L15. Anticancer drugs I

Question 1

methotrexate

Answer 1

• anti-metabolite
• inhibits thymidine synthesis thus DNA synthesis
• competitive antagonist that inhibits DHF reductase thus inhibiting THF which is necessary for thymidine synthesis
• drug starves cells from thymidine

Question 2

leucovorin

Answer 2

• THF analog
• at low doses, can enter normal cell to bypass the need for DHF reductase
• can limit side effects of methotrexate

Question 3

5-FU

Answer 3

• anti-metabolite
• inhibits thymidine synthesis thus DNA synthesis
• small metabolite that inhibits pyrimidine synthesis
• pro-drug, metabolized into FdUMP
• FdUMP is a pyrimidine analog that will inhibit thymidylate synthase thus blocking the conversion of dUMP to dTMP
• result: dNTPS imbalance, increased dUMP which damages DNA

Question 4

cytarabine

Answer 4

• mimics deoxycytidine
• converted to cytosine triphosphate
• modification of OH group in the wrong position leads to conformational change that does not favor elongation
• causes chain termination
• at high doses: DNA polymerase inhibitor

Question 5

melphalan

Answer 5

• nitrogen mustard gas
• reactive electrophile
• surrounded by chloroethyl groups
• chlorine is released to seek e- to gain e-

Question 6

mechloroethamine

Answer 6

• nitrogen mustard gas
• reactive electrophile
• surrounded by chloroethyl groups
• chlorine is released to seek e- to gain e-

Question 7

cyclophosphamide

Answer 7

• nitrogen mustard gas
• forms active phosphoramide mustard alkylating agents by adding OH

Question 8

phosphoramide mustard

Answer 8

• bifunctional alkylating agent
• cross links DNA
• powerful since cross links are more difficult to repair

Question 9

acrolein

Answer 9

• nitrogen mustard gas
• very toxic

Question 10

platins/cisplatins

Answer 10

• alkylating agents without chloroethyl groups
• replaces chlorine with water which is then replaced with N-heterocyclic DNA bases
• enters via passive diffusion of CTR1 transporter

Question 11

anti-tumour antibiotics

Answer 11

poison the enzyme by stabilizing TOP II
> prevents proteins to rejoin

Question 12

paclitaxel

Answer 12

• plant alkaloid
• binds the interior surface of microtubules and stabilizes them in polymerized state
• cell blocked in mitosis
• poorly soluble so formulated with surfactant
• hypersensitivity so requires premedication with corticosteroid

Question 13

abraxane

Answer 13

• developed to increase efficacy and reduce toxicity of paclitaxel
• albumin nanoparticle
• overall toxicity profile better BUT incidence of sensory neurotoxicity is higher