Primjeri:

 TPMT  i  CYP2D6  
 Thiopurine  methyltransferase  
•  TPMT  
Protein  
Thiopurine methyltransferase (TPMT)

involved in the metabolism of the immunosupressant drugs azathioprine

and 6-mercaptopurine (used in ALL, organ transplantation, autoimmune
disease etc)
in individuals deficiency in TPMT activity, thiopurine metabolism
proceeds by other pathways, one of which produces active thiopurine
which is toxic to the bone marrow at high concentrations

10% of individuals are heterozygous for low-activity variants of TPMT

0.3% of individuals are homozygous for low-activity variants of TPMT
3 variants account for 90% of the low-activity alleles

homozygous individuals require lower doses of the drugs (6-10% of

standard dose) or risk bone marrow toxicity and suppression
 Funkcija  
S-­‐me@lacija  aromatskih  i  heterociklicnih  
sulAidril  spojeva,  ukljucujuci  i  an@kancer  
lijekove  kao  sto  je    6-­‐mercaptopurin  (6MP),  6-­‐
thioguanin  (6TG),  i  imunosupresivni  lijek  
azathioprine  (AZA)      
•  Tiopurinska  methyltransferaza  me@lira  
@opurinske  spojeve  
•  Methil  donor  je  S-­‐adenosil-­‐L-­‐me@onin,  koji  je  
konver@ran  u  S-­‐adenosil-­‐L-­‐homocistein.  
THIOPURINE  METHYLTRANSFERASE  (TPMT)  

8  
 Sta  su  @opurini?  
Tiopurini  su  pro-­‐lijekovi  kojima  je  neophodan  
metabolizam  da  bi  mogli  djelova@  kao  citotoksicni  agen@  
 
•  Sukcesivni  koraci  koji  formiraju  citotoksicne  nukleo@de  
koji  se  inkorporiraju  u  DNA  ili  RNA,  uzrokujuci  DNA-­‐
protein  kros-­‐veze,  single-­‐stranded  breaks,  interstrand  
breaks  kao  i  razmjenu  hroma@da  (sister  chroma@ds)  
   
 
   

11  
 Pacijent  sa  ALL  
•  Razvija  tesku  hematopoetsku  toksicnost  
•  Iden@ficiraju  se  mutacije  kod  TPMT  
WWW.OMIM.ORG  
Thiopurine S-methyltransferase (TPMT) pharmacogenetics

The frequency distribution shows the level of red blood

cell (RBC) TPMT activity in 298 randomly selected
Caucasian blood donors. Presumed genotypes for the
TPMT genetic polymorphism are also shown. TPMTL
and TPMTH (low and high, respectively) were allele
designations used before the molecular basis for the
polymorphism was established

Human thiopurine S-methyltransferase (TPMT) alleles

TPMT *1 is the most common allele (wild type), TPMT

*3A is the most common variant allele in Caucasians,
and TPMT *3C is the most common variant allele in
East Asian subjects
 TPMT
Genetic Polymorphism
Clinical Consequences  
•  Low TPMT
–  Increased thiopurine toxicity
–  Increased risk for secondary
neoplasm

•  High TPMT
–  Decreased therapeutic effect
TPMT  gen  
Selected Human TPMT Alleles  
Primjer  djecije  ALL  
 ALL  
100 1996-2000
(n=3421)
1989-1995
80 (n=5121)
Ukupno  prezivljenje  

1983-1988
(n=3711)
60 1978-1983
(n=2984)
1975-1977
40 (n=1313)
1972-1975
(n=936)
20 1970-1972
(n=499)
1968-1970
0 (n=402)
0 2 4 6 8 10 12

Godine  
 ALL  Therapy  

Interim Delayed
Induction Consolidation Maintenance
Maintenance Intensification

L-Asp Steroids MTX VCR 6-MP/6-TG AraC Doxorubicin Cyclophosphamide

 6-Mercaptopurine
•  Otkriven 1951; ukljucen u klinicke studije u
1952 i odobren od FDA 1953
•  Prvi klinicki koristan lijek koji je dizajniran i
sintetiziran da djeluje kao anti-purin
Kovertira se u tioguanin koji se onda
inkorporiraju u DNK  
 6-Mercaptopurine

•  Komponent gotovo svih ALL rezimena u

zadnjih 40 godina
•  Dnevna oralna terapija x 2-3 godine
mala toksicnost
•  Intenzitet 6-MP terapije korelira sa EFS
(Relling et al, 1999)
•  Sinergistican sa metotreksatom
 Tiopurinska Metiltransferaza

•  Variabilnost u TPMT aktivnosti

(Weinshilboum & Sladek, 1980)
– 88.6% visoku enzimsku aktivnost;
11.1% srednju; 0.3% nedektabilnu
aktivnost

•  Djeca sa ALL (Evans et al, 1991) imala

veliku mijelosupresiju; jako visok nivo RBC
TGN i TPMT deficijencija
 Low TPMT and Risk of 2nd Cancer
Following Thiopurine Therapy

•  Higher risk of radiation-induced brain tumors

among children with high TGN or TPMT
deficiency (Relling et al, 1999)

–  Unique combination with delivery of oral 6-

MP during the delivery of 18-24 Gy CRT
–  3/6 with brain tumors had TPMT deficiency
 Low TPMT and Risk of sMDS/tAML
Following Thiopurine Therapy

•  Trend towards a higher incidence of

Etoposide induced AML with lower TPMT
activity (p = 0.16) (Relling et al 1998)

•  Greater risk of sMDS/AML with TPMT activity

< 14 U/ml RBC (p = 0.03) in NOPHO ALL-92
(Thomsen et al,1999)
•  Therapy did not include Etoposide; total
alkylating dose (cyclo)- 3 gm/m2
 Za  sljedeci  put    14.11.2014  
•  Ispit:  
–  CYP2D6  
–  h]p://www.pharmgkb.org/gene/PA128?
tabType=tabVip