Principles of selective toxicity Flashcards
1
Q
What are the hallmarks of cancer?
A
- Resisting cell death
- Sustaining proliferative signalling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
2
Q
What are the aims of chemo?
A
- Eradicate the disease
- Induce remission
- Control symptoms
3
Q
What is combination therapy?
A
- using multiple different drugs to allow for lower dosage
4
Q
What are the characteristics of cytotoxic drugs?
A
- 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
5
Q
What is the MoA of alkylating agents?
A
- 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
6
Q
What are the main targets for antimicrobial action?
A
- Peptidoglycan of bacterial cell wall
- Protein synthesis
- Intermediary metabolism (folate coenzymes)
- Biosynthesis of DNA or RNA and cell membranes
7
Q
What is the bacterial cell wall made from?
A
- 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
8
Q
What is the action of transpeptidase?
A
- Forms a peptide bridge that cross-links the peptides coming off NAM
- Forms tight knit molecular complex
9
Q
What is the mechanism of action of penicillin?
A
- 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
10
Q
In general, what do aminoglycosides do?
A
- Interfere with microbe protein synthesis by acting on ribosomes
11
Q
What is the MoA of chloramphenicol?
A
- Binds to the 50S portion and inhibits the formation of a peptide bond between AAs
12
Q
What is the MoA of tetracycline?
A
- Interferes with the attachment of tRNA to mRNA-ribosome complex
13
Q
What is the MoA of erythromycin?
A
Binds to 50S portion, prevents movement of ribosome along the mRNA
14
Q
What is the MoA of streptomycin?
A
- Changes the shape of the 30S portion, causing mRNA to be read incorrectly
15
Q
What are the 3 main fungal groups that cause disease?
A
- Moulds - athlete’s foot, ring worm
- True yeasts - cryptococcal meningitidis and lung infections in immunocompromised
- Yeast-like fungi - oral and vaginal thrush, septicaemia
16
Q
Where can ant-fungals act?
A
- Cell wall (ergosterol)
- Cell membranes
- Nuclear division
- Nucleic acid synthesis
17
Q
What is the MoA of amphotericin B?
A
- 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)
18
Q
What is the life cycle of HIV (brief)?
A
- 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
19
Q
What is the MoA of zidovudine (ZDV)?
A
- 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
20
Q
What is the MoA of antifolates?
A
- Direct competition with substrate
- Stop folate synthesis
- Parasites have to make their folic acid from PABA, we can get it from diet
21
Q
What is the MoA of Proguanil (chloroquanide)?
A
- 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
22
Q
What is the MoA of methotrexate?
A
- 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
23
Q
What is the MoA of Sulphonamides?
A
- 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
