7.0 Chemotherapy Flashcards Preview

MedST IB: Mechanisms of Drug Action (MoDA) > 7.0 Chemotherapy > Flashcards

Flashcards in 7.0 Chemotherapy Deck (80)
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1

Aciclovir [acyclovir]

- Class = Purine analogue
- Target = Viral DNA polymerase
- Mechanism = Lacks the 3-OH group required for additional nucleotide polymerisation
- Steps:
1) Taken up by cell and monophosphorylated by herpes virus thymidine kinase
2) Cellular enzymes then convert it to triphosphate
3) Aciclovir triphosphate competitively + permanently inhibits with viral DNA pol
4) Also incorporated into growing chain but cannot continue adding more nucleotides because it aciclovir lacks the 3- OH group
- Info:
Selective for viral infected cells because:
1) Only virally infected cells have thymidine kinase (for monophosphorylation)
2. Drug preferentially binds to virally encoded DNA pol. (30x stronger bond on viral cf. host)
-Resistance:
Viral thymidine kinase changes substrate sensitivity thus does not monophosphate acyclovir

2

Amantadine

- Class = Antiinfluenza drug
- Target =
1) M2 channel protein
2) HA processing
- Mechanism =
1) Blocks function of M2 channel → prevents uncoating of virus
2) Interferes with HA processing → ↓ binding to host (HA needed to bind to sialic acid)
- Steps:
- Info:
Used as prophylaxis or anti-influenza A
Not effective against influenza B

3

Amoxicillin

- Class = Antibiotic (beta-lactam)
- Target = Cell wall biosynthesis
- Mechanism = Inhibits Peptidoglycan transpeptidase
- Steps:
1) PG transpeptidase mistakes amoxicillin for an uncrossed PG chain terminatinf 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
Often combined with clavulanic acid (beta-lactamase inhibitor)

4

Amphotericin B

- Class = Polyene (antifungal)
- Target = Ergosterol in fungal plasma membrane
- Mechanism = Binds to ergosterol → pore formation
- Steps:
Preferentially binds to egosterol (in fungal membranes) as opposed to cholesterol (in human plasma membrane) → selectivity
Pore formation → ion + macromolecule leakage
- Info:
Ergosterol is also found in Leishmania (parasite)

5

Anastrozole

- Class = Hormone therapy (anticancer)
- Target = Aromatase
- Mechanism = Inhibitor
- Steps:
• Aromatase = enzyme in the oestrogen biosynthetic pathway that converts androgen precursor to estradiol
• Inhibition of this enzyme ⟶ ↓ oestogen
- Info:
Used instead of, or after, treatment with tamoxifen
Also used in post-menopausal women with breast CA to prevent formation of oestrogens at peripheral sites such as muscle and fat

6

Artemisinin

- Class = Antimalarial
- Target = -
- Mechanism = Less well known
- Steps:
?Production of reactive oxygen radicals using peroxide bridge?
?Inhibition of parasite electron transport chain?
?Inhibits parasite SERCA pump?
- Info:
Rapid action
Also inhibits development of oocytes in mosquitos

7

Cephalosporin

- Class = Antibiotic (beta-lactam)
- Target = Cell wall biosynthesis
- Mechanism = Inhibits Peptidoglycan transpeptidase
- Steps:
1) PG transpeptidase mistakes cephalosporin for an uncrossed PG chain terminatinf 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

8

Cetuximab

- Class = Monoclonal antibody (anticancer)
- Target = EGFR
- Mechanism = Inhibition
- Steps:
EGFR = RTK
Binding of specific ligand ⟶ conformational changes ⟶ ↑ RTK activity ⟶ ↑ cell activity such as proliferation and differentiation
Abnormal EGFR expression involved in many malignancies
Inhibition achieved by preventing ligand binding with anti-EGFR antibody
- Info:
Human-mouse chimeric monoclonal antibody
Cetuximab can reverse the resistance of colorectal cancers to topoisomerase inhibitors
Used in combination with irinotecan (top. inhibitor)

9

Chloramphenicol

- Class = Antibiotic
- Target = 50S ribosomal subunit
- Mechanism = Blocks aminoacyl-tRNA interaction with P site of peptidyl transferase centre
- Steps:
- Info:
Bacteriostatic

10

Chloroquine

- Class = Antimalarial
- Target = Haem polymerisation by plasmodium spp
- Mechanism = Inhibits formation of hemozoin
- Steps:
Events during Plasmodium erythrocytic cycle:
-Plasmodium in RBCs use haemoglobin as nitrogen source ⟶ accumulation of heme
-Could accumulate to toxic levels (up 200-500mM)
- This causes production of reactive oxygen species ⟶ harming the parasite
- Parasites ∴ polymerise toxic heme ⟶ non-toxic hemozoin (in food vacuole)
Mechanism of Chloroquine:
Inhibits formation of hemozoin via 2 methods:
1. Inhibiting polymerase
2. Complexation of heme
It also ↑ pH in food vacuole
- Info:
-Resistance:
Parasites achieve resistance by efflux of cholorquine out of food vacuoles

11

Ciprofloxacin

- Class = Antibiotic (fluoroquinolone)
- Target = Topoisomerases (Type II)
- Mechanism = Inhibits DNA gyrase and topo IV (both type II topoisomerases)
- Steps:
1) Type II topoisomerases cleave both strands of DNA in an ATP dependent manner (DNA gyrase can supercoild DNA, Topo IV cannot)
2) Fluoroquinolones affect double strand cleavage/re-ligation cycle
3) Build up of complexes → effect on replication forks → cell death
- Info:
Used in UTI, osteomyelitis, gastroenteritis

12

Cisplatin

- Class = Platinum compound (anticancer)
- Target = N7 atoms of guanine and adenine in tumour cells
- Mechanism =
Covalently binds DNA ⟶ intrastrand cross-linking ⟶ prevents DNA replication
- Steps:
• Only active in cis form
• Small size ⟶ crosslinking occurs between two neigbouring pGpG (intrastrand crosslinking)
• This induces a major bend in dsDNA ⟶ changes in major groove
• This (along with physical block provided by platinum adduct) ⟶ inhibition of DNA pol. ⟶ inhibition of DNA replication
- Info:
Used in sarcomas, some carcinomas (sc lung cancer, ovarian), lymphomas and germ cell tumours (large improvement in testicular CA treatment)
IV administration (no bioavailability if oral)
Inactivated by reastions with SH groups in glutathione and metallothioneins
- Side effects = renal toxicity + bone marrow suppression

13

Clavulanate

-Class: Beta-lactamase inhibitor
-Target: Beta-lactamase
-Mechanism: forms a slowly hydrolysing acyl enzyme intermediate with Beta-lactamase to inhibit the enzyme - suicide substrate

NO EFFECT ON B TYPE BETA LACTAMASE
-Info:
-used with amoxicillin to overcome Beta-lactamase induced resistance to Beta-lactam antibiotics. The combination of amoxicillin with clavulanate is Augmentin/co-amoxiclav

14

Co-trimoxazole

"- Class = Combination drug (sulfamethoxazole + trimethoprim)
- Target = Folate synthesis (DHPS + DHFR)
- Mechanism =
Sulfamethoxazole → inhibits DHPS
Trimethoprim → inhibits DHFR
- Steps:
- Info:
Link with Steven Johnson syndrome

"

15

Cyclophosphamide

- Class = Nitrogen mustard (anticancer)
- Target = DNA
- Mechanism = Covalently binds DNA and prevents DNA replication + gene expression
- Steps:
Needs to be metabolised by cytochrome p450 to be activated (cyclophosphamide → phophoramide)
1) