Anticancer Antimetabolites Drugs – Classification, Uses, Doses, Side Effects

  • Structural analogues of naturally occurring substances required for specific biochemical reactions.
  • Fraudulently substitute themselves for purines or pyrimidines or they can inhibit critical enzymes that are involved in nucleic acid synthesis.
  • They affect DNA, RNA, protein synthesis and cellular replication.
  • Interfere with nucleic acid synthesis rather than preformed acids. Have little effect in G0 phase and maximal effect in S phase
  • Dosing plateau at clinical doses due to complete target inhibition and phase specificity
  • Not associated with delayed or prolonged myelosupression
  • Minimial risk of leukemogenesis or carcinogenesis


  • Folate antagonists
      • Methotrexate (MTX)
      • Pemetrexed
      • Aminopterin
      • Trimetrexate
      • Pralitrexate
  • Pyrimidine antagonists
      • Cytarabine
      • Gemcitabine
      • Capecitabine
      • 5-Fluorouracil
      • Tegafur Uracil
  • Purine antagonists
      • 6-Mercaptopurine
      • 6-Thioguanine
      • Azathioprine
  • Adenosine Deaminase inhibitors
      • Fludarabine
      • Clofarabine
      • Cladribine
      • Nelarabine
      • Pentostatin

Folate Antagonists


methotrexate-antimetabolite folate antagonist


  • Methotrexate (4-amino-N methyl pteroylglutamic acid)is a potent competitive antagonist of enzyme dihydrofolate reductase(DHFR).
  • It is structurally similar to folic acid.
  • Differs from folic acid in only two areas
      • Amino group in the 4- carbon position  takes the place of hydroxyl group
      • Methyl group at the N-(10) position substitutes for the hydrogen atom.

Mechanism of Action

  • Competing with folate for uptake into cells by inhibiting folate coenzymes
  • Inhibiting one or more reactions mediated by folate coenzymes
  • Inhibitor of Glycinamide ribonucleotide transformylase (GARFT) and Aminoimidazole carboxamide transformylase (AICARFT). Both use the formyl groups of the reduced folate N(10)-formyl tetrahydofolate to initiate synthesis of adenosine and guanosine.
  • Inhibition of methionine biosynthesis causing increased level of homocysteine and SAH which is an potent inhibitor of folate dependent reactions
  • ??Antiangiogenic properties



  • Rapidly and well absorbed at low doses (<25 mg/m2)
  • 60% bioavailability (BA)
  • Incomplete at large doses
  • Time to peak concentration is 1 to 2 hours by oral route and 10 to 30 minutes by parenteral route


  • Very water soluble molecule
  • Primarily distributes to total body water
  • Low volume of distribution; 0.4 – 0.8 L/kg
  • 50% protein bound
  • Intracellular concentrations reach steady state in <30 minutes
  • Penetrates slowly into 3rd space fluids (pleural effusions, ascites). Subsequently exits slowly. This causes prolonged MTX exposure.
  • Poor distribution into CNS. High CSF levels can be obtained by IT administration. Enhanced levels after CNS irradiation. Blood-brain barrier returns to normal after ~ 4 weeks.


  • By liver to 7-OH Mtx by hepatic aldehyde oxidase
  • Extent of other routes of metabolism unknown
  • <10% degradation by intestinal flora to DAMPA by carboxypeptidase
  • Third metabolic product is MTX polyglutamate. Can be found in circulating RBCs and compliance can be assessed but not found in plasma or urine because of GGH activity


  • Renal excretion accounts for 44 to 100%
  • 50-80% of IV dose eliminated unchanged in urine during first 12 hours
  • Not dialyzable
  • More than creatinine clearance because of active secretion from proximal tubule
  • Biliary excretion accounts for about 10%

Mechanism of Resistance

  • Reduced folate carrier
  • Differing ability to form long chain Mtx polyglutamates
  • Increased expression of DHFR
  • Lack of Rb protein
  • Mutation in MDR protein and ABCG 2


  • Low-dose – <50 mg/m2
  • intermediate-dose-50- 500 mg/m2
  • high-dose – ≥500 mg/m2


Drug Interactions

  • Aspirin, penicillins, probenecid, nonsteroidal anti-inflammatory agents,and phenytoin- inhibit renal excretion & increased MTX
  • Leucovorin & Thymidine- rescues the host toxic effects of methotrexate and may also impair the antitumor activity
  • Increases warfarin action by displacing warfarin from protein

Treatment Regimens

  • Trophoblastic neoplasms
      • 15 – 30mg/day PO/IM for 5 days, repeat in 7 days for 3 – 5 courses
  • Mycosis fungoides (cutaneous T-cell lymphoma)
      • 5 – 10mg PO daily
        • 50mg IM once weekly or 25 mg IM twice weekly
  • Bladder cancer (part of MVAC)
      • 30mg/m2 IV on day 1, 15, and 22 every 4 weeks
  • Breast Cancer (part of CMF)
      • 40mg/m2 IV on Day 1 and 8 every 3 – 4 weeks
  • Primary CNS Lymphoma
      • 8gm/ m2 iv over 4hours every 2 week till CR or upto 8 cycles followed by monthly infusion for 11 months
  • Osteosarcoma
      • 8 – 12gm/m2 IV every 4 weeks
  • Intrathecal use
      • 12 mg IT (age > 3 years old)

