Antimetabolites (MC) - Block 4 Flashcards
What is the general MOA of antimetabolites?
Stop de novo synthesis of DNA by inhibiting formation of nucleotides:
1. Inhibit enzymes or promote incorporation of false nucleotides into DNA strands
What are false substrates?
Looks like endogenous substrates
* If cell can’t synthesize nucleotides -> DNA synthesis and tumor growth is stopped
What phase of mitosis do antimetabolites target?
S phase
What is the natural ligand targeted by pyrimidine antagonist?
dUMP: drug blocks formation of dTMP
Describe the MOA of dTMP synthesis?
dUMP is attacked by thymidylate synthase
* Cofactor (THF) removes hydrogen from 5th position
Describe the activity of fluorouracil?
5-Fluorinated dUMP (replaced H with F) -> 5-F-dUMP
* C6 postion more electrophilic (F is EWG) -> Cys195 attacks very fast -> C5-H can’t be removed because it is absent
* THF and drug are permanently bound together (irreversible inhibitor)
How is fluorouracil inactivated?
DPD (deficiency leads to toxicity)
Describe the formulation/PK of fluorouracil?
Prodrug that gets activated by the addition of a sugar and phosphate (5-F-dUMP)
Describe the mechanism and metabolism of capecitabine?
Carbamylated cytidine analog but also a 5-F-dUMP prodrug:
* Metabolized to fluorouracil than 5-F-dUMP
* Thymidine phophorylase is more active in tumors -> tumor selective generation of fluorouracil -> less side effect (hand foot syndrome and diarrhea)
7 steps to get activated
Formulation of capecitabine?
PO
Metabolism/DDI s of capecitabine?
InhibitionCYP2C0 and competes for albumin binding
* DDI with warfarin and pheyntoin
What are the methods of inactivating dTMP?
- Pyrimidine analogs
- Antifolates
MOA of methotrexate?
Completes witth 7,8-DHF for DHFR:
* Amine at N4 -> N1 is more basic -> misorients in proteins -> pseudoirrevesibly bound
* Inhibits THF from forming dTMP
What makes methotrexate tumor selective?
Gets polyglutamated by FPGS which traps it at site of action (because of negative charges) -> more efficient in tumor cells due to the entrappment of glutamates
ADRs of methotrexate? How is toxicity treated?
Lung disease and fatal skin reactions:
* Can give leucovorin to replace folates
Describe the imporvements of pemetrexed compared to methotrexate?
Targeting higher affintiy for FPGS -> more polyglutamed drug gets generated and trapped
* mono and polyglutamed can all inhibti enzyme
COunseling when administering pemetrexed?
- Take foic acid and vitamin B12 to reduce bone marrow suppression
- Pretreat with corticosteroids (rash) and antiemetics
Describe the MOA purine antagonist?
Inhibit de novo biosynthesis of AMP and GMP through inactivation of amidophosphoribosyl transferase
Describe the activation of purine antagonist?
Prodrugs that need to be converted to nucleotides through the addition of a phosphate and sugar
What are complications associated with purine antagonists?
Thiopurines are inactivated by TPMT:
* TPMT forms more active metabolite from active thiopurine ribonucleotide (more for mercaptopurine than thioguanine)
* Poor TPMT metabolizers -> no inactivation of prodrug -> more active drug (dose must be decreased)
* Extensive TMPT metabolizers for mercaptopurine will have more highly active metabolite -> drug sensitivity
How is the unique structure of mercaptopurine?
6-thio analog of purine
What are the major use-limiting toxicity of mercaptopurine?
Bone marrow suppression
Hepatotox in high doses
What is the structure and main structure of thioguanine?
6-thio analog of guanine
MOA: incorporation of di and triphosphate deoxy and ribonucleotides into DNA and RNA -> stops further elongation
What is the major use-limiting side effect of DNA Polymerase/DNA Chain Elongation Inhibitors?
Myelosuppression
Describe the structural similarities of DNA Polymerase/DNA Chain Elongation Inhibitors?
Halogenated and/or ribose-modified DNA nucleoside analogs/prodrugs that gets converted into triphosphate nucleotides
* Drugs based off DNA/RNA bases need to be nucleotides to be active otherwise they are prodrugs
What is the nucliec acid base of cytarabine and gemcitabine?
Cytidine (pyrimidine)
Elimination properties of gemcitabine?
Sex-dependent
* Women have greater risk for tox due to lower renal clearance
General structure of Cytarabine and Gemcitabine?
Missing triphosphate
What is the nucleic acid base of fludarabine?
Adenosine (Purine)
* Contains a phosphate group
What structure prevents some metabolism of fludarabine?
2-halogen
Why is fludarabine a monophosphate nucleotide?
Enhanced water solubility for IV but rapidly cleaved in bloodstream -> uses normal transport proteins
ADRs of fludarabine?
- Hemolytic anemia
- High doses -> CNS tox
- Potent immunosuppressant -> opportunisitc infection (for PCP prophylaxisis: Bactrim for 1 yr)
What is the MOA of pentostatin?
Ring-expanded purine ribonucleoside -> inhibits adenosine deaminase by elevating deoxyadenosine triphosphate levels -> inhibiting ribonucleotide reductase -> halting DNA synthesis
What is the MOA of hydroxyurea?
Blocks DNA synthesis by trapping tyrosyl free radicals at catalytic site of ribonucleotide reductase
Benefits and ADRs of hydroxyurea?
Increases effectiveness of radiation therapy (selective tox to cells in radiation-resistant S phase and stalls G1 stage, not achieved by radiation)
ADR: mild toxicities indefinitely
