Principles of Selective Toxicity

Question 1

CANCER CHEMOTHERAPY:
What does it aim to do?

What is the Therapeutic Index of Cytotoxic drugs? What does this mean?

Antifolates:
How is Folic acid made in cancer cells?
→ What enzyme converts DHF to THF?

What does Methotrexate do?
→ Why are Healthy cells unaffected by this drug?

What is used to produce Folic acid in Bacteria?
→ How do Sulphonamides work here?

Answer 1

• Eradicate cancer, Induce remission (state of no disease), or Control symptoms
• Therapeutic Index of 1 - Conc. that kills cancer cells is the same conc. that causes toxicity
• DHF (Dihydrofolic) acid → THF (Tetrahydrofolic) acid → Folic acid
  → DHFR (Dihydrofolate Reductase)
• DHFR inhibitor
  → They use PREMADE Folic acid from diet instead of making it
• PABA
  → Similar structure to PABA and competitively inhibit PABA from binding to its enzymes

Question 2

ANTIVIRALS:
How does Zidovudine (ZDV) work against viruses?
→ How does it have selectively affect the virus?

Antifolates:
What is Proguanil (Chloroguanide)? How does it work?
→ What is it used for?

Answer 2

• Prodrug and is phosphorylated into ZDVTP. Thymidine is also phosphorylated to TTP, which competes with ZDVTP due to their similar structures
  o ZDVTP causes Chain termination and Selective inhibition of Reverse Transcriptase (RT)
  → Very high affinity for RT compared to other polymerases
• Converted to active Triazine metabolite (Cycloquanil), which Selectively inhibits DHFR Thymidylate Synthase = Inhibition of DNA synthesis/repair
  → Malaria

Question 3

ANTIFUNGALS:
Give an example of a Polyene Macrolide drug

How does this drug work against Fungi?

Why does this drug not affect Human cells?

Answer 3

• Amphotericin B
• Binds to Ergosterol in fungal cell membrane, forming Pores = Cell death
• Human cell walls have Cholesterol, not Ergosterol