Principles of selective toxicity

Question 1

What are the hallmarks of cancer?

Answer 1

• Resisting cell death
• Sustaining proliferative signalling
• Evading growth suppressors
• Activating invasion and metastasis
• Enabling replicative immortality
• Inducing angiogenesis

Question 2

What are the aims of chemo?

Answer 2

• Eradicate the disease
• Induce remission
• Control symptoms

Question 3

What is combination therapy?

Answer 3

• using multiple different drugs to allow for lower dosage

Question 4

What are the characteristics of cytotoxic drugs?

Answer 4

• active against cycling/ proliferating cells
• Phase-specific drugs - affect certain points of cell cycle
• Antimetabolites = s-phase specific
• Mitotic inhibitors = M=phase specific
• Cycle-specific drugs - affect cycling cells throughout the cell cycle
• Affect DNA synthesis
• less activity against resting/ senescent cells

Question 5

What is the MoA of alkylating agents?

Answer 5

• Form highly reactive carbonium ions (central carbon is a cation)
• This causes transfer of the alkyl groups to nucleophilic sites on DNA bases by covalent bonding
• Nuclear and cellular damaging effects - DNA cross-linking, abnormal base pairing, DNA strand breakages and RNA and protein damage

Question 6

What are the main targets for antimicrobial action?

Answer 6

• Peptidoglycan of bacterial cell wall
• Protein synthesis
• Intermediary metabolism (folate coenzymes)
• Biosynthesis of DNA or RNA and cell membranes

Question 7

What is the bacterial cell wall made from?

Answer 7

• Peptidoglycan (sugars and AAs)
• Polysaccharide portion has NAG and NAM
• Protein portion = short chains of AAs that link layers of polysaccharide togerther by NAM
• LPS has Lipid portion called lipid A and polysaccharide portion

Question 8

What is the action of transpeptidase?

Answer 8

• Forms a peptide bridge that cross-links the peptides coming off NAM
• Forms tight knit molecular complex

Question 9

What is the mechanism of action of penicillin?

Answer 9

• Side chain from beta-lactam ring determines the unique pharmacological properties of the different penicillins
• Bactericidal
• Binding to penicillin binding proteins on susceptible microbes - inhibition of peptide cross-linking within the microbial cell wall
• Autolytic enzymes -> cell lysis and death

Question 10

In general, what do aminoglycosides do?

Answer 10

• Interfere with microbe protein synthesis by acting on ribosomes

Question 11

What is the MoA of chloramphenicol?

Answer 11

• Binds to the 50S portion and inhibits the formation of a peptide bond between AAs

Question 12

What is the MoA of tetracycline?

Answer 12

• Interferes with the attachment of tRNA to mRNA-ribosome complex

Question 13

What is the MoA of erythromycin?

Answer 13

Binds to 50S portion, prevents movement of ribosome along the mRNA

Question 14

What is the MoA of streptomycin?

Answer 14

• Changes the shape of the 30S portion, causing mRNA to be read incorrectly

Question 15

What are the 3 main fungal groups that cause disease?

Answer 15

• Moulds - athlete’s foot, ring worm
• True yeasts - cryptococcal meningitidis and lung infections in immunocompromised
• Yeast-like fungi - oral and vaginal thrush, septicaemia

Question 16

Where can ant-fungals act?

Answer 16

• Cell wall (ergosterol)
• Cell membranes
• Nuclear division
• Nucleic acid synthesis

Question 17

What is the MoA of amphotericin B?

Answer 17

• anti-fungal
• interacts hydrophobically with ergosterol in fungal cell membrane and forms pores within it - aggregates in the membrane
• Loss of cell contents and cell death ensues
• Selectively toxic (we have cholesterol instead)

Question 18

What is the life cycle of HIV (brief)?

Answer 18

• Binding to cell
• Internalisation
• Uncoating
• reverse transcription of ssRNA
• Integration of dsDNA into cell DNA
• translation of viral mRNA into viral proteins - degraded by protease
• Viral peptides and genomic RNA stored in vesicle, budded off from membrane

Question 19

What is the MoA of zidovudine (ZDV)?

Answer 19

• ZDV is thymidine analogue, but has N3 instead of OH
• Series of phosphorylations from ZDV to ZDVTP via thymidine kinase
• ZDVTP is incorporated into growing DNA strand and terminates synthesis due to lack of OH
• Causes selective inhibition of reverse transcriptase as has higher affinity
• Stops virus from infecting

Question 20

What is the MoA of antifolates?

Answer 20

• Direct competition with substrate
• Stop folate synthesis
• Parasites have to make their folic acid from PABA, we can get it from diet

Question 21

What is the MoA of Proguanil (chloroquanide)?

Answer 21

• Converted into an active metabolite (cycloquanil)
• Selective inhibitor of plasmodial DHFR and thymidylate synthesis
• Thymidylate synthase (phosphorylation of thymidine) - DNA synthesis and repair
• Inhibits DNA synthesis and folate factors become depleted

Question 22

What is the MoA of methotrexate?

Answer 22

• Anti-tumour agent
• A folic acid analogue
• Binds avidly to DHFR, causing inhibition of conversion of DHF to THF
• Inhibition of metabolic processes interferes with DNA, RNA and key cellular proteins
• Human cell also require folic acid by utilise preformed from diet so unaffected by methotrexate

Question 23

What is the MoA of Sulphonamides?

Answer 23

• Bacteria make their own folic acid using PABA
• Sulphonamides are structurally similar to PABA - competitively inhibit dihydropteroate synthase (DHPS)
• This stops the PABA binding to pteridine residue to form the next precursor of folic acid
• Makes pseudofolate, which is metabolically injurious to the bacter -> dies