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Methotrexate, 5-Fluorouracil, Purine Antagonists and Antibiotics Used in Cancer Chemotherapy


Anti metabolites are used to inhibit different metabolic pathways, as rate of metabolism and required metabolites are much higher for malignant cells.

3 groups are present:


Mechanism of Action
  • Inhibits dihydrofolate reductase – blocks conversion to tetrahydrofolate for synthesis of many cellular components.        
  • Interferes with synthesis of thymidylate, purine, serine, methionine, proteins, RNA, DNA


  • Given orally, I/V or by intrathecal route
  • In cells, it is converted to methotrexate polyglutamate by addition of glutamate residues required for therapeutic effects.
  1. decrease in permeability into cells
  2. decrease in formation of polyglutamate in cells
  3. alteration in target enzyme dihydrofolate reductase (decreased affinity or increased production)
  4. formation of P170 glycoprotein –efflux pumps pump out drug from cells

       1.  anticancer (head & neck, breast, CNS, bladder osteogenic sarcoma, NH lymphoma)

2. rheumatoid arthritis
3. psoriasis (autoimmune)


General / mucositis

– Lucovorin rescue (increased levels of methotrexate lead to leucovorin reduced formation so folates are given, called leucovorin rescue)


Purine analog


  • Given I/V, it is a prodrug, inside body converted into active metabolites, fluorouridine monophosphate
  • Metabolized and dihydropyridine dehydrogenase in some is completely or partially deficient, thus toxicity may be seen.

colorectal ( FOLFOX)

– solid tumors (breast, stomach, pancreas, esophagus, liver, head & neck, anus)

  1.  Bone marrow suppression
  2. GIT toxicity
  3. Head foot syndrome of skin
  4. Neurotoxicity
Mechanism of Action & Pharmacological effects

Converted into

Different metabolites affect DNA, RNA, protein synthesis and function.

  1. One is 5 FdUMP having affinity for thymidylate synthase and reduced folate. It inhibits synthesis of thymidylate which is in turn responsible for DNA synthesis and function.
  2. FUTP interferes with RNA processing and translation.
  3. FdUTP directly incorporates into DNA inhibiting DNA function.

Purine Antagonists


2 agents are commonly used:

1.      6-Mercaptopurine
  • Prodrug –different metabolites  6-thioinosinic acid.
  • Both monophosphate and triphosphate forms produce effect, interfere with purine synthesis, ultimately DNA, RNA synthesis is affected.
  • Inactivated by xanthine oxidase into 6-thiouric acid–
  • Use –ALL

When used in blood cancers (leukemia) in which rapid cell turn over occurs, leading to increased uric acid and allopurinol is given, which is xanthine oxidase inhibitor, toxicity may be seen. 50-70% dose reduction is done.

2.      6-Thioguanine
  • Has no drug interaction with allopurinol, is metabolized by TPMT (thiopurine methyltransferase). Some patients are genetically deficient in this enzyme, so toxicity may be seen.


  • Produced by Streptomyces peucetius var caesius
Mechanism of Action
  1. Cause Cross linking of DNA strands
  2. Cause DNA breaks
  3. Inhibit Topoisomerase II, when DNA has to undergo replication it exists in supercoiled form, for the purpose of uncoiling certain breaks in DNA strand are made, which are then resealed. Topoisomerase II is responsible for breaks in double stranded DNA, thus no brakes are produced
  4. Change in membrane fluidity & ion transport, disrupting cellular functions
  5. Produce oxygen free radicals – cardiotoxicity

Pharmacokinetics – I/V



– Mucositis

– Cardiotoxicity

I. acute –first 2,3 days in form of arrhythmias, changes in ECG, myocarditis, pericarditis

II. chronic ­–occurs late as dilated cardiomyopathy, cardiac failure

For prevention, patient is administered iron chelating agents. Dexrazoxane used because formation of free radicals is iron dependent, thus no iron is available.

Radiation recall reaction

If patient is already undergoing radiotherapy leads to redness, erythema, acne.


1. Cancer – breast, endometrium, ovary, testicle, thyroid, stomach, liver,lung, bladder, head & neck, soft tissue sarcoma

2. Pediatric cancers – neuroblastoma, Ewing’s sarcoma

3. Hematological cancers – ALL / AML / CML / M. myeloma /  lymphoma

  • Antitumor antibiotic, when given, in cells converted into compounds which acts like alkylating agents.
  • Hypoxic tumor stem cells –favourable areas for reduction of mitomycin
  • Drug of choice with radiation therapy to kill hypoxic stem cells
  1. Squamous cell Carcinoma – cervix / anus
  2. Breast / Gastric / Pancreatic
  3. Administered intravasically for superficial bladder Cancer

Antitumor antibiotic, small peptide having 2 binding sites:

  1. DNA
  2. Iron

Mechanism of Action – DNA-bleomycin-Fe complex is formed which is responsible for breaks

Usesskin, cervix, vulva, head/neck, germ cell, Lymphomas

Toxicity – Pulmonary, cough, dyspnea.

On examination, inspiratory crackles are heard.

On X ray chest, infiltrates are seen. 

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