2. Objective
Differentiate between folate antagonist and pyrimidine
analogue according to their pharmacological aspects
with two drug example for each
2
3. Lesson Plan
Background
Introduction
Building bridge
Animated slides
Question and
answer session
Activity 1
Activity 2 Summarize
lesson
Recommended
book
4
10. Mechanism of Action of Methotrexate
FH2
FH4
dTMP
dUMP
MTX
DNA
Dihydrofolate
Reductase
Thymidylate
Synthase
11
11. Mechanism of Action of Fluorouracil
FH2
FH4
dTMP
dUM
P
DNA
Dihydrofolate
Reductase
Thymidylate
Synthase
Cytarabine
Fluorouracil
12
12. Activity 2
Group Discussion
1. Why are antimetabolites generally considered cell-specific?
2. Analyse two differences between folate antagonist and pyrimidine
analogue.
Exit slips
13
13. Closure
James Ritter Rod Flower Graeme Henderson Yoon Kong Loke David
MacEwan Humphrey Rang. Rang and dale’s Pharmacology, 9th edition. Elsevier.
● https://youtu.be/kYmLQP2M-qo
● www.youtube.com/watch?v=RqDzfe7XZ8U&t=45s
14
Summarize lesson
Recommended book and video links
14. Assessment
Differentiate between methotrexate and fluorouracil on the basis of
their mode of action.
Which of the following statements is FALSE?
a. Alkylating agents are a group of genotoxic chemotherapy treatments
b. Alkylating agents work by modifying DNA bases
c. Alkylating agents disrupt DNA replication and transcription
d. Alkylating agents act on G2 phase of cell cycle
3
Editor's Notes
in 2001 (for example) 270000 new cases were reported in the UK
Cancer is also responsible for approximately one-quarter of all deaths in the UK, with lung and bowel cancer comprising the largest category
The terms cancer, malignant neoplasm (neoplasm simply means 'new growth') and malignant tumour are synonymous. Both benign and malignant tumours manifest uncontrolled proliferation, but the latter are distinguished by their capacity for dedifferentiation, their invasiveness and their ability to metastasise (spread to other parts of the body)
. (for example antifolates interfere with the use of folic acid).
In structure, folates consist of three elements: a pteridine ring, p-aminobenzoic acid and glutamic acid (Fig. 51.7). Folates are actively taken up into cells, where they are converted to polyglutamates. In order to act as coenzymes, folates must be reduced to tetrahydrofolate (FH4). This two-step reaction is catalysed by dihydrofolate reductase, which converts the substrate first to dihydrofolate (FH2), then to FH4 (Fig. 51.8). FH4 functions as an essential cofactor carrying the methyl groups necessary for the transformation of 2´-deoxyuridylate (DUMP) to the 2´-deoxythymidylate (DTMP) required for the synthesis of DNA and purines. During the formation of DTMP from DUMP, FH4 is converted back to FH2, enabling the cycle to repeat. Methotrexate has a higher affinity than FH2 for dihydrofolate reductase and thus inhibits the enzyme (Fig. 51.8), depleting intracellular FH4. The binding of methotrexate to dihydrofolate reductase involves an additional bond not present when FH2 binds. The reaction most sensitive to FH4 depletion is DTMP formation.