Adverse Effects/Toxicities

Bone Marrow Suppression

  • Neutropenia – rarely Grade III or IV
    • Nadir: ~ day 10
    • Duration: 14 – 21 days
    • More prevalent at higher doses
  • Anemia
  • Thrombocytopenia

Emetogenic Potential

  • Very low (< 10%) – </=50mg/m2
  • Low (10% to 30%) – 50-250mg/m2
  • Moderate (30 to 60%) – 250-1000mg/m2
  • High (60 to 90%) – >1000 mg/m2


  • Potential to precipitate in kidneys when using intermediate or high dose MTX
  • Hydration and alkalinization may be used to prevent precipitation of MTX in the renal tubules
  • Methylxanthines promote Mtx excretion

Mucositis and diarrhea

  • Onset 3 – 5 days after administration
  • Duration ~14 days


  • Acute elevations in transaminases and bilirubin. Usually returns to normal within 10 days.
  • Hepatic fibrosis in patients receiving chronic daily administration of methotrexate. Intermittent and less associated with weekly therapy. Possibly related to lipid deposition in the liver, exact mechanism unknown.

Dermatologic Effects

  • Rash, pruritis, photosensitivity, radiation recall

CNS Toxicity

  • Chemical arachnoiditis
      • Arises immediately after administration
      • Severe headaches, nuchal rigidity, vomiting, fever
  • Subacute form
      • Occurs after third or fourth course of IT therapy in ~10% of patients
      • Most common in adults with active meningeal leukemia
      • consists of motor paralysis, cranial nerve palsy, and seizures or coma
      • Change in therapy is absolutely indicated
      • Continued treatment with IT MTX may result in death
  • Chronic, demyelinating encephalopathy
      • Occurs primarily in children months to years after IT MTX therapy
      • Dementia, limb spasticity, and, in advanced cases, coma


  • Self-limiting lung process
  • Characterized by fever, cough, and interstitial pulmonary infiltrates
  • No current recommended therapy

High dose MTX therapy

  • Occasionally associated with acute, transient cerebral dysfunction
  • Paresis, aphasia, and behavioral abnormalities, and seizures
  • Symptoms occur within 6 days of MTX treatment
  • Completely resolve within 48 to 72 hours
  • Incidence: 4 – 15% of patients

Dose Adjustment

Dosage in renal impairment

  • Conventional-Dose MTX
    • 61 – 80 mL/min – Reduce dose by 25%
    • 51 – 60 mL/min – Reduce dose by 30%
    • 10 – 50 mL/min – Reduce dose by 50 – 70%
    • < 10 mL/min – Avoid use
  • High-dose MTX
    • < 60 mL/min – Avoid use

Dosage in hepatic impairment

  • Bilirubin < 3 mg/dL – No adjustment necessary
  • Bilirubin 3.1 – 5 mg/dL or AST > 180 – Reduce dose by 25%
  • Bilirubin > 5 mg/dL – Avoid use

Special Precautions

  • Doses between 100 – 500mg/m2 may require leucovorin rescue
  • Dose > 500 mg/m2 require leucovorin rescue
  • Factors associated with toxicity and delayed clearance
    • Renal dysfunction
    • “Third space” fluid (pleural effusions, ascites, gastrointestinal obstruction)
    • Hepatic dysfunction

Methods to Reduce Toxicity

Leucovorin Rescue

  • Goldin developed the rescuing normal cells from toxicity by giving reduced folates to bypass the metabolic block induced by MTX
  • 24 to 36 hrs after administration of MTX was able to prevent MTX-induced host toxicity without diminishing antitumor activity
  • To overcome competetive inhibition

Alternative Rescue Techniques

  • Alternatives are Extra corporeal removal by PD, Hemodialysis, hemoperfusion, charcoal hemofiltration, LV with Thymidine, carboxypeptidase G2
  • Removal of MTX by peritoneal dialysis is ineffective and other dialysis methods are of limited effectiveness
  • Glucarpidase (carboxypeptidase G2)
    • In Renal failure, exogenous carboxypeptidase G2 rapidly lower serum MTX levels
    • Single 50 u/ kg bolus IV over 5 min by 98 % in the first 30 minutes
    • MTX molecule is cleaved at the c-terminal glutamate residue into glutamate and the inactive metabolite DAMPA (2,4-diamino-N-methylpteroic acid)


aminopterin antimetabolite folate antagonist

  • Greater clinical potency
  • More efficient conversion to polyglutamates
  • Greater accumulation in cell
  • Increased bioavailability


trimitrexate-antimetabolite folate antagonist

  • Non classical antifolate
  • Enters cells by passive or facilated diffusion
  • With leucovorin, it selectively rescues normal cells
  • Mutation in DHFR may or may not be cross resistant
  • Mutation in P glycoprotein leads to resistance
  • Trimetrexate followed by 5FU and leucovorin leads to synergistic response in contrast to Mtx
  • Phase 3 studies show the combination results in delay of progression in colorectal cancer


pemetrexed-antimetabolite folate antagonist

  • Thymidylate synthetase inhibitor
  • Enters cells through RFC and an unique transporter present in mesothelioma
  • Metabolized to polyglutamate forms which leads to inhibition
      • Thymydylate synthetase
      • Glycinamide ribonucleotide formyltransferase,
      • DHFR,
      • 5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase,
      • C1-tetrahydrofolate synthase
  • Toxicity (myelosuppression, rash, etc) depends on serum homocysteine levels
  • Vit B12 and folic acid supplementation improves toxicity profile while maintaining anti-tumor activity

