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23 Cards in this Set
- Front
- Back
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Describe the general process of DNA synthesis.
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Pyrimidines precursors --> Pyrimidines --> Ribonucleotides --> Deoxyribonucleotides --> DNA --> RNA --> Protein
Purine precursors + Folate --> Inosine monophosphate (IMP) --> Ribonucleotides --> Deoxyribonucleotides --> DNA --> RNA --> Protein |
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How do anti-metabolites work?
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They inhibit the synthesis of nucleotides, which act as the building blocks for both DNA and RNA.
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Name the two Purines.
Name the two Pyrimidines. |
Purines = AG
Pyrimidines = CUT |
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AGCUT are the bases
Nucleosides are the base + a sugar (either ribose or deoxyribose) Nucleotides are the base + a sugar + a mono, di or triphosphate |
Ribonucleotide (RNA) is the base + ribose + a phosphate group
Deoxyribonucleotide (DNA) is the base + deoxyribose + a phosphate Nucleoside has no phosphate gropu Nucleotide has a phosphate group |
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What specific chemical conversions are dependent on Folate?
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The formation of Inosinate Monophosphate in Purine synthesis as well as the conversion of dUMP (deoxyuridylate monophosphate) to dTMP (deoxythymidylate monophosphate) in Pyrimidine synthesis
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In Purine synthesis, IMP is created and converted to either AMP or GMP and then dAMP and dGMP.
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In Pyrimidine synthesis, UMP is created and converted to CMP which is converted to dCMP or dUMP, which is then converted to dTMP via Dihydrofolate Reductase.
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What enzyme is responsible for the conversion of Ribonucleotides (ATP, GTP, UTP, and CTP) to Deoxyribonucleotides (dATP, dGTP etc.)?
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Ribonucleotide reductase
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The conversion from dUMP to dTMP is a methylation catalyzed by what enzyme and methyl donor?
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Thymidylate synthase
Methyl donor = methylene-tetrahydrofolate |
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When Methylene-tetrahydrofolate donates the methyl group, it is converted to dihydrofolate and must be reduced to tetrahydrofolate by dihydrofolate reductase and then converted to MTHF to again serve as the cofactor.
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Inhibition of Dihydrofolate Reductase prevents the regeneration of tetrahydrofolate and therefore the conversion of dUMP to dTMP resulting in an insufficient level of dTMP for DNA replication.
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Describe the 3 most general classes of antineoplastic agents by how they function.
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Anti-metabolites = either inhibit the enzymes involved in nucleotide synthesis, or are incorporated as analogues into DNA and result in chain termination. These usually act during the S phase during DNA replication.
Cytotoxic agents = Modify DNA structure or damage DNA. Include alkylating agents, platinum compounds, bleomycin and topoisomerase inhibitors Inhibitors of microtubule assembly/depolymerization. Interfere with mitosis. |
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dTMP is converted from dUMP via Thymidylate synthase and the cofactor methylene-tetrahydrofolate. What agent is an inhibitor of Thymidylate synthase?
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5-Fluorouracil
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What specific neoplasms is 5-Flurouracil used for?
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Carcinomas of the Breast and GI tract
This agent depletes thymidylate from normal cells as well as cancer cells and is highly toxic. |
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What is the orally available prodrug version of 5-FU?
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Capecitabine
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What cancer's is this drug approved for?
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Metastatic colorectal cancer and second line for metastatic breast cancer.
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What is Leucovorine?
What is it used for? |
A combination of 5-FU and Folinic acid used as first line therapy for colorectal cancer. This agent works better than 5-FU alone as increasing the levels of MTHF potentiates the effects of 5-FU.
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What is Pemetrexed?
What is it used for? |
A folate analogue that is transported into cells and inhibits thymidylate synthase.
It is approved in the second line treatment of nonsmall cell lung cancer as well as in combination with cisplatin in the treatment of malignant pleural mesothelioma. |
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What is 6-Mercaptopurine?
How does it work? Azathioprine? |
6-Mercaptopurine is an inosine analogue that inhibits the interconversions among purine nucleotides. Once having entered the cell, 6-Mercaptopurine is converted to T-IMP, which inhibits the enzymes that convert iMP to AMP and GMP, including IMP dehydrogenase. This causes a marked decrease in AMP and GMP levels.
Azathioprine is the prodrug of 6-Mercaptopurine. |
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What is 6-Mercaptopurine used for?
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Acute Lymphoblastic Leukemia
Its activity against lymphocytes makes it useful as an immunosuppressive agent. Azathioprine is more effect for 6-Mercaptopurine in this application. |
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What drug interaction is vital to remember when giving 6-Mercaptopurine or Azathioprine?
Describe why this is. |
The effectiveness and toxicity of 6-Mercaptopurine are potentiated by allopurinol.
Allopurinol inhibits xanthine oxidase |
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How does Hydroxyurea work?
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By inhibiting ribonucleotide reductase.
This is the enzyme that converts ribonucleotides to deoxynucleotides |
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What is hydroxyurea typically used for?
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It is approved for use in the treatment of adult sickle cell disease and certain neoplastic diseases.
It has been shown to increase the expression of the fetal isoform of hemoglobin HbF, which inhibits the polymerization of sickle hemoglobin. |
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Name the agents that are incorporated into DNA.
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These are called anti-metabolites
Thioguanine Fludarabine Phosphate Cladribine Cytarabine 5-Azacytidine Gemcitabine |
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Describe what each of these drugs are used for.
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Thioguanine - Acute Myelocytic Leukemia
Fludarabine Phosphate - Chronic Lymphocytic Leukemia and B-cell Lymphoma Cladribine - Hairy cell leukemia Cytarabine - Acute Myelocytic Leukemia 5-Azacytidine - Myelodysplasia Gemcitabine - Several solid tumors including pancreatic cancer and nonsmall cell lung cancer |
