Drug target 1 (DNA synthesis) : Anti cancer

what is the intermediate before forming purine ribonucleotides (Ex. AMP + GMP)

• inosine monophosphate (IMP)

what is the enzyme that converts intermediate IMP → AMP/GMP

• IMPDH

  • IMP dehydrogenase

what enzyme converts ribonucleotides to deoxyribonucleotides?

• ribonucleotide reductase

what is the process of converting dUMP → dTMP

• thymidylate synthase enzyme

  • uses MTHF (cofactor) → DHF

what is the cofactor required for thymidylate synthase to work?

• MTHF

  • methyl tetrahydrofolate

process of MTHF recycling

• MTHF → DHF → (DHF reductase) → THF → MTHF

what enzyme converts to DHF → THF

• DHF reductase

what type of drug is methotrexate

a) analog for IMP

b) analog of DHF

c) analog of dUMP

d) analog of GMP

b) analog of DHF

methotrexate MOA

• DHF analog

  • binds to DHFR (DHF reductase) → inhibition of DHFR = no recycling

which enzyme does methotrexate inhibit?

a) thymidylate synthase

b) IMPDH

c) ribonucleotide reductase

d) DHFR

d) DHFR

which drug can cause abortions and should not be given to pregnant women?

a) 5-Fluorouracil

b) Azathioprine

c) Methotrexate

d) Hydroxyurea

c) Methotrexate

specific mechanism of resistance for methotrexate

• overexpression of DHFR

Leucovorin is also known as ….

• folinic acid

Leucovorin MOA

• gives rise to THF → MTHF

  • opposes methotrexate

how is Leucovorin administered with Methotrexate? what is that called?

• administer Leucovorin ONE DAY after methotrexate (Leucovorin rescue)

  • leucovorin accumulates in normal cells → helps with DNA

  • rescues normal cells from methotrexate toxicity

T/F: cancer cells can accumulate leucovorin

• false

  • only normal cells accumulate leucovorin

5-fluorouracil is converted to ________

• 5-fluoro-dUMP

  • analog of dUMP

which enzyme does 5-fluoro-dUMP inhibit?

a) thymidylate synthase

b) IMPDH

c) ribonucleotide reductase

d) DHFR

a) thymidylate synthase

what type of drug is 5-fluoro-dUMP (from 5-fluorouracil or Capecitabine)

a) analog for IMP

b) analog of DHF

c) analog of dUMP

d) analog of GMP

c) analog of dUMP

specific mechanism of resistance for 5-Fluorouracil (5-FU) or Capecitabine

• overexpress thymidylate synthase

what is Capecitabine

• oral prodrug of 5-FU

how is leucovorin administered with 5-FU or Capecitabine

• administered TOGETHER (not next day)

  • MTHF cofactor is needed for 5-fdUMP to bind to thymidylate synthase

how are azathioprine and 6-mercaptopurine metabolized to become inactive

• xanthine oxidase

what is azathioprine

• prodrug → 6-mercaptopurine

what enzyme converts 6-mercaptopurine to 6-TIMP (6-thio-IMP)

• HGPRT enzyme

azathioprine or 6-mercaptopurine MOA

• converted to 6-TIMP by HGPRT → 6-TIMP (analog of IMP) binds to IMPDH instead instead

what type of drug is 6-TIMP (from azathioprine or 6-mercaptopurine)

a) analog for IMP

b) analog of DHF

c) analog of dUMP

d) analog of GMP

a) analog for IMP

should you administer 6-mercaptopurine or azathioprine with allopurinol (xanthine oxidase inhibitor)

• no

  • may block xanthine oxidase to increase [cancer drug] but will also increase ADE

  • little benefit to help with cancer

what are specific mechanisms of resistance for 6-mercaptopurine or azathioprine

1. overexpress IMPDH

2. overexpress XO (xanthine oxidase)

3. underexpress HGPRT

how is thioguanine converted to 6-thio-GMP

• HGPRT enzyme

thioguanine MOA

• converted to 6-thio-GMP by HGPRT

• 6-thio-GMP acts as an analog of GMP

  • incorporated into DNA → causes breakage

what type of drug is 6-thio-GMP (from thioguanine)

a) analog for IMP

b) analog of DHF

c) analog of dUMP

d) analog of GMP

d) analog of GMP

hydroxyurea MOA

• inhibits ribonucleotide reductase

  • blocks entire pathway

which enzyme does hydroxyurea inhibit?

a) thymidylate synthase

b) IMPDH

c) ribonucleotide reductase

d) DHFR

c) ribonucleotide reductase

which anti-cancer drug causes leukemia (WBC cancer) ?

a) leucovorin

b) hydroxyurea

c) methotrexate

d) thioguanine

b) hydroxyurea

what is an additional indication for hydroxyurea

• also used in treating sickle cell anemia

what type of drug is Cladribine

• purine analog (adenosine)

what type of drug is Clofarabine

• purine analog (adenosine)

purine analog MOA

• incorporated into DNA instead of adenosine → DNA becomes unstable → cell death

what type of drug is Cytarabine

• pyrimidine analog (cytidine)

what type of drug is Gemcitabine

• pyrimidine analog (cytidine)

pyrimidine analog MOA

• incorporated into DNA instead of cytidine → DNA becomes unstable → cell death

which of the following is an inhibitor of thymidylate synthase?

a) capecitabine

b) methotrexate

c) hydroxyurea

d) azathioprine

a) capecitabine

which of the following is an inhibitor of purine metabolism?

a) capecitabine

b) methotrexate

c) hydroxyurea

d) azathioprine

d) azathioprine