Antimetabolites are a class of chemotherapy drugs that work by interfering with DNA and RNA synthesis in cancer cells. They include folic acid analogs like methotrexate, purine analogs like mercaptopurine, and pyrimidine analogs like 5-fluorouracil. These drugs are used to treat many types of cancer including leukemias, lymphomas, and solid tumors in organs like breast, lung, and colon. While they can be effective, their use is often limited by bone marrow suppression and other toxicities due to their effects on rapidly dividing normal cells.

1. ANTI
METABOLITES
Dr Anu Chandran

2. CANCER is the uncontrolled growth of
abnormal cells
There are a number of
causes
 Chemicals/toxins
 Sun exposure
 Obesity
 Viruses
 Genetic factor
 Radiation
 unknown

3. 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

4. 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

5. S – Phase
Anti metabolites

6. Folic acidFolic acid
analogsanalogs
• MethotrexateMethotrexate
• PemetrexedPemetrexed
• RaltitrexedRaltitrexed
• LometrexolLometrexol
• TrimetrexateTrimetrexate
• PralatrexatePralatrexate

9. MOA
 (-) Dihydrofolate reductase
(-)Thymidylate synthetase
 Deprives cancer cells of various folate
Co enzymes & essential components
of DNA
 DNA, RNA & protein synthesis (-)

10. METHOTREXATE
World Health Organization's List of Essential
Medicines
ORAL /IV/IT

11. 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 %)

12. 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

13. Non neoplastic USENon neoplastic USE
∗ Psoriasis
∗ Refractory RA
∗ Steroid resistant asthma
∗ Crohn’s disease
∗ Wegener’s granulomatosis
∗ Glomerulonephritis
∗ Dermatomyositis
∗ Immunosuppressive agent
∗ Abortifacient

14. 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

18. ∗ BM: Myelosupression,thrombocytopenia
∗ Liver: Fibrosis,cirrhosis
∗ GIT: Nausea,vomiting,diarrhoea,mucositis,
stomatitis,desquamation
∗ Skin: Erythema,rash,urticaria,alopecia,
dermatitis
∗ Resp:Interstitial pneumonitis
∗ CNS: Meningismus,headache,seizure,coma
∗ Genital:Defective oogenesis,spermatogenesis
∗ Teratogenicity and abortions
∗ High dose:Nephrotoxicity

19. 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.

20. PEMETREXED(MTA)PEMETREXED(MTA)
New pyrrole pyrimidine folate
antagonist
MULTITARGETED
(-)Thymidylate synthetase
(-)GART & DHFR
Use-Mesothelioma
Non small cell lung Ca
(with cisplatin 1st
line)
A/E same as Mtx

21. RALTITREXEDRALTITREXED
(-) Thymidylate synthetase
LLOMETREXOLOMETREXOL
(-) Early steps in purine
synthesis
TRIMETREXATETRIMETREXATE
Lipid soluble
Penetrate BBB
Use : P jiroveci pneumonia

22. Purine analogsPurine analogs
• ThiopurinesThiopurines
6 Mercaptopurine6 Mercaptopurine
6 Thioguanine6 Thioguanine
• PentostatinPentostatin
• Fludarabine PO4Fludarabine PO4
• CladribineCladribine
• ClofarabineClofarabine
• nelarabinenelarabine

23. Purine analogs
• Hitchings and Elion 1942
• Treatment of
1.Malignancy
2.Autoimmune disease
3.Organ transplantation
4.viral

24. 6 Mercaptopurine and 6 Thioguanine
First of the thiopurine analogs
found
Inactive in its parent form
 6MP---Analog of hypoxanthine
6TG---Analog of guanine

27. Pharmacokinetics
 Oral – 10 to 50 %
 T half after IV – 50 min
Metabolised
1.xanthine oxidase
2.Methylation by TPMT ( thiopurine
methyl transferase)

28. USES
∗ALL - ( 50- 100mg/m2
)
∗ Pediatric non-Hodgkin's lymphoma
∗Crohn’s disease

29. ADVERSE EFFECTS
Bone marrow depression
GIT -stomatitis
Hepatotoxicity,
Hyperuricemia
Hyperuricosuria
Teratogenicity
Opportunistic infections
AML on prolonged use

30. 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

31. FLUDARABINEFLUDARABINE
 Analog of Vidarabine
(adenosine analog)
 Prodrug
 MOA (-)DNA polymerase,primase ,ligase
Incorporate to DNA/RNA
 IV and orally ,t1/2 – 10 hrs
 Dose – 25mg/m2 for 5 days

32. ∗ Use :
a)CLL,
b)NHL
c)HCL,
d)cut T cell lymphoma
e)Immunosuppressant
A/E :
myelosupression
Peripheral neuropathy
Seizure
TLS

33. 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

34. 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

35. CLOFARABINE
•Pediatric ALL
NELARABINE
•Refractory T cell leukemia and
lymphoma

36. Pyrimidine analogs
Halogenated
• 5 Fluorouracil
• Floxuridine
• Idoxuridine
• Capecetabine
Cytidine
analogues
• Cytarabine
• 5 Azacytidine
• Gemcitabine
• Decitabine

37. 5 flurouracil
• Most important medication
• Inhibit DNA and RNA function
• PARENTALLY - IV
• 5 to 10 % excreted in urine

40.  Irreversible inhibition
of thymidylate synthase
 DPD –
Dihydropyrimidine
dehydrogenase

42. Injection -IV
Topical solution
Dose -500 mg/m2 iv
infusion over 1-3 hours for
6-8 weeks

43. Uses
Systemic –
1.Ca breast
2.Ca colon
3.Ca Bladder
4.Ca liver
5.Ca upper GIT
Topical –
1.BCC,
2.premalignant keratosis

45. FLOXURIDINEFLOXURIDINE
 Analog of 5-fluorouracil
Treatment of hepatic mets from colorectal c

46. CAPECITABINECAPECITABINE
∗5FU Analog, Prodrug
∗ORAL
∗Uses:
Stage III colon cancer
Metastatic breast
Metastatic colorectal cancer

48. Higher toxicity if given alone
Capecitabine plus oxaliplatin

49. CYTARABINE (Ara-C)CYTARABINE (Ara-C)
 Combines a cytosine base with an
arabinose
sugar.
 IV/IT
Uses: AML ,HL,NHL,ALL, CML
Dose ; 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

51. A/E:
BM suppression
Non cardiogenic pulmonary oedema
Seizure
ataxia,
conjunctivitis,
dermatitis,
GIT

52. Gemcitabine
 Dose ranges from 1-1.2 g/m2
 2,2’ difluorodeoxycytidine
 Given IV
 Potent radiosensitiser,dont use with
radiotherapy
Uses:
a.Metastatic pancreatic adeno Ca,
b.Ca ovary
c.,Non small cell lung
d. Ca,bladder
e. NHL

54. SIDE EFFECTS
Flu-like symptoms such as muscle
pain,headache, chills, fatigue
Fever (within 6–12 hours of first dose)
Fatigue
Nausea (mild)
Vomiting
Poor appetite
Allergic reaction
Diarrhea
Weakness
Hair loss

55. SUMMARY
• ANTIMETABOLITES
• CLASSIFICATION
• S PHASE
• SOLID TUMORS,LEUKEMIA AND
LYMPHOMA
• CLADIBRINE – HCL
• SIDE EFFECT – MYELOSUPRESSION

56. THANK YOU