ANTI METABOLITES

Dr Anu Chandran

CANCER is the uncontrolled growth of abnormal cells

There are a number of causes

Chemicals/toxinsSun exposureObesityVirusesGenetic factorRadiationunknown

Goals for Treatment•  #1 – Cure: Complete remission for

more than 5 years• #2 – Disease control: Partial or

temporary remission• #3 – Relieve symptoms: Relieve

symptoms of the cancer, and includes pallative care

Antimetabolites

Chemical agent by virtue of its similarity in structure to a metabolite,blocks its action

Prevent combination of metabolite with specific enzyme

Combine with specific enzyme-get transformed

S – PhaseAnti metabolites

Folic acid Folic acid analogsanalogs•MethotrexateMethotrexate •Pemetrexed Pemetrexed •Raltitrexed Raltitrexed • Lometrexol Lometrexol • Trimetrexate Trimetrexate •PralatrexatePralatrexate

MOA (-) Dihydrofolate reductase(-)Thymidylate synthetase Deprives cancer cells of various

folate Co enzymes & essential components of DNA

DNA, RNA & protein synthesis (-)

METHOTREXATEWorld Health Organization's List of Essential Medicines

ORAL /IV/IT

Pharmacokinetics

• Rapidly absorbes from git at dose <25mg/m2• Peak concentration – 1 to 10µM (25 to

100mg/m2)• IV – triphasic fashion• 50% ppb• Excretion-urine ( 90%)• Retained for long as – POLYGLUTAMATE Do not cross BBB ( 3 %)

NeoplasticNeoplastic UseUse• Choriocarcinoma • ALL in children• Meningeal leukaemia, lymphoma• Burkitt’s lymphoma,NHL,Ca breast,head & neck• AML• HDM-L Osteosarcoma CNS lymphoma Childhood ALL

Non neoplastic USENon neoplastic USE

Psoriasis Refractory RA Steroid resistant asthma Crohn’s disease Wegener’s granulomatosis Glomerulonephritis Dermatomyositis Immunosuppressive agent Abortifacient

Leucovorin rescue

Folinic acid,citrovorum factor,leucovorin,N5 formyl FH4(reduced folate)

Bypass blockade of DHFR enzyme-replenishes folate

Used in case of Mtx toxicity/high dose Should be kept minimum Do not reverse neurotoxicity

BM: Myelosupression,thrombocytopeniaLiver: Fibrosis,cirrhosisGIT:

Nausea,vomiting,diarrhoea,mucositis, stomatitis,desquamation

Skin: Erythema,rash,urticaria,alopecia, dermatitisResp:Interstitial pneumonitisCNS:

Meningismus,headache,seizure,comaGenital:Defective

oogenesis,spermatogenesisTeratogenicity and abortionsHigh dose:Nephrotoxicity

Mechanism of resistance Impaired transport of Mtx to cells Increased expression of multidrug

resistant proteins Decreased ability to synthesise

Mtx-PG Synthesis of increased levels of

DHFR through gene amplification Altered DHFR with reduced affinity

for methotrexate.

PEMETREXED(MTA)PEMETREXED(MTA)

New pyrrole pyrimidine folate antagonist

MULTITARGETED (-)Thymidylate synthetase (-)GART & DHFRUse-Mesothelioma Non small cell lung Ca (with cisplatin 1st line)A/E same as Mtx

RALTITREXEDRALTITREXED(-) Thymidylate synthetase

LLOMETREXOLOMETREXOL(-) Early steps in purine synthesis

TRIMETREXATETRIMETREXATELipid soluble Penetrate BBBUse : P jiroveci pneumonia

Purine analogsPurine analogs

• Thiopurines Thiopurines 6 Mercaptopurine6 Mercaptopurine 6 Thioguanine6 Thioguanine• Pentostatin Pentostatin • Fludarabine PO4Fludarabine PO4• Cladribine Cladribine • Clofarabine Clofarabine • nelarabinenelarabine

Purine analogs• Hitchings and Elion 1942

• Treatment of1.Malignancy2.Autoimmune disease3.Organ transplantation4.viral

6 Mercaptopurine and 6 Thioguanine

First of the thiopurine analogs found

Inactive in its parent form

6MP---Analog of hypoxanthine

6TG---Analog of guanine

Pharmacokinetics Oral – 10 to 50 % T half after IV – 50 minMetabolised 1.xanthine oxidase2.Methylation by TPMT ( thiopurine

methyl transferase)

