7.0 Chemotherapy Flashcards

Question

Goseraline

Answer 1

- Class = Hormone therapy (anticancer)
- Target = GnRH receptor
- Mechanism = GnRH analogue → biochemical castration
- Steps:
• GnRH ⟶ ↑ LH + FSH ⟶ ↑ testosterone secretion
• Testosterone can stimulate prostate cancer
• Normal secretion of GnRH is pulsatile
• Continuous GnRH ⟶ immediate ↑ LH + FSH ⟶ complete inhibition of their release
Goseraline effectively does this (causes biochemical castration)
- Info:

Answer 2

- Class = Small molecule inhibitor (anticancer)
- Target = BCR-ABl
- Mechanism = Inhibition
- Steps:
BCR-ABl = RTK
- Info:
• Most chronic myeloid leukaemia patients carry the philadelphia chromosome, resulting from a reciprical exchange of the long arms of chromosomes 9 and 22 - this generates a fusion gene, leading to a BCR-ABL protein with tyrosine kinase activity. Imatinib blocks this activity to prevent excessive proliferation
• Can also inhibit c-kit tyrosine kinase activity, the encoding gene of which is overexpressed in gastrointestinal stomal tumours (GISTs)
Marketed as Gleevec

Answer 3

- Class = Antimicrobial
- Target = Mycolic acid synthesis
- Mechanism = Inhibition of mycolic acid synthesis
- Steps:
M.tuberculosis has significant intrinsic resistance to many antimicrobial compounds compared to other bacteria due to the high mycolic acid content in the lipid bilayer
- Info:
-first line treatment for tuberculosis against M. tuberculosis.
-other bacteria, which do not feature mycolic acid, have a high intrinsic resistance to this drug

Answer 4

- Class = Folate source
- Target = -
- Mechanism = Provides a metabolic equivalent to folate
- Steps:
• Can be converted to reduced folic acid derivatives (e.g. tetrahydrofolate) ∴ has a vitamin activity equivalent to folic acid
• ∵ does not rely on DHFR, it is unaffected by methotrexate

- Info:
Selectively is achieved ∵ proliferating tumour cells have much higher tetrahydrofolate requirement, thus leucovorin doesn't help them as much as it does healthy cells

Answer 5

- Class = Nitrosurea (anticancer)
- Target = DNA
- Mechanism = Not well understood
- Steps:
Cause alkylation and carbamoylation
Can produce inter strand cross-links
Bind preferentially to guanine
- Info:
Oral administration
Lipophilic → good brain penetration → Important for brain tumours
-Side effects:
↓WBC, ↓ Platelets + damage organs

Answer 6

- Class = Arsenic compound (anti-parasitic)
- Target = Lipoic acid dependent enzymes
- Mechanism = Inhibition
- Steps:
Enzymes inhibited = 2-oxo-decarboxylase and pyruvate dehydrogenase
Affects ATP synthesis
Melarsoprol = prodrug (drug = melarsan oxide)
- Info:
Specific for Leishmaniasis

Answer 7

- Class = Antibiotic (beta-lactam)
- Target = Cell wall biosynthesis
- Mechanism = Inhibits Peptidoglycan transpeptidase
- Steps:
1) PG transpeptidase mistakes methicillin for an uncrossed PG chain terminating in D-Ala-D-Ala
2) Active site serine attacks the beta lactam ring of the antibiotic → acyl-enzyme intermediate in which the beta-lactam ring has opened
3) This resulting covalent penicilloyl enzyme is very slow to hydrolyse → ↓↓↓ further PG synthesis
4) Causes cell lysis because of continued activity of autolysins
- Info:
Only proliferating cells in which autolysins are active are sensitive to beta lactam antibiotics
Introduced following emergence of penicillin-resistant gram positive bacteria (has a bulky 2,6-dimethoxybenzoyl substitute to reduce the susceptibility of the intermediate enzyme to hydrolysis)
-Resistance mechanism:
MecA gene which (encodes a beta-lactam resistance bi-functional transpeptidase/transglycosylase)
Fem genes (contribute to resistance by adding a cross bridge to PG strands, which allows PG to act as a better substrate for MecA transpeptidase)

Answer 8

"- Class = Folic acid antagonist
- Target = DHFR (dihydrofolate reductase)
- Mechanism = Inhibition
- Steps:
Disruption of nucleotide synthesis ⟶ disruption of DNA replication
- Info:
↑↑ use of methotrexate ⟶ toxicity to normal cells (leucovorin can help with this)

"

Answer 9

- Class = Imidazole (antifungal)
- Target = Enzymes involved with ergosterol synthesis
- Mechanism = Inhibition
- Steps:
↓ ergoesterol → alters fluidity of membrane → alters permeability + activity of membrane associated enzymes
- Info:
Also works on parasites (Leishmania)

