Antimetabolites - Pyrimidines Flashcards
Which of the following statements regarding antimetabolites is incorrect?
A. their main target is enzymes involved in nucleotide biosynthesis
B. bind reversibly to rate-limiting step enzymes
C. purine antagonists block synthesis of AMP and GMP
D. pyrimidine antagonists block synthesis of dTMP
E. one MOA is stopping DNA chain elongation
(B) antimetabolites IRREVERSIBLY bind to the rate-limiting step enzymes
*Antimetabolites can arrest DNA chain elongation by promoting the incorporation of abnormal nucleotides into the growing DNA strand thereby stopping cell growth
What is the general MOA of antimetabolites?
stop DNA synthesis by inhibiting nucleotide formation
Name the enzyme and cofactor required for dTMP biosynthesis from dUMP (biosynthesis of a pyrimidine)?
Enzyme - Thymidylate synthase
Cofactor - Folate
Which of the following statements is incorrect?
A. methyl transfer to dUMP is the rate-limiting step in dTMP biosynthesis
B. dTMP biosynthesis involves formation of a ternary complex
C. direct inhibitors of thymidylate synthase all posses a fluorine atom
D. false ternary complex cannot breakdown b/c N10 cofactor’s inability to abstract F
E. All are correct
(E) all are correct
- the ternary complex consists of thymidylate synthase, dUMP, and folate
- N10 would normally abstract the 5-H atom leading to breakdown of ternary complex. Since a 5-F atom is added, N10 can no longer abstract b/c F is very electronegative which repels N10
Which enzyme is responsible for ultimately re-forming the cofactor folate using dihydrofolate (DHF) and NADPH (electron donor)? What intermediate is formed before converting DHF to folate?
Dihydrofolate reductase (DHFR)
Tetrahydrofolate (THF)
*7,8-DHF + DHFR & NADPH = THF + SHMT = Folate
All of the following statements are true except?
A. The F in thymidylate synthase inhibitors is small and has no steric hindrance
B. Thymidylate synthase is regenerated in the production of dTMP under normal conditions
C. 5-FU is light sensitive
D. Capecitabine has improved tumor selectivity
E. Floxuridine has widespread effects in many parts of the body
(E) The effects of Floxuridine are limited to the liver b/c of the 5-FU + deoxysugar structure. Thus, Floxuridine is only used for the palliative Tx of GI adenocarcinoma that has metastasized to the liver and cannot be managed surgically
*D - Capecitabine has improved tumor selectivity b/c the enzyme that converts the drug to Fluorouracil (and subsequently to active 5-F-dUMP) is more active in tumor cells than normal cells (the enzyme is thymidine phosphorylase)
True or False - direct inhibitors of thymidylate synthase are all made to look like uracil?
True - if they look like uracil they can be incorporated into the ternary complex and inhibit the formation of dTMP from dUMP
True or False - direct inhibitors of thymdylate synthase result in irreversible inhibition of thymidylate synthase?
True - they form a stable fluorinated ternary complex
Which of the following are prodrugs?
A. Fluorouracil B. Floxuridine C. Capecitabine D. A & B only E. All of the above
(E) all of the above are prodrugs
Which of the following drugs are direct inhibitors of thymidylate synthase?
A. Floxuridine B. Pemetrexed C. Methotrexate D. Capecitabine E. Both A & D
(E) both Floxuridine and Capecitabine are DIRECT inhibitors of thymidylate synthase.
Methotrexate and Pemetrexed are INDIRECT inhibitors of thymidylate synthase
Which of the following statements is incorrect?
A. Thymidine phosphorylase is less active in tumors than healthy tissue
B. A potentially deadly SE of 5-FU is GI ulceration
C. Floxuridine is administered via hepatic artery
D. The prodrug Capecitabine conversion in vivo involves 5-FU as an intermediate
E. Floxuridine is used in the palliative Tx of GI adenocarcinoma
(A) thymidine phosphorylase is MORE active in tumors than healthy tissue
*thymidine phosphorylase is involved in the conversion of Capecitabine to 5-F-dUMP. Specifically it liberates 5-FU from sugar allowing typical formation (add sugar, phosphorylate, reduce, dephosphorylate) of false substrate 5-F-dUMP
Which of the following statements regarding 5-FU (Fluorouracil) are true?
A. Administered IV only
B. Can only be given up to max of 12 days
C. 5-F-dUMP is the active form of the false substrate
D. B & C only
E. All of the above
(D) 5-FU can be administered IV AND TOPICALLY
5-FU is administered IV in the palliative Tx of breast, stomach, pancreas, and colorectal cancers, and solid tumors AND topically for Tx of premalignant keratoses
Which direct thymidylate synthase inhibitor is used as first-line therapy in colorectal cancer?
Capecitabine (Xeloda ®)
Explain the in-vivo conversion of direct inhibitors of thymidylate synthase?
Fluorine containing compounds conversion in-vivo to false substrate involves the following steps:
- sugar and phosphate are installed on the antimetabolite drug forming a fake nucleotide.
- compound is phosphorylated, reduced (to form deoxy compound) then de-phosphorylated to form the active false substrate (ex 5-F-dUMP)
The primary reason Capecitabine has improved tumor selectivity is because:
A. It’s orally available
B. Significant D/D interaction with warfarin
C. Carboxyesterase transforms the prodrug after it penetrated a cell
D. thymidine phosphorylase is much more active in tumor cells
E. Capecitabine does not have improved tumor selectivity
(D) Capecitabine has improved tumor selectivity because thymidine phosphorylase is much more active in tumor cells and thymidine phosphorylase is what activates Capecitabine. So, the drug is activated right at the sight of tumors
*C - carboxyesterase is involved in the first step in the conversion of Capecitabine to active 5-F-dUMP
