the genetic code.
  • inactive metabolite by dihydropyrimidine dehydrogenase, similarly to uracil. In people having a deficient in this enzyme the efficacy and also the toxicity of 5-FU is very increased and its dosage must be reduced.

5-fluorouracile, cytarabine and gemcitabine

On a pharmacokinetic level, 5-FU is administered by intravenous route, has a very short plasma half-life, approximately 15 minutes, is taken up preferentially by tissues with rapid growth: tumor cells, bone marrow, intestinal mucosa. 5-FU passes rather well into the cerebral spinal fluid. 5-FU and its metabolites are eliminated in the urines and, after degradation, by respiratory tract in the form of CO2.

The principal clinical indications of 5-FU are the tumors of the digestive tract, breast, ovary, head and neck…

Cream is used for the treatment of senile keratosis and superficial basal cell carcinoma.

Its adverse effects are common to the majority of the antineoplastic agents:

5-fluorodeoxyuridine is also used in therapeutics in some countries.

Capecitabine

Capecitabine is a prodrug which after administration by oral route is converted into 5-FU.

Capecitabine is hydrolyzed by the hepatic carboxylesterase into 5 ' - DFCR (5 ' - deoxy-5-fluorocytidine) then in 5 ' DFUR (5 ' - deoxy-5-fluorocytidine) by cytidine deaminase and finally in 5-FU by the pyrimidine nucleoside phosphorylase, enzyme present in tumors.

Conversion of capecitabine into 5-FU

Capecitabine (Xeloda*) is indicated in the metastatic colorectal cancer and breast cancer topically advanced or metastatic.

Tegafur-uracil

Tegafur-uracil is an association of tegafur, prodrug for 5-FU and uracil, inhibitor of dihydropyrimidine dehydrogenase, enzyme involved in the inactivation of 5-FU. Tegafur-uracil (UFT*) is used, in combination with folinic acid, in the treatment of metastatic colorectal cancer.

Below is an overview of metabolism and effects of 5-FU, capecitabine and tegafur-uracil.

Conversion of capecitabine and tegafur into 5-FU


Métabolism and effects of 5-FU (d = deoxy, U = uridine, FU = fluorouridine, MP = monophosphate, DP = diphosphate, TP = triphosphate, TS = thymidilate synthase, DPD = dihydropyrimidine déhydrogenase)

Notice

Flucytosine or 5-fluorocytosine (Oncotil*) is the only structural analog of pyrimidine bases used, generally in combination, for the treatment of severe candidiasis, cryptococcosis, chromomycosis, certain aspergilloses.

Fluorocytosine is active on the microorganisms which have the enzymatic equipment, cytosine deaminase, able to transform it into 5-fluoro-uracil which is the active metabolite. In theory the human cells have not this possibility but the intestinal flora could have it and flucytosine could sometimes give hematological disorders in addition to the digestive disorders.

Cytarabine

Cytarabine, also called cytosine arabinoside or Ara-C, is a structural analog of deoxycytidine.

The structural modification of cytarabine is located not on the pyrimidine base but on the ribose. In normal ribose, the two OH groups are in cis position, whereas in cytarabine, they are in trans position, which impairs the rotation of the ribose nucleus. The incorporation of the Ara-C in DNA, after its phosphorylation in mono, di and triphosphates, Ara-CMP, Ara-CDP and Ara-CTP, disturbs dimensional structure and the functioning of DNA.

Cytarabine (DepoCyt*) is one of the antimetabolites the most used in acute myeloid leukemias and acute lymphoblastic leukemias.

Resistance to cytarabine can result, among other possibilities, from the failure of its transformation into cytarabine triphosphate, the active metabolite.

To the usual toxic effects of the antineoplastic agents, hematological and digestive, it is necessary to add cerebellar disorders, nystagmus, dysarthria and ataxia, which appear especially at high doses. Cytarabine and 5-fluoro-uracil are contraindicated during pregnancy and lactation.

Azacitidine

Azacitidine (Vidaza*) is an antimetabolite having properties close to those of cytarabine. It is used in the treatment of myelodysplastic syndromes .

Decitabine

Decitabine (Dacogen*) is a molecule structurally related to azacitidine. Azacitidine and decitabine are also classified as inhibitors of DNA methyl transferase.

Gemcitabine

Gemcitabine or diflurodeoxycytidine is a pyrimidine analog where two fluorine atoms replace two hydrogen atoms of the deoxyribose ring. Like the molecules of the same type, gemcitabine is converted into phosphate metabolites which are incorporated in the metabolism of pyrimidine bases and disturb DNA synthesis.

Gemcitabine (Gemzar*) is used in cancer therapy: non-small cell lung cancer, pancreatic cancer, bladder cancer and metastatic breast cancer.

Its adverse effects are hematological, gastrointestinal, pulmonary (pulmonary fibrosis), renal (proteinuria, hematuria).

3-D model of gemcitabine, giving a better idea of its spatial aspect
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