Answer 10

- Class = Antibiotic (aziridine containing antibiotic/anticancer)
- Target = DNA template
- Mechanism = Covalent bonding
- Steps:
Alkylates DNA (Preferentially at guanine bases at GC positions in complementary DNA strands)
Results in the cross-linking of two guanine bases, one in each strand of the double helix ⟶ prevents strand separation during DNA replication and transcription
- Info:
Can also be used as an anticancer medication
More reactive in low oxygen conditions

Answer 11

- Class = Anthracyclin (anti-cancer)
- Target = DNA
- Mechanism = Non-covalent binding
- Steps:
Intercalation causes unwinding of the helix → DNA + RNA pol affected → ↓ transcription and replication
- Info:
This is a modified version of doxorubicin - it lacks the hydroxyquinone moiety therefore does not produce the free radicals that caused all the side effects (cardiac shit)
Also inhibits topoisomerase II

Answer 12

- Class = Reverse transcriptase inhibitor (non-nucleoside)
- Target = HIV reverse transcriptase
- Mechanism = Inhibition
- Steps:
Binds to target enzyme near catalytic site and denatures it
- Info:
Component of HAART
Reverse transcriptase activity is early in replication cycle, therefore this drug only has effect early

Answer 13

- Class = Anti-influenza drug
- Target = Neuraminidase
- Mechanism = Inhibitor
- Steps:
Inhibits NA → ↑ viral aggregation + ↓ release from host
- Info:
Oseltamivir is an ethyl ester pro-drug
Cleaved by esterases in the plasma + gut on adsorption

Answer 14

- Class = Antibiotic (beta-lactam)
- Target = Cell wall biosynthesis
- Mechanism = Inhibits Peptidoglycan transpeptidase
- Steps:
1) PG transpeptidase mistakes penicillin for an uncrossed PG chain terminating in D-Ala-D-Ala
2) Active site serine attacks the beta lactam ring of the antibiotic → acyl-enzyme intermediate in which the beta-lactam ring has opened
3) This resulting covalent penicilloyl enzyme is very slow to hydrolyse → ↓↓↓ further PG synthesis
4) Causes cell lysis because of continued activity of autolysins
- Info:
Only proliferating cells in which autolysins are active are sensitive to beta lactam antibiotics

Answer 15

- Class = Hormone therapy (steroid)
- Target = Glucocorticoid receptor
- Mechanism = Agonist
- Steps:
• Used in the treatment of inflammatory and autoimmune conditions
• Has a lymphocytic effect and is useful against leukaemias

- Info:
Administered as prodrug prednisone, and is converted to active prednisolone by the liver

Answer 16

"- Class = Antiparasitic
- Target = DHFR (dihydrofolate reductase)
- Mechanism = Inhibition
- Steps:
This inhibition traps folate co-enzyme in its useless form (dihydrofolate)
Leads to rapid depletion of tetrahydrofolate
- Info:
Can be combined with sulfadoxin (Fansidar)

"

Answer 17

- Class = Antibiotic
- Target = Beta subunit on DNA-dependent RNA polymerase
- Mechanism = Inhibition of RNA synthesis
- Steps:
1) Non-covalent binding to an allosteric site on the β subunit of the DNA-dependent RNA polymerase → blocks elongation of RNA chain
2) Directly blocks the elongating RNA chain at the di- or tri-nucleotide stage → inhibits new RNA synthesis
But synthesis in progress at the time of drug exposure is not affected
- Info:
Derivative of Rifamycin B
Binding ratio = one mole drug : one mole enzyme

Answer 18

- Class = HIV protease inhibitor
- Target = HIV Asp protease
- Mechanism = Inhibition
- Steps:
1) HIV asp protease cleaves translated gag protein → mature protein
2) Lack of functioning Asp. protease means that virus is not infectious
- Info:
Mutation in enzymes → ↓ interaction between enzyme and inhibitor

Answer 19

- Class = Antibiotic (aminoglycoside)
- Target = 30S subunit of ribosome
- Mechanism = Prevents initiation
- Steps:
1) Binds near the A site for aminoacyl-tRNA binding
2) Decreases fidelity of translation
- Info:
Bacteriocidal (because reduces fidelity of proteins made, therefore wrong aminoacid → leaky protein etc)
-Resistance mechanism:
-covalent modification of OH and NH2 residues that allow specific binding to 16S rRNA of 30S subunit. 3 types of modication: N-acetylation, O-phosphoryl trasnfer and O-adenylyl transfer.
-reduced number of porins or modifications of LPS layer in Pseudomonas aeruginosa reduces uptake. Mutations in active tranporters required for uptake from periplasm
-active efflux

Answer 20

"- Class = Sulfonamide
- Target = DHPS (dihydropteroate synthase)
- Mechanism = Inhibition
- Steps:
Shuts off de-novo synthesis of folate (nneded for thymidine synthesis)
causes a slow killing mechanism
- Info:
Can be combined with prymethamine (Fansidar)
Drug analogue = sulfamethoxazole (antibiotic)
P-aminobenzoate analogue

"

Answer 21

"- Class = Sulfonamide
- Target = DHPS (dihydropteroate synthase)
- Mechanism = Inhibition
- Steps:
Shuts off de-novo synthesis of folate (needed for thymidine synthesis)
causes a slow killing mechanism
- Info:
Can be combined with trimethoprim (co-trimoxazole)
P-aminobenzoate analogue

"

Answer 22

- Class = Trypanocidal drug
- Target = Glycerol-3-phosphate oxidase + NAD⁺-dependent glycerol-3-phosphate dehydrogenase
- Mechanism = Inhibition
- Steps:
Inhibition of the above enzymes → interference with reoxidation of NADH → ↓ ATP synthesis
- Info:

Answer 23

- Class = Hormonal therapy (anticancer)
- Target = Oestrogen receptor
- Mechanism = Inhibitor
- Steps:
• Competitively binds to oestrogen receptor (lower affinity than oestrogen)
• Once bound ⟶ complex translocates to nucleus ⟶ attenuation of oestrogen-responsive genes involved in development and growth of breast CA
- Info:
70% of breast CA is +ve for oestrogen + progesterone receptor ∴ responsive to this therapy
Tamoxifen can exert oestrogen agonist effect in other tissues (bone and uterus)
Toremifene = tamoxifen analogue without this oestrogen agonist issue

Answer 24

- Class = Taxane
- Target = Free tubular dimers
- Mechanism = Prevents mitosis
- Steps:
• Disrupts the equilibrium between free dimers amd microtubules by shifting it in the direction of assembly rather than disassembly
• Leads to the stabilization of ordinary cytoplasmic microtubules and the formation of abnormal bundles of microtubules to inhibit mitosis
- Info:
Used in antiproliferative drug eluting stents in coronary angioplasty for the treatment of angina and ischaemic heart disease
Used in treatment of lung, ovarian, breast, head and neck cancer, and in Kaposi's sarcoma

Answer 25

- Class = Antibiotic
- Target = 30S subunit
- Mechanism = Blocks rotation of aminoacyl-tRNA into A site
- Steps:
1) Interacts with Mg²⁺ ion + nucleotides in 16S rRNA of 30S
2) Does not block initial binding of aminoacyl-tRNA, but blocks subsequent rotation into A site
3) Therefore no bond would be formed and peptide would be released prematurely
- Info:
Bacteriostatic
Shows activity against some protozoa (Plasmodium)

Answer 26

- Class = Topoisomerase type I inhibitor
- Target = Topoisomerase type I (human)
- Mechanism = Inhibition
- Steps:
- Info:
Used in ovarian and lung CA

Answer 27

"- Class = Antibiotic
- Target = DHFR (dihydrofolate reductase)
- Mechanism = Inhibition
- Steps:
This inhibition traps folate co-enzyme in its useless form (dihydrofolate)
Leads to rapid depletion of tetrahydrofolate
- Info:
Can be combined with sulfamethoxazole (co-trimoxazole)

"

Answer 28

- Class = Antibiotic (Ionophore)
- Target = Cell membrane
- Mechanism = Disruption of cell membrane
- Steps:
Forms a circular structure that coordinates K⁺ ion
Diffuses across the membrane therefore acts as a K⁺ uniporter
Effect is due to dissipation of transmembrane ion gradients
This disturbs ion homeostasis and energy metabolism and induce leakage of macromolecules from the bacteria
- Info:
Contains 3 repeating units of (L-lactate)- (L-valine)-(D-hydroxyisovalerate)-(D-valine)
Lacks specificity (phospholipid bilayer not only in bacteria)

Answer 29

- Class = Antibiotic (glycopeptide)
- Target = Cell wall biosynthesis
- Mechanism = Inhibits Peptidoglycan transpeptidase action
- Steps:
1) Vancomycin binds to pentapeptidyl tails in PG repeating units that end in D-Ala-D-Ala
2) this makes D-Ala-D-Ala terminus unavailable for transpeptidase enzyme
Also reduces availability for the peptidoglycan transglycosylase enzyme
- Info:
Only proliferating cells in which autolysins are active are sensitive to this antibiotic
-Resistance mechanism:
-E. faecalis has acquired the Van genes, two tandemly arranged operons. One operon encodes a his-As phosphorelay that activates the second when exposed to antibiotics. The second encodes enzymes that change (D-Ala)5 to (D-lactate)5 in PG pentapeptide to prevent vanc binding.

Answer 30

- Class = Vinca alkaloid
- Target = Free tubular dimers
- Mechanism = Antimitotic
- Steps:
• Bind to free tubulin dimers ⟶ prevent microtubule assembly
• ∴ disrupt the equilibrium between polymerisation and depolymerisation to inhibit mitosis of tumour cells
- Info:
Results in the disappearance of microtubules
Cause granulocytopenia in animals
Used in Hodgkin's lymphoma, non small cell lung cancer, breast cancer and testicular cancer

Answer 31

- Class = Anti-influenza drug
- Target = Neuraminidase
- Mechanism = Inhibitor
- Steps:
Inhibits NA → ↑ viral aggregation + ↓ release from host
- Info:
Zanamivir is an active drug

Answer 32

- Class = Reverse transcriptase inhibitor (Nucleoside)
- Target = Reverse transcriptase
- Mechanism = Thymidine analogue → inhibits reverse transcriptase
- Steps:
1) Thymidine analogue therefore acts as substrate for reverse transcriptase
2) Lack the 3'OH group therefore causes termination of elongation
3) Usually administered with hydroxyurea (this ↓ natural pyriminadine nucleotides thus enhances the effect of AZT)
- Info:
Must be phosphorylated by host cell before becoming active
Reverse transcriptase activity is early in replication cycle, therefore this drug only has effect early
- Resistance:
Mutation in enzymes → ↓ interaction between enzyme and inhibitor

Answer 33

Effective against both Gram +ve and Gram -ve

Answer 34

Effective against either Gram +ve or Gram -ve

Answer 35

Effective against a single organism

Answer 36

Chemically modifying drug to extend spectrum

Answer 37

Stop bacteria from growing
Elimination of bacteria is dependent on human immune system

Answer 38

Cause cell death → ↓ cell count

Answer 39

MIC = Minimum inhibitory concentration

Minimum conc. that prevents bacterial growth

Measure of effectiveness of bacteriostatic drugs

Answer 40

MIC = Minimum bactericidal concentration

Minimum conc. that kills bacterial cells

Measure of effectiveness of bactericidal drugs

Answer 41

Infecting organism is inhibited/killed without damage to host cells

Answer 42

Also known as therapeutic ratio

Maximum non-toxic dose / minimum effective dose

Answer 43

Peptidoglycan (PG)

Answer 44

Gram +ve
- Thicker PG
- Teichoic acid polymers

Gram -ve
- Thinner PG
- Has an outer membrane

Answer 45

Two types of cross linking occur:

1) Glycan stands
- Enzyme = transglycosylase

2) Peptide strands
- Enzyme = transpeptidase

Peptide cross-links → introduce covalent bonds (provides strength + is a structural barrier)

Answer 46

UDP + NAG → UDP-NAG → NAM-tripeptide
NAM-tripeptide → NAM-pentapeptide

NAM binds to bactoprenol phosphate
NAG links to NAM → NAG-NAM
This complex is transporter to outer surface of cell wall

On outer surface - PG polymer is formed
PG transglycosylase adds building unit to existing PG
PG transpeptidase cross links these units

Answer 47

It is a serine hydrolase
Attacks aminde bond between terminal D-ala₄ D-Ala₅
D-Ala₅ released as free amino acid
Intermediate is covalently linked to PG
Acyl transfer occurs with neighboring peptide → cross-linking

Answer 48

Formylmethionine

Answer 49

STAGE 1 - Initiation

1) mRNA binds to 30S
- Needs IF3
2) tRNA-formylmethionine combines with mRNA-30S
- Needs IF1 + IF2 + GTP
3) 50S joins this complex
- GTP hydrolysed and all initiation factors are released

STAGE 2 - Elongation
Needs elongation factors and GTP
1) Amino acids are side by side on the 50S
2) Amino acids get linked by peptide bond (50s has transpeptidyl transferase activity)
3) tRNAs move along (P → E and A → P)
4) 30S unit moves along one codon

Continues until stop codon

Answer 50

Generally bacteriostatic

Answer 51

1) Organism lacks receptor for drug
2) Concentration of drug at the target is inadequate

Answer 52

Due to high content of mycelia acids in a complex lipid layer outside their PG.

This layer is impermeable to many drugs

Answer 53

1) Enzymatic inactivation of drug
2) Replacement/ amplification/ modification of drug target
3) Decreased drug uptake or increased efflux

Answer 54

Beta lactamase is an enzyme (serine enzyme) that hydrolyses the beta lactam ring.