Anti metabolites

presentation on antimetabolites, cancer chemotherapy

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 acid Folic acid
analogsanalogs
•MethotrexateMethotrexate
•Pemetrexed Pemetrexed
•Raltitrexed Raltitrexed
•Lometrexol Lometrexol
•Trimetrexate Trimetrexate
•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 1
st
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
•Thiopurines Thiopurines
6 Mercaptopurine6 Mercaptopurine
6 Thioguanine6 Thioguanine
•Pentostatin Pentostatin
•Fludarabine PO4Fludarabine PO4
•Cladribine Cladribine
•Clofarabine Clofarabine
•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/m
2
)
* 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 ca.
 

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/m
2
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/m
2
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