Date post: | 15-Apr-2017 |
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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