USES

ALL - ( 50- 100mg/m2) Pediatric non-Hodgkin's lymphomaCrohn’s disease

ADVERSE EFFECTS

Bone marrow depressionGIT -stomatitisHepatotoxicity,HyperuricemiaHyperuricosuriaTeratogenicityOpportunistic infectionsAML on prolonged use

AZATHIOPRINEAZATHIOPRINE Converted to 6MP

USE – Immunosuppresant in Crohn’s Organ transplantation Metabolised - Xanthine oxidase A/E:opportunistic infection,SCC Dose - 3 to 5 mg mg/kg/day .1

to 2 mg/kg/day

FLUDARABINEFLUDARABINE Analog of Vidarabine (adenosine analog) Prodrug MOA (-)DNA

polymerase,primase ,ligaseIncorporate to DNA/RNA IV and orally ,t1/2 – 10 hrs Dose – 25mg/m2 for 5 days

Use :a)CLL,b)NHLc)HCL,d)cut T cell lymphomae)ImmunosuppressantA/E :myelosupressionPeripheral neuropathySeizureTLS

Cladribine• (-)DNA polymerase & Ribonucleotide

reductase• T1/2- 61/2 hours• IV• Dose- 0.09mg/kg/day for 7 days Uses: Hairy cell leukemia CLL Low grade lymphoma

PENTOSTATINPENTOSTATIN• (-)Adenosine deamine• Streptomyces antibioticus• Accumulation of adenosine • Incorporate in DNA Route IV,t ½ - 5.7 hrs Excreted in kidney A/E: BM suppression ,Renal,CNS Uses: Hairy cell leukemia,CLL,CML

CLOFARABINE•Pediatric ALL

NELARABINE•Refractory T cell leukemia and lymphoma

Pyrimidine analogs

Halogenated

• 5 Fluorouracil

• Floxuridine

• Idoxuridine

• Capecetabine

Cytidine analogues

• Cytarabine

• 5 Azacytidine

• Gemcitabine

• Decitabine

5 flurouracil •  Most important medication 

• Inhibit DNA and RNA function

• PARENTALLY - IV

• 5 to 10 % excreted in urine

Irreversible inhibition of thymidylate synthase

DPD –Dihydropyrimidine dehydrogenase

Injection -IV

Topical solution

Dose -500 mg/m2 iv infusion over 1-3 hours for 6-8 weeks

Uses

Systemic –1.Ca breast2.Ca colon3.Ca Bladder4.Ca liver5.Ca upper GITTopical – 1.BCC,2.premalignant keratosis

FLOXURIDINEFLOXURIDINE Analog of 5-fluorouracil

Treatment of hepatic mets from colorectal ca. 

CAPECITABINECAPECITABINE5FU Analog, Prodrug ORALUses:Stage III colon cancerMetastatic breastMetastatic colorectal cancer

Higher toxicity if given alone

Capecitabine plus oxaliplatin

CYTARABINE (Ara-C)CYTARABINE (Ara-C) Combines a cytosine base with an 

arabinose  sugar. IV/ITUses: AML ,HL,NHL,ALL, CMLDose ; 100 mg/m2 OD or BD for 10

days or Continues iv for 5-7 days rapidly deaminated in the body into the

inactive uracil derivative

A/E:BM suppressionNon cardiogenic pulmonary oedema

Seizureataxia, conjunctivitis,dermatitis,GIT

Gemcitabine

Dose ranges from 1-1.2 g/m2

2,2’ difluorodeoxycytidine

Given IV Potent radiosensitiser,dont use with

radiotherapyUses:a.Metastatic pancreatic adeno Ca,b.Ca ovaryc.,Non small cell lungd. Ca,bladdere. NHL

SIDE EFFECTS  

Flu-like symptoms such as muscle pain,headache, chills, fatigue

Fever (within 6–12 hours of first dose)FatigueNausea (mild)VomitingPoor appetiteAllergic reactionDiarrheaWeaknessHair loss

SUMMARY• ANTIMETABOLITES• CLASSIFICATION• S PHASE• SOLID TUMORS,LEUKEMIA AND

LYMPHOMA• CLADIBRINE – HCL• SIDE EFFECT – MYELOSUPRESSION

THANK YOU