Lecture 4 Antimetabolites Flashcards
pyrimidines
cytosine
thymine
uracil
purines
adenine
guanine
nucleosides
ribose = RNA
deoxyribose = DNA
purines change to -osine: adenosine, guanosine
pyrimidines change to - idine: uridine, thymidine, and cytidine
AMP
adenosine monophosphate
CDP
cytidine diphosphate
dGTP
deoxy-guanosine triphosphate
dTTP
deoxy-thymidine triphosphate
cAMP
3-5 cyclic adenosine monophosphate
nucleotides
adding one or more phosphates to the sugar portion of a nucleoside results in a nucleotide
antimetabolite
similar in structure to native molecules required for normal biochemical rxns, yet slightly different to interfere with normal function of cells
antimetabolites are analogues of
vitamins –> coenzymes
nitrogenous bases, nucleosides, adn nucleotides
antimetabolite general MOA
- interfere with production of nucleic acids by:
- inhibiting key enzymes for nucleotide synthesis
- substituting normal purines or pyrimidines - antimetabolites inhibit DNA and RNA synthesis
- antimetabolites inhibit cell growth and proliferation
- usually cell-cycle S phase dependent
antimetabolite examples
folate antagonists
pyrimidine antagonists
purine antagonists
Folate antagonists
antifolate
methotrexate (MTX, Trexall)
pemetrexed (Alimta)
Folic acid
B9
essential for cell growth and fetal development -> low folic acid can lead to neural tube defects
What is folic acid reduced to
tetrahydrofolate (FH4 active) by dihydrofolate reductase (DHFR)
What is FH4
coenzyme for the biosynthesis of purines and in the conversion od dUMP to dTMP
Methotrexate
MTX, analogue of folic acid
most widely used antifolate in cancer chemotx
activity against wide range of malignancies, including solid tumors and hematologic
What does MTX inhibit
dihydrofolate reductase (DHFR) -> prevents synthesis of FH4 -> crucial enzyme required for DNA synthesis and therefore exerts its effect on the S phase of the cell cycle.
What reverses methotrexate
leucovorin (reduced folate)
cells during S phase most sensitive
MOA of 5-fluorouracil (5-FU)
- 5-FU is ribosylated and phosphorylated -> nucleotide analogs
- 5-FUTP (instead of UTP) is incorportated into RNA -> inhibition of RNA processing
- 5-FdUMP inhibits irreversibly thymidylated syntase -> decrease dTMP -> decrease DNA synthesis
Combo leucovorin with 5-FU
- FH4 acts as a coenzyme for TS. In the presence of the fake substrate, it won’t work
- when given with 5-FU or capecitabine, it allows 5-FU to form a more stable bond to TS
- inhibition of TS in enhanced
cytotoxic effects of 5-FU are enhanced - Leucovorin allows TS To bind more tightly so when the TS binds 5-FU active metabolite, it allows the 5-FU to be more strongly inhibitory
What is TS
Thymidylate synthetase
MOA of 5-FU
LEUCOVORIN IS COENZYME TO TS -> BINDS AND ENHANCES BINDING TO 5-FU -> 5-FU WE WANT TO BIND TO MAKE TS STOP MAKING DNA SYNTHESIS (BLOCKS ENZYME LONGER) -> NO LONGER MAKING dTMP, SO NO DNA SYNTHESIS
MOA of capecitabine/Xeloda
can be taken orally unlike 5-FU
taken as 5-FU + X + Y
metabolized to 5-FU-X in liver, then metabolized in tumor tissue to 5-FU
highly selective analog
Cytarabine
analog of cytidine or deoxycytidine (nucleoside analogues)
Structure of cytarabine
AraC (cytarabine arabinoside) difference in sugar only for leukemias and lymphomas effective when combined with idareubicin cell cycle S phase specific
Cytarabine MOA
active metabolite at triphosphate stage –> AraCTP
- AraCTP is incorporated into DNA and RNA -> inhibits chain elongation and ligation
- AraCTP is a competitive inhibitor of DNA polymerase -> reduce DNA synthesis
Gemcitabine
analog of cytidine or deoxycytidine
Nucleoside analog
Gemcitabine application
- structurally similar to cytarabine
- Wider anti-tumor activity
- S and G1/S cell cycle phase specific
Gemcitabine MOA
- Gemcitabine is phosphorylated to gemcitbine di (dDdCPD) and tri (dFdCTP) phosphate
1. dFdCDP inhibits the ribonucleotide reductase -> decreases dCTP pool -> reduces DNA synthesis
2. dFdCTP inhibits DNA polymerase -> decrease DNA synthesis and induces apoptosis
3. dFdCTP is incorporated into DNA -> inhibits chain elongation and ligation
substrates of ribonucleotide reductase
diphosphate forms: ADP, GDP, UDP, and CDP
Toxicity of pyrimidine antagonist
5-FU: N/V, oral and GI ulceration, bone marrow depression
capecitabine: myelosupression, N/V (less than 5_FU)
Cytarabine: N/V, bone marrow depression, megaloblastosis, leukopenia thrombocytopenia
Gemcitabine
Purine Antagonists
6-thioguanine
6-mercaptopurine
fludarabine phosphate
MOA purine analogs
After ribosylation and phosphorylation DNA incorporation.
DNA incorporation inhibition of DNA synthesis.
MOA 6-TG and 6-MP
6-Thioguanine and 6-Mercaptopurine are
analogs of Guanine (=O -SH).
For childhood acute leukemias.
Triphosphate nucleotides formed from 6-MP and 6-TG DNA incorporation inhibition of DNA synthesis.
Fludarabine phosphate
nucleotide analog
MOA fludarabine
- Fludarabine phosphate is first dephosphorylated (extracellular).
- The intermediate is then phosphorylated (intracelluarly).
- The triphosphate metabolite inhibits DNA polymerase; incorporated into DNA and RNA; diphosphate metabolite inhibits ribonucleotide reductase -> reduces DNA synthesis.
For chronic lymphocytic leukemia (CLL)
Purine Antagonist Toxicity
Thioguanin and Mercaptopurine: well tolerated, bone marrow suppresion at high doses and TPMT deficient pt
Fludarabine: myelosupression, neurotoxicity at high doses
