4. cancer chemotherapy: antimetabolites

what are the 3 main targets for antimetabolites

what are the 3 main targets for antimetabolites

1. dihydrofolate reductase

2. thymidylate synthetase

3. n5,n10-methenltetrafolic acid

what is de novo pyrimidine synthesis

N5-N10-methylene-tetrahydrofolate to dehydrofolate by thymidylate synthetase

• addition of CH3

• dUMP to dTMP

effectiveness of pyrmidine antimetabolises (5-FU, 5-FdUMP)

• 5-Fu needs to be metabolised to a more potent 5-FdUMP

what are 3 examples of antifolates

1. dihydrofolate reductase

2. aminopterin

3. methotrexate

pyrimidine antimetabolises: how are they incorporated into nucleic acids

• FU is also incorporated into RNA & DNA,

• RNA: disruption of function

pyrimidine antimetabolites: what causes cell death

thymidylate synthase inhibition often to be lethal lesion however thymidine should protect

what are 2 new 5-FU analogues

1. gemcitibine

2. capecitabine (undergoes transition to 5’-DFCR to 5’-DFUR to 5'-FU)

what are examples of 2 purine antimetabolites and what are their biological analogues

1. 6-mercaptopurine (6-MP)

   • analogue for 6-thioguanine (6-TG)

2. Hypoxanthine

   • analogue for Guanine

what are the site of action for purine antimetabolites

• inhibition of purine synthesis

• incorporation into DNA, disruption of base-pairing, failure to act as proper replication template

• effect: cell cycle arrest

Pyrimidine antagonists: what are the uses, mode of action and toxicity of 5-FU and 5-FdUMP

uses

• colorectal cancer

• breast cancer

• pancreatic cancer

mode/site of action:

• inhibition of pyrmidine synthesis

• disruption of RNA, DNA function

toxicity

• bone marrow depression

• mucositis

purine antagonists: what are the 2 drugs, their uses, their mode of action and toxicity

1. 6-mercaptopurine

2. 6-thioguanine

uses:

• acute lymphocytic leukeamia

mode/site of action:

• inhibition of purine synthesis

• disruption of DNA replication

toxicity:

• bone marrow depression

• nausea + vomiting

what is a folate anatgonist drug, its uses, mode of action and toxicity

folate antagonist: methotrexate

uses:

• acute lymphocytic leukaemia

• breast cancer

mode/site of action

• inhibition of pure/pyrmidine synthesis

toxicity

• bone marrow depression