Pyrimidine Antagonists

Cytarabine (Ara-C)

cytarabine-antimetabolite pyrimidine antagonist

Mechanism of Action

  • Requires intracellular activation to the nucleotide metabolite ara-CTP. Antitumor activity of cytarabine is determined by a balance between kinase: deaminase
  • Incorporation of ara-CTP into DNA resulting in chain termination and inhibition of DNA synthesis and function.
  • Ara-CTP inhibits several DNA polymerases which then interferes with DNA synthesis, DNA repair and DNA chain elongation.
  • Ara-CTP inhibits ribonucleotide reductase, resulting in decreased levels of essential deoxyribonucleotides required for DNA synthesis and function.
  • Prolonged exposures of tumor cells to ARAC increase fraction of cells with “S” phase exposed to drug.- greater cytotoxicity


Absorption: less than 20% of dose absorbed by G.I.T.

Distribution: widely distributed into tissues

Elimination: It exhibit biphasic elimination; Initial half life of ten min.Secondary half life of almost 2-3 hrs.

Excretion: mainly excreted by kidney about 70-80% with 90%as metabolite and 10%as uncharged drugs

After S/c, I.m injection, peak plasma levels  are achieved after  20 to 60 minutes

CNS Pharmacokinetics

  • Achieves good concentration in CSF
  • Cytotoxic concentration is maintained for a long time
  • Little conversion to ara-U takes place in CSF
  • Elimination is proportional to CSF flow rate
  • IT dose:
      • 20mg <1year
      • 30mg 1-2yr
      • 50 mg 2-3yr
      • 70mg >3yr



Standard dose

100 mg/m2 /day IV on days 1–7 as a continuous IV infusion as induction chemotherapy for AML in combination with anthracycline


1.5–3.0 g/m2 IV q 12 hours for 3 days as a consolidation regimen for AML.

Rationale for High Dose

  • ARAC phosphorylation is the rate limiting step in its activation: this path becomes saturated at dose of 20 micro mol/L ( corresponds to 3gm/m2/12hr – 6 dose)
  • Any further increase in dose does not increase phosphorylation


10–30 mg intrathecal (IT) up to three times weekly in the treatment of leptomeningeal carcinomatosis.

Adverse Effects

  • Myelosuppression is dose-limiting. Thrombocytopenia > leukopenia are common. Nadir usually occurs by days 7–10, with recovery by days 14–21. 86% require platelet transfusion at high dose therapy. Megaloblastic anemia has also been observed
  • Nausea and vomiting. Mild to moderate emetogenic agent. Anorexia, diarrhea, and mucositis usually occur 7–10 days after therapy.
  • Cerebellar ataxia, lethargy, and confusion. Neurotoxicity develops in up to 10% of patients. Onset usually 5 days after drug treatment and lasts up to 1 week. In most cases, CNS toxicities are mild and reversible. Risk factors for neurotoxicity include high-dose therapy, age older than 40, abnormal renal function, and abnormal liver function.
  • Transient hepatic dysfunction with elevation of serum transaminases and bilirubin. Most often associated with high-dose therapy.
  • Acute pancreatitis.
  • Ara-C syndrome:  Described in pediatric patients and represents an allergic reaction to cytarabine. Characterized by fever, myalgia, malaise, bone pain, maculopapular skin rash, conjunctivitis, and occasional chest pain. Usually occurs within 12 hours of drug infusion. Steroids appear to be effective in treating and/or preventing the onset of this syndrome.
  • Pulmonary complications include non-cardiogenic pulmonary edema, acute respiratory distress and Streptococcus viridans pneumonia. Observed with high-dose therapy.
  • Erythema of skin, alopecia, and hidradenitis are usually mild and self limited.
  • Conjunctivitis and keratitis. Associated with high-dose regimens.
  • Seizures, alterations in mental status, and fever may be observed within the first 24 hours after IT administration.

Drug Interactions

  • Digoxin – Digoxin levels should be monitored closely while on therapy as ARAC decreases the oral bioavailability of digoxin, thereby decreasing its efficacy.
  • Cisplatin – ARAC enhances the cytotoxicity of cisplatin by inhibiting DNA repair mechanisms.
  • Methotrexate – Enhanced cytotoxicity on pretreatment with methotrexate as it enhances the formation of ara-CTP metabolites
  • L-Asparaginase – Increased risk of pancreatitis when L-asparaginase is given before ARAC
  • Fludarabine and/or hydroxyurea – Pretreatment with these potentiates the cytotoxicity of cytarabine by enhancing the formation of cytotoxic ara-CTP metabolites

Ara-C Analogs


(syn by SORM n colleagues in 1963)

  • Cell cycle–specific with activity in the S-phase. Requires activation to the nucleotide metabolite azacitidine triphosphate. Which  is misincorporated into DNA  and RNA, affecting their function.
  • Incorporation of azacitidine triphosphate into DNA, resulting in inhibition of DNA methyltransferases, which then leads to a loss of DNA methylation and gene reactivation. Aberrantly silenced genes, such as tumor suppressor genes, are reactivated and expressed..
  • Absorption: Not available for oral use and is administered via the SC and IV route.
  • The bioavailability of S/c azacitidine is 89% relative to IV azacitidine .
  • Elimination via deamination by cytidine deaminase, found principally in the liver but also in plasma, granulocytes, intestinal epithelium, and peripheral tissues.
  • Urinary excretion is the main route of elimination. T1/2 -4 hrs
  • FDA-approved for treatment of patients with myelodysplastic syndromes (MDS),  Recommended dose is 75 mg/m2 SC/IV daily for 7 days. Cycles should be repeated every 4 weeks. Minimum of 4 cycles
  • Toxicity: Myelosuppression with neutropenia and thrombocytopenia. GI toxicity in the form of nausea/vomiting, constipation, and abdominal pain. Renal toxicity with elevations in serum creatinine, renal tubular acidosis, and hypokalemia. Peripheral edema.
  • Requires activation to the nucleotide metabolite decitabine triphosphate. . Which is misincorporated into DNA  and RNA, affecting their function.
  • Administered only by the IV route.
  • Elimination pathways is via deamination.
  • FDA-approved for treatment of patients with MDS
  • The recommended dose is 15 mg/m2 continuous infusion IV over 3 hours repeated every 8 hours for 3 days. Repeated every 6 weeks. An alternative schedule is 20 mg/m2 IV over 1 hour daily for 5 days given every 28 days. treated for a minimum of 4 cycles.
  • Toxicity similar to azacytidine


gemcitabine-antimetabolite pyrimidine antagonist

Mechanism of Action

  • Cell cycle-specific : S-phase.
  • Requires intracellular activation by deoxycytidine kinase to the monophosphate form and then into cytotoxic triphosphate nucleotide metabolite (dFdCTP).
  • Pyrimidine inhibitor
  • Fluorine substituted deoxycytidine analogue causes inhibition of DNA synthesis and function.
  • Inhibits the enzyme ribonucleotide reductase, resulting in reduced DNA synthesis and function.
  • Incorporation into RNA resulting in alterations in RNA processing and mRNA translation.
  • Kills cells in S phase and blocks progression through G1-S
  • Transports through hENT pathway


  • Administered by the IV route
  • Distribution and half life depends upon the duration of infusion proportionally
  • With infusions <70 minutes, drug is not extensively distributed. In contrast, with longer infusions, drug is slowly and widely distributed into body tissues.
  • With short infusions <70 minutes, t1/2 ranges 30 to 90 minutes, while for infusions >70 minutes, t1/2 ranges 4–10 hours. Plasma clearance is also dependent on gender and age. Clearance is 30% lower in women and in elderly patients
  • Undergoes extensive metabolism by deamination, >90% of metabolite excreted in urine.
  • Plasma clearance is dependent on gender and age. Clearance is 30% lower in women and in elderly patients.

Mechanism of Resistance

  • Decreased expression of the anabolic enzyme deoxycytidine kinase.
  • Increased breakdown of drug by the catabolic enzymes cytidine deaminase and dCMP deaminase.
  • Decreased nucleoside transport of drug into cells.
  • Increased expression of ribonucleotide reductase


  • Pancreatic cancer—FDA-approved as monotherapy or in combination with erlotonib for first-line treatment of locally advanced or metastatic disease.
  • Non–small cell lung cancer—FDA-approved in combination with cisplatin for first-line treatment of inoperable, locally advanced or metastatic disease.
  • Breast cancer—FDA-approved in combination with paclitaxel for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy.
  • Ovarian cancer—FDA-approved in combination with carboplatin for patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.
  • Bladder cancer.
  • Soft tissue sarcoma.
  • Hodgkin’s lymphoma.
  • Non-Hodgkin’s lymphoma.


  • Pancreatic cancer: (alone) 1,000 mg/m2 i.v weekly x 7, followed by 1 week rest. Treatment then once weekly x 3 repeat every 28d. Or in combination with erlotinib, oxaliplatin,  cisplatin, capecitabine, irinotecan
  • Bladder cancer: 1,000 mg/m2 IV on days 1, 8, and 15 every 28 days in combination with cisplatin(GC)
  • Non–small cell lung cancer: 1,200 mg/m2 IV on days 1, 8, and 15 every 28 days in combination with cisplatin. Or vinorelbine, carboplatin, paclitaxel+ carboplatin

With Cisplatin and Radiation Therapy

  • Cisplatin—Gemcitabine enhances the cytotoxicity of cisplatin by increasing the formation of cytotoxic platinum-DNA adducts. Increased alopecia, nausea n vomiting, more myelosuppression, neurotoxicity n nephrotoxicity
  • Radiation Therapy—Gemcitabine is a potent radiosensitizer. With concurrent RT( given together or <7 day gap) can produce life threatening mucositis and pneumonitis


  • Myelosuppression is dose-limiting. Neutropenia more common than thrombocytopenia. Nadir occurs by days 10–14, with recovery by day 21. Modify dose with ANC > 1000, platelet >1 lakh:100% dose, ANC 500-1000, platelet 50-1,00,000 give 75% of full dose
  • Nausea and vomiting – Usually mild to moderate, occur in 70% of patients. Diarrhea and/or mucositis observed in 15%–20% of patients.
  • Flu-like syndrome manifested by fever, malaise, chills, headache, and myalgias. Seen in 20% of patients. Fever, in the absence of infection, develops in 40% of patients within the first 6–12 hours after treatment but generally is mild.
  • Transient hepatic dysfunction with elevation of serum transaminases and bilirubin.
  • Pulmonary toxicity in the form of mild dyspnea and drug-induced pneumonitis. ARDS has been reported rarely.
  • Infusion reaction presents as flushing, facial swelling, headache, dyspnea, and/or hypotension. Usually related to the rate of infusion and resolves with slowing or discontinuation of infusion.
  • Mild proteinuria and hematuria. In rare cases, renal microangiopathy syndromes, including hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported. Should be stopped with 1st sign of HUS- falling Hb, platelet, raising s.creat, BUN,LDH and s.bilirubin
  • Maculopapular skin rash generally involving the trunk and extremities and pruritus. Alopecia is rarely observed.
  • Use with caution in person with pre existing renal or hepatic disease.

5 Fluorouracil (5FU)

5 flurouracil-antimetabolite pyrimidine antagonist

Mechanism of Action

  • Fluoropyrimidine synthesized by Dr. Charles Heidelberger in 1957
  • Antimetabolite
  • Cell cycle specific, “S” phase
  • Enters the cell by facilitated uracil transport system

Effect on DNA

Requires Short term exposure and is Cell cycle dependent

  • Enters cells via uracil transport mechanism
  • Anabolised to cytotoxic nucleotide forms
  • Incorporation into DNA
  • Inhibition of DNA synthesis and function

Effect on RNA

Requires Long time exposure and is Cell cycle independent

  • Incorporation into RNA
  • Alterations in RNA processing and mRNA translation
  • Inhibition of TS
  • Depletion of Deoxythymidine triphosphate
  • Interfering with DNA biosynthesis and repair.

Other Mechanisms

  • Genotoxic stress resulting from TS inhibition
  • Fas signalling pathway

Mechanism of Resistance

  • Increased expression of thymidylate synthase
  • Alterations in thymidylate synthase with decreased binding affinity of enzyme for FdUMP
  • Decreased incorporation of 5-FU into RNA.
  • Decreased incorporation of 5-FU into DNA.
  • Increased activity of DNA repair enzymes, uracil glycosylase and dUTPase.
  • Decreased levels of reduced folate substrate 5, 10 methylenetetrahydrofolate for thymidylate synthase reaction
  • Increased expression of dihydropyrimidine dehydrogenase.



Oral absorption is variable and erratic


After IV administration, 5-FU is widely distributed to tissues with highest concentration in GI mucosa, bone marrow, and liver. Penetrates into third-space fluid collections such as ascites and pleural effusions. Crosses the blood-brain barrier and distributes into CSF and brain tissue


85% inactivated by DPD(Dihydropyrimidine dehydrogenase)

Effect of Dihydorprimidine Dehdrogenase (DPD)

  • Liver expresses maximum amount of DPD, but expressed in GIT and lymphocytes
  • 85% of 5FU is metabolized
  • Deficiency of DPD
    • Autosomal Recessive inheritence
    • 3-5% of population
    • Either partial or complete, may experience life-threatening or fatal toxicity when treated with fluoropyrimidine-based chemotherapy
    • Several molecular defects, including point mutations and deletions due to exon skipping, have been identified in DPD-deficient patients



Increasing tumor toxicity

  • Leucovorin
  • Methotrexate
  • Platinum analogue/Irradiation

Sparing of host toxicity

  • Allopurinol
  • Uridine

5FU and Leucovorin

  • Stable ternary complex is critical for drug sensitivity.
  • Proportional to intracellular reduced folate concentration
  • More binding to Thymidylate synthase
  • Endogenous reduced folate concentration is insufficient
  • Leucovorin expands the intracellular reduced folate pool and permit maximal ternary complex formation
  • Increases cytotoxicity of 5FU in time and concentration dependent manner
  • Tolerated dose of 5FU becomes less
  • Increase GI toxicity

5FU and Thymidine

  • Thymine produced from catabolism of thymidine competes with 5FU for DPD thus increasing the level of 5FU
  • dThd can compete with FdUrd for dThd kinase, thereby decreasing FdUMP formation. Subsequent metabolism of dThd monophosphate to dTTP will expand the dTTP pools;  in turn, acts as a feedback inhibitor of dThd kinase and ribonucleotide reductase.
  • Inhibition of the latter enzyme prevents FUDP conversion to FdUDP and consequently FdUMP, thus allowing enhanced FUTP formation and its incorporation into RNA. dThd acts as a donor of the deoxyribose moiety to promote the direct conversion of 5-FU to FdUrd by dThd phosphorylase
  • More RNA mediated cytotoxicity

5FU and Cisplatin

  • Increases cytotoxic effect
  • Increase formation of reduction folate through inhibition of methionine uptake
  • Enhanced DNA damage
Bolus infusion Continuous infusion(CI)
Toxicity: myelosuppression, mucositis, diarrhea Toxicity: Stomatitis, diarrhea, hand foot syndrome
50-1000 fold lower drug levels detected in bone marrow of pts with CI
Larger dose can be given by CI, i.e. 15 mg/kg/day bolus x 5 days= 25 mg/kg/day 2 hr infusion x 5 days
1gm/day CI well tolerated with only stomatitis n diarrhea
Lower tumor response with bolus (14% vs. 22% in CI arm, lower overall survivall
Cardiotoxicity more common- 1gm/m2/day x 5 day 2% develop symptoms of angina, arrythmia, sudden death
Higher dose 3- 3.5gm/m2 CI 24hr toxicity profile changes- ataxia, leucopenia seen


Side Effects


Dose-limiting for the bolus or weekly schedules, less frequently observed with infusional therapy. Neutropenia and thrombocytopenia more common than anemia.

  • Onset 7-10 days
  • Nadir 10-14 days

Recovery 21-28 days

Hand Foot Syndrome (Palmer Plantar Erythrodysesthesia)

Starts 5-6 weeks after treatment

  • Characterized by tingling, numbness, pain, erythema, dryness, rash, swelling, increased pigmentation,nail changes, pruritus of the hands and feet, and/or desquamation.
  • Most often observed with infusional therapy and can be dose-limiting
  • Vitamin B6 , Celecoxib, bland and mild moisturizer


  • Mucositis and diarrhoea
  • Neurological toxicity
  • Cardiac toxicity – Due to vasospasm
  • Dermatological toxicity
  • Ocular toxicity

Pathophysiology of Diarrhea

  • Maturation arrest of intestinal enterocytes
  • Temporary depletion of mature villous cells
  • Disruption of water, electrolyte & nutrient transport
  • Decreased fluid absorption and Increased fluid secretion
  • Diarrhea of 5FU almost always reversible No relationship between severity of diarrhea and effectiveness ≥ grade 3 diarrhea refractory to Loperamide, 500 µg of octerotide TDS


capecitabine-antimetabolite pyrimidine antagonist

  • Oral 5FU prodrug
  • Was first initially approved in 1998 for metastatic breast cancer resistant to anthracyclines and taxanes
  • Rapidly and extensively metabolized by gut mucosa
  • 80% bioavailability


  • Peak plasma level of capecitabine in 1.5 hours
  • Peak plasma level of 5FU in 2 hours
  • Metabolites excreted through kidney
  • Contraindicated in patients with creatinine clearance less than 3oml/min


  • Colorectal cancer
      • First line therapy for metastatic disease
      • Adjuvant to post surgery in Dukes C
  • Breast
      • Combination with docetaxel when anthracycline based chemotherapy has failed
      • Monotherapy as third line after paclitaxel and anthracycline
      • Monotherapy as second line after paclitaxel is contraindicated


  • 1,250 mg/m2 PO twice daily for 2 weeks after meal


  • Diarrhoea
  • Hand foot syndrome
  • Myelosuppresion
  • Neuropathy


  • Altered coagulation parameters when used with warfarin
  • Increase toxicity of phenytoin
  • Liquid antacids increase bioavailability by 16-35%
  • LV enhances anti tumor effect

Purine antagonists

6-Mercaptopurine (6-MP)

6 mercaptopurine-antimetabolite purine antagonist

Mechanism of Action

  • Cell cycle–specific purine analog with activity in the S-phase.
  • Parent drug is inactive. Requires intracellular phosphorylation by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to the cytotoxic monophosphate form, which is then metabolized to the eventual triphosphate metabolite.
  • Inhibits de novo purine synthesis by inhibiting 5-phosphoribosyl-1 pyrophosphate (PRPP) aminotransferase.
  • Incorporation of thiopurine triphosphate nucleotides into DNA resulting in inhibition of DNA synthesis and function.
  • Incorporation of thiopurine triphosphate nucleotides into RNA resulting in alterations in RNA processing and/or translation.

Mechanism of Resistance

  • Decreased expression of the activating enzyme HGPRT.
  • Increased expression of the catabolic enzyme the conjugating enzyme thiopurine methyltransferase (TPMT).
  • Decreased transmembrane transport of drug.


  • Absorption: Oral absorption is erratic and incomplete. Only 25- 50% of an oral dose is absorbed.
  • Distribution: Widely distributed in total body water. Does not cross the blood brain barrier.
  • Low bioavailability is due to high 1st pass metabolism. About 20%–30% of drug is bound to plasma proteins.
  • Metabolism: in the liver by methylation to inactive metabolites and via oxidation by xanthine oxidase to inactive metabolites. About 50% of parent drug and metabolites are eliminated in urine within the first 24 hours.


  • Acute lymphoblastic leukemia.

Dosage Range

  • Maintenance therapy: 75mg/m2 PO daily x 3weeks.


  • Anticoagulant effects of Coumadin are inhibited by mercaptopurine through an unknown mechanism. Monitor coagulation parameters (PT and INR), and adjust dose accordingly.
  • Allopurinol—Allopurinol inhibits xanthine oxidase and the catabolic breakdown of mercaptopurine, resulting in enhanced toxicity. Dose of mercaptopurine must be reduced by 50%–75% when given concurrently with allopurinol.
  • Septran DS may enhance the myelosuppressive effects of mercaptopurine when given concurrently.


  • Dose reduction of 50%–75% is required when mercaptopurine is given concurrently with allopurinol. This is because allopurinol inhibits the catabolic breakdown of mercaptopurine by xanthine oxidase.
  • Use with caution in patients with abnormal liver and/or renal function.
  • Patients with a deficiency in the metabolizing enzyme 6-thiopurine methyltransferase (TPMT) are at increased risk for developing severe toxicities
  • Administer on an empty stomach to facilitate oral absorption.


  • Mild to moderate with leukopenia more common than thrombocytopenia.
  • Mucositis and/or diarrhea. Usually seen with higher doses.
  • Hepatotoxicity: 3 types –commonly transient transaminitis, rarely severe cholestatic jaundice, very rarely VOD due to endotelial injury. Not asssoc with TPMT polymorphism.
  • Mild nausea and vomiting.
  • Dry skin, urticaria, and photosensitivity.
  • Increased risk of bacterial, fungal, and parasitic infections.
  • Mutagenic, teratogenic, and carcinogenic


6 thioguanine-antimetabolite purine antagonist

Mechanism of Action

  • Cell cycle–specific: S-phase.
  • Parent drug is inactive. Requires intracellular phosphorylation by the enzyme HGPRT for activation
  • Incorporation into DNA and RNA leading to cytotoxicity
  • Less effective on purine metabolism because of decreased formation of methyl inosine monophosphate
  • Dose of drug does not need to be reduced in the presence of concomitant allopurinol therapy


  • Only 30% of an oral dose is absorbed
  • Metabolized in the liver by the processes of deamination and methylation.
      • Main pathway of inactivation is catalyzed by guanine deaminase (guanase)
      • Methylated product is non toxic


  • ALL
  • AML


  • Myelosuppression
  • Mucositis
  • Immunosupression
  • Sensory neuropathy


  • Prodrug
  • Metabolism: rapidly converted to 6MP by non enzymatic mechanism
  • Inhibits T cell activity greater than B cell, marked immunosuppressant action than anti tumor action.
  • Used to prevent graft rejection, and in treatment of auto immune disorders

Adenosine Deaminase Inhibitors


fludarabine-antimetabolite-adenosine deaminase inhibitor


  • Purine analogue
  • Analogue of Arabinofuranosyl adenosine (Ara-A)
  • 2 fluro group on adenosine ring renders the drug ineffective

Mechanism of Action

  • Considered a prodrug. Following administration, it is rapidly dephosphorylated to 2-fluoro-ara-adenosine (F-ara-A)
  • Antitumor activity against both dividing and resting cells.
  • Inhibition of DNA polymerase- and DNA polymerase- by the triphosphate metabolite resulting in inhibition of DNA synthesis and DNA repair.
  • Induction of apoptosis.

Mechanism of Resistance

  • Decreased expression of the activating enzyme, deoxycytidine kinase.
  • Decreased nucleoside transport of drug.


  • Fludarabine is orally bioavailable, in the range of 50–65%, and a tablet form is now available. Absorption is not affected by food.
  • Widely distributed throughout the body.
  • Major route of elimination is via the kidneys, and approximately 25% of 2-fluoro-ara-A is excreted unchanged in urine.
  • t1/2 10–20 hours.


  • Chronic lymphocytic leukemia (CLL)
  • Relapsed AML
  • Cutaneous T cell lymphoma
  • Waldenstorm macroglobilemia
  • Hairy cell leukemia
  • Mantle cell lymphoma(R-FCM)

Drug Interactions

  • Fludarabine may enhance the antitumor activity of cytarabine by inducing the expression of deoxycytidine kinase.
  • Fludarabine may enhance the antitumor activity of cyclophosphamide, cisplatin, and mitoxantrone by inhibiting nucleotide excision repair mechanisms.
  • Increased incidence of fatal pulmonary toxicity when fludarabine is used in combination with pentostatin. Use of this combination is absolutely contraindicated

Adverse Effects

  • Myelosuppression
  • Transfusion-associated graft-versus-disease can occur rarely after transfusion of non-irradiated products in patients treated with fludarabine.
  • Use with caution in patients with abnormal renal function.
  • Rarely produces hypersensitivity reaction with maculopapular skin rash, erythema, and pruritus.
  • Autoimmune side effects like autoimmune hemolytic anemia, arthritis, and hypothyroidism have been reported
  • Tumor lysis if tumor burden is large


cladribine-antimetabolite-adenosine deaminase inhibitor

Mechanism of Action

  • Purine nucleoside
  • Antitumor activity against both dividing and resting cells.
  • Metabolized intracellularly to 5-triphosphate form (Cld-ATP), which is the presumed active species
  • Gets inorporated into DNA and RNA leading to cytotoxicty
  • Induces apoptosis


  • Oral absorption is variable with about 50% of drug orally bioavailable
  • Widely distributed throughout the body. Crosses the blood-brain barrier, but CSF concentrations reach only 25% of those in plasma.
  • Terminal half-life is on the order of 5–7 hours. Cleared by the kidneys via a cation organic carrier system. Renal clearance is approximately 50%, with 20%–35% of drug eliminated unchanged.


  • Hairy cell leukemia.
  • Chronic lymphocytic leukemia.
  • Non-Hodgkin’s lymphoma (low-grade).
  • Mulitple sclerosis
  • Relapsed AML


  • T cell depletion.Complete recovery of CD4 counts to normal may take up to 40 months.
  • Fever occurs in 40%–50% of patients. Most likely due to release of pyrogens and/or cytokines from tumor cells. Self limiting
  • Mild nausea and vomiting observed in less than 30% of patients.
  • Tumor lysis syndrome. Rare event, most often in the setting of high tumor cell burden.
  • Skin reaction at the site of injection.


clofarabine-antimetabolite adenosine deaminase inhibitor

Mechanism of Action

  • Cell cycle–specific with activity in the S-phase.
  • Intracellular activation to triphosphate nucleotide metabolite.
  • Incorporation into DNA resulting in chain termination and inhibition of DNA synthesis and function.
  • Induces apoptosis
  • Inhibits the enzyme ribonucleotide reductase, resulting in inhibition of DNA synthesis and function.

Mechanism of Resistance

  • Decreased activation of drug through decreased expression of the anabolic enzyme deoxycytidine kinase.
  • Decreased transport of drug into cells.


  • Not absorbed via the oral route.
  • Renal clearance is approximately 50%–60%. The terminal elimination half-life is 5 hours.


  • FDA-approved for the treatment of pediatric patients 1–21 years of age with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens.
  • Recommended dose is 52 mg/m2 IV over 2 hours daily for 5 days every 2–6 weeks.

Side Effects

  • Myelosuppression
  • Systemic inflamatory response syndrome/capillary leak syndrome.
  • Pericardial effusion
  • GIT toxicity.
  • Hepatic dysfunction
  • Increased risk of opportunistic infections
  • Renal toxicity with elevation in serum creatinine observed in up to 10% of patients.


pentostatin-antimetabolite adenosine deaminase inhibitor

Mechanism of Action

  • Fermentation product of Streptomyces antibioticus.
  • Inhibits the enzyme adenosine deaminase, which results in accumulation of deoxyadenosine and deoxyadenosine triphosphate (dATP). dATP is cytotoxic to lymphocytes.
  • Feedback inhibition of ribonucleotide reductase by dATP resulting in inhibition of DNA synthesis and function.
  • Inhibits S-adenosyl-L-homocysteine hydrolase resulting in inhibition of one-carbon dependent methylation reactions

Mechanism of Resistance

  • Decreased nucleoside transport resulting in decreased intracellular accumulation of drug.
  • Increased expression of ribonucleotide reductase.


  • Given only by the IV route.
  • Widely distributed in total body water. Crosses the blood-brain barrier(10% )
  • Greater than 90% of drug is eliminated in unchanged form and/or metabolites in urine. Elimination half-life is about 5–6 hours


  • Hairy cell leukemia
  • Chronic lymphocytic leukemia
  • Cutaneous T-cell lymphoma
  • Adult T cell lymphoma

Adverse Effects

  • Both B and T lymphocytes are suppressed.
  • Combination of pentostatin and fludarabine has been associated with fatal pulmonary toxicity and is absolutely contraindicated.
  • Use with caution in patients with abnormal renal function.
  • Fluid status of patient is important, and hydration with at least 2 liters of D5NS is required to ensure sufficient urine output (2 liters) on the day of drug administration.
  • Dose-related headache, lethargy, and fatigue.Use with caution in patients on sedative and hypnotic drugs as CNS toxicity may be enhanced.


nelarabine-antimetabolite adenosine deaminase inhibitor

Mechanism of Resistance

  • Decreased activation of drug through decreased expression of the anabolic enzyme deoxycytidine kinase.
  • Decreased transport of drug into cells.


  • Administered only by the IV route.
  • Extensively distributed in the body
  • Undergoes metabolism by adenosine deaminase to form ara-G, which undergoes subsequent hydrolysis to form guanine, which is in turn converted to xanthine and uric acid. A minor route of nelarabine metabolism is via hydrolysis to form methylguanine, which is then demethylated to form guanine. Ara-G is rapidly eliminated from plasma with a half-life 3 hours.


  • FDA-approved for T-cell acute lymphoblastic leukemia (T-ALL) and lymphoma(T-LBL) that has not responded to or has relapsed following treatment with at least 2 chemotherapy regimens.


  • Pediatric patients: 650 mg/m2 /day IV over 1 hour on days 1–5 every 21 days. Response rate is 23%
  • Adult patients: 1,500 mg/m2 /day IV over 2 hours on days 1, 3, and 5 every 28 days. Response rate is 31%, with median survival of 20 wks and 25% alive at 1 year.

Drug Interaction

  • Treatment with adenosine deaminase inhibitors, such as pentostatin, may reduce the conversion of nelarabine to its active form

Adverse Effects

  • Myelosuppression
  • Nausea and vomiting
  • Neurotoxicity – Patients treated previously or concurrently with intrathecal chemotherapy and/or previously with craniospinal radiation therapy may be at increased risk for developing neurotoxicity.
  • Mild hepatic dysfunction with elevation of serum transaminases and bilirubin.


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