Lecture 19 - Principles of Chemotherapy

Question 1

What are the mechanisms of selective targeting in chemotherapy?

Answer 1

1. Unique targets - unique to pathogen or cancer cell not present in host (high theraputic index)
2. Similar targets - similar but not identical to cells in the host
3. Common targets - Targets shared with host but vary in importance between pathogen and host

Question 2

What is a popular unique target for antibacterial drugs?

Answer 2

The biochemical pathway that leads to synthesis of the bacterial peptidoglycan cell wall (ex penicillin, vancomycin)

Question 3

What is a popular unique target for treating fungal infections?

Answer 3

Ergosterol is essential for fungi cell membrane made up of glucan and chitin

Question 4

Selective inhibition of similar targets - Vemurafenib

Answer 4

Preferably inhibits B-raf protein kinase mutated in skin cancer

Question 5

Selective inhibition of similar targets - Nilotinib

Answer 5

selectively inhibits mutated BCR-Abl kinase

Question 6

Selective inhibition of similar targets - Streptomycin

Answer 6

Inhibitor of bacterial protein synthesis, targets ribosomal RNA and proteins utilized in bacteria

Question 7

Selective inhibition of similar targets - DHFR (dihydrofolate reductase) inhibitors

Answer 7

Blocks folate metabolism, DHFR protein sequeces cross species vary greatly

Question 8

What causes chronic myeloid leukemia (CML)?

Answer 8

Translocation on chromosome 9 of the ABL1 proto-oncogene which encodes a cytoplasmic and nuclear protein tyrosine kinase to chromosome 22 –> can result in a hybrid Bcr-Abl protein which causes it to be constitutively active

Question 9

What drug inhibits dihydropteroate synthase in bacteria?

Answer 9

Sulfonamides

Question 10

What drugs inhibit DHFR in humans and bacteria?

Answer 10

Trimethoprim, Methotrexate, Pyrimethamine

Question 11

What drugs inhibit the conversion of tetrehydrofolate to thymidine required for DNA synthesis in humans and bacteria?

Answer 11

S-fluorouracil and Flucytosine

Question 12

Common target drugs - Maraviroc

Answer 12

An antiviral drug that inhibits human chemokine receptor CCR5 which is essential for entry of certain strains of HIV into cells, but is dispensible for human health

Question 13

Common target drugs -
5-fluorouracil (5-FU)

Answer 13

An antimetabolite that inhibits thymidylate synthase (converts dUMP to dTMP) by causing DNA damage, induces the cell to activate its apoptotic pathway. Does not affect on-dividing cells

Question 14

Antineoplastic drug classes - Inhibitors of DNA synthesis and integrity

Answer 14

• Antimetabolites
• Folate pathway inhibitors
• Topoisomerase inhibitors

Question 15

Antineoplastic drug classes - DNA damagin agents

Answer 15

• Alkylating agents
• Antitumor antibiotics
• Platinum complexes

Question 16

Antineoplastic drug classes - Inhibitors of microtubule function

Answer 16

• Vinca alkaloids
• Taxanes

Question 17

Antibacterial drug classes - Inhibitors of cell wall synthesis

Answer 17

• Fosfomycin
• Cycloserine
• Vancomycin
• Penicillins
• Cephalosporins
• Monobactams
• Carbapenems
• Ethambutol
• Pyrazinamide
• Isoniazid

Question 18

Antibacterial drug classes - Inhibitors of transcription and translation

Answer 18

• Rifampin
• Aminoglycosides
• Spectinomycin
• Tetracyclines
• Macrolides
• Chloramphenicol
• Linocosamides
• Streptogramins
• Oxazolidinones
• Pleuromutilines

Question 19

Antibacterial drug classes -Inhibitors of DNA synthesis and integrity

Answer 19

• Sulfonamides
• Trimethoprim
• Quinolones

Question 20

Unique antifungal agents - Flucytosine

Answer 20

An antimetaolite that inhibits fungal DNA synthesis

Question 21

Unique antifungal agents - Griseofulvin

Answer 21

Inhibits fungal mitosis by disrupting mitotic spindles, arresting metaphase in cell division

Question 22

Unique antifungal agents - Allylamines, benzylamines, imidazoles, triazadoles

Answer 22

Inhibit the ergosterol synthesis pathway in the endoplasmic reticulum

Question 23

Unique antifungal agents - Echinocandins

Answer 23

Inhibits the synthesis of glucan formation for fungal cell walls

Question 24

Unique antifungal agents - Polyenes (Amphotericin B)

Answer 24

Binds to ergosterol in the fungal membrane disrupting plasma membrane integrity (forms cation-selective pores in the membranes)

Question 25

Mechanisms of genetic drug resistance - Reduced intracellular concentration of drug with antimicrobial examples

Answer 25

1. Inactivate drug - Inactivation of beta-lactam antibiotics by beta-lactamase 2. Prevent uptake of drug - Prevention of aminoglycoside entry by altered porins 3. Promote efflux of drug - Efflux of multiple drugs by MDR membrane efflux pump

Question 26

Mechanisms of genetic drug resistance - Reduced intracellular concentration of drug with antineoplastic examples

Answer 26

1. Inactivate drug - Inactivation of antimetabolites by deaminase 2. Prevent uptake of drug - Decreased methotrexate entry by decrease expression of reduced folate carrier 3. Promote efflux of drug - Efflux of multiple drugs by p170 membrane efflux pump (MDR1)

Question 27

Mechanisms of genetic drug resistance - Target based mechanisms with antibacterial examples

Answer 27

1. Altered drug target - Expression of altered peptidoglycan that no longer binds vancomycin 2. Bypass metaolic requirement for target - Inhibition of thymidylate synthase bypassed by exogenous thymidine

Question 28

Mechanisms of genetic drug resistance - Target based mechanisms with antineoplastic examples

Answer 28

1. Altered drug target - Expression of muant DHFR that no longer binds methotrexate 2. Bypass metabolic requirement for target - Loss of estrogen receptor-dependent growth results in tamoxifen resistance

Question 29

Mechanisms of genetic drug resistance - Sensitivity to apoptosis with antineoplastic drugs

Answer 29

Loss of active p53

Question 30

What is the multidrug resistance protein 1 (MDR1)?

Answer 30

Aka P-glycoprotein 1, a member of the ABC (ATP-binding cassette) family of efflux transporters (drug compounds are actively transported back into the intestinal lumen and reduces some drug bioavalability)

Question 31

How do cancer cells make the tumor less sensitive to chemotherapy or targeted treatments?

Answer 31

Cancer cells can use DNA methylation or histone modification to silence key tumor-suppressor genes or regulate genes involved in drug metabolism - These epigenetic changes can upregulate expression of ABC transporters which actively pump out chemotherapy drugs from the cancer cell

Question 32

What are the advantages of combination chemotherapy?

Answer 32

- Additive or synergistic effects - Increased spectrum of activity - Decreased drug resistance

Question 33

What are the disadvantages of combination chemotherapy?

Answer 33

- Possible antagonistic effects - Increased risk of drug interactions - May have increased toxicity - Increased cost

Question 34

What type of combination chemotherapy is the result of DHFR inhibitors and sulfonamides and why is it more effective?

Answer 34

Sequential blockade - sulfonamide decreases the intracellular concentration of dihydrofolate --> increases the effctiveness of the DHFR inhibitor --> competes with DHF for binding to the enzyme - Resistance to drug combination develops much slower