PURINE & PYRIMIDINE ANALOGS

• All purine analogs may cause immunosuppression on long-term use.
• Should be given cotrimoxazole for Pneumocystis prophylaxis.
• Drugs included:
  • 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), fludarabine phosphate & cladribine.

Important drug details:

1. 6-mercaptopurine (6-MP) & 6-thioguanine (6-TG):

• MOA:
  • Purine antimetabolites activated by hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) –> Resulting nucleotides –> Inhibiting several enzymes in purine biosynthesis & metabolism.
• 6-MP:
  • Metabolized by xanthine oxidase.
  • When administered along with allopurinol (xanthine oxidase inhibitor), 6-MP dose (also azathioprine) should be reduced to 1/4th of original dose.
• Uses:
  • Mainly for leukemias treatment (both acute leukemias & CML).
• Adverse effects:
  • Bone marrow suppression (dose-limiting toxicity).
  • Hepatotoxicity.

2. Fludarabine phosphate:

• DOC for chronic lymphocytic leukemia (CLL).
• Severe pulmonary toxicity – Combination of pentostatin with Fludarabine.

3. Cladribine (adenine analogs):

• Resistant to degradation by adenosine deaminase.
• DOC for hairy cell leukemia treatment.

II) PYRIMIDINE ANALOGS:

• Drugs included: 
  • Cytarabine (cytosine arabinoside), 5-fluorouracil (5-FU), capecitabine, gemcitabine, 5-azacytidine & decitabine.

Important drug details:

1. Cytarabine:

• Single most effective agent for induction of remission in AML.
• MOA: 
  • Activated by kinases to form arabinoside CTP
  • Arabinoside CTP – DNA polymerase inhibitor.
• Adverse effect: 
  • Neurotoxicity (ataxia & peripheral neuropathy) – High dose.

2. 5-FU:

• MOA: 
  • Converted to 5’-dUMP inhibiting TS.
  • Causes single strand breaks thus affecting both DNA & RNA.
  • 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD).
• Metabolism:
  • Conversion to CO (major route of metabolism) & elimination by respiratory pathway.
  • Leucovorin augments of 5-FU action.

3. Capecitabine:

• Oral pro-drug of 5-FU.
• Can cause hyperbilirubinemia.
• Adverse effects:
  • Capecitabine & 5-FU: Causes hand and foot syndrome (a form of erythromelalgia manifested as tingling, numbness, pain, erythema, swelling and increased pigmentation).

4. Thiopurines (6MP & 6-TG): Metabolized by thiopurine methyltransferase 2 (TPMT).

5. Gemcitabine:

• Very potent radiosensitizer.
• DOC for pancreatic cancer.

6. 5‘-Azacytidine:

• MOA: Acts by DNA hypomethylation.
• Approved for myelodysplasia treatment.