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Antimetabolites in cancer chemotherapy


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Summary of Anti metabolites in Cancer Chemotherapy

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Antimetabolites in cancer chemotherapy

  2. 2. 1. ANTIFOLATES Methotrexate  Is a folic acid analog that binds with high affinity to the active catalytic site of DHFR.  This results in inhibition of the synthesis of tetrahydrofolate (THF).  Inhibition of metabolic processes interferes with the formation of DNA, RNA, and key cellular proteins.
  3. 3. Resistance 1. Decreased drug tr’port via the reduced folate carrier or folate receptor protein, 2. Decreased formation of cytotoxic MTX polyglutamates,. 3. Increased levels of the target enzyme DHFR through gene amplification 4. Altered DHFR protein with reduced affinity for MTX.
  4. 4. PK  administered by the IV, intrathecal, or oral route.  Bioavailability is saturable and erratic at doses greater than 25 mg/m2  Renal excretion is the main route of elimination  Care must be taken when MTX is used in the presence of drugs such as aspirin, nonsteroidal anti-inflammatory agents, penicillin, and cephalosporins.  These agents inhibit the renal excretion of MTX.
  5. 5. Antimetabolites: Clinical activity toxicities
  6. 6. Pemetrexed  Is a pyrrolopyrimidine antifolate analog. Has activity in the S phase of the cell cycle. transported into the cell via reduced folate carrier Requires activation by FPGS to yield higher polyglutamate forms MOA is inhibition of thymidylate synthase.  Approved for use in comb with cisplatin in the treatment of mesothelioma,  Mainly excreted in urine.  Vit sup with folic acid and vitamin B 12 appear to reduce toxicities.
  7. 7. Pralatrexate  A 10-deaza-aminopterin antifolate analog.  T’ported into the cell via the reduced folate carrier (RFC) and requires activation by FPGS to yield higher polyglutamate forms.  Excreted in the urine MOA 1. Inhibits DHFR, 2. Inhibits enzymes in de novo purine nucleotide biosynthesis. 3. Inhibits thymidylate synthase.  Treatment of relapsed or refractory peripheral T- cell lymphoma.
  8. 8. 2. FLUOROPYRIMIDINES 5-Fluorouracil  Inactive in its parent form and requires activation  MOA: inhibition of DNA synthesis through “thymineless death.” o Incorporat into cellular DNA, resulting in inhibition of DNA synthesis and function  Treatment of colorectal cancer.  Solid tumors, eg cancers breast cancer, stomach, pancrea s, esophagus, liver, head and neck, and anus.
  9. 9. Capecitabine  Fluoropyrimidine carbamate prodrug  Undergoes extensive metabolism in the liver.  Converted to 5-FU directly in the tumor  Used in the treatment of metastatic breast cancer.  Approved for use in adjuvant therapy of stage III and high-risk stage II colon cancer .  For treatment of metastatic colorectal cancer as monotherapy.  Main toxicities include diarrhea and the hand- foot syndrome.
  10. 10. 3. DEOXYCYTIDINE ANALOGS Cytarabine  An S phase-specific antimetabolite that  converted by deoxycytidine kinase to the 5'-mononucleotide to di and tri.  Ara-CTP triphosphate is the cytotoxic metabolite. MOA: competitively inhibits DNA polymerase-α & β, resulting in blockade of DNA synthesis and DNA repair, respectively.  Incorporation into DNA leads to interference with chain elongation  Use for hematologic malignancies
  11. 11. Gemcitabine  A fluorine-substituted deoxycytidine analog.  Phosphorylated by the enzyme deoxycytidine kinase to the mono, di & triphosphate nucleotide forms.  MOA  Inhibition of DNA polymerase-α & β, resulting in blockade of DNA synthesis & repair.  Incorporation of triphosphate into DNA, results in chain termination.
  12. 12. 4. PURINE ANTAGONISTS  6-Thiopurines  6-Mercaptopurine (6- MP) was the first of the thiopurine analogs  Used primarily in the treatment of childhood acute leukemia.  6-MP is inactive in its parent form.  Inhibits several enzymes of de novo purine nucleotide synthesis.  The monophosphate form is metabolized to the triphosphate  Which can then be incorporated into both RNA and DNA.
  13. 13. MOA of 6-mercaptopurine and 6-thioguanine.
  14. 14. Fludarabine  Phosphorylated intracellularly by deoxycytidine kinase to the triphosphate.  The triphosphate metabolite interferes with DNA syn & repair thru’ inhibition of DNA polymerase α & β.  The diphosphate metabolite inhibits ribonucleotide reductase  Induces apoptosis in susceptible cells.  Used mainly treatment of low-grade non- Hodgkin’s lymphoma & chronic lymphocytic leukemia
  15. 15. Cladribine  Purine nucleoside analog with high specificity for lymphoid cells.  Inactive in parent form,  Phosphorylated by deoxycytidine kinase to the mono & metabolized to the triphosphate.  The triphosphate metabolite interferes with DNA synthesis & repair by inhibiting DNA polymerase-α& β  indicated for treatment of hairy cell leukemia, CLL and low-grade non-Hodgkin’s lymphoma.  immunosuppressive effects.
  16. 16. THE END Calmness of mind is one of the beautiful jewels of wisdom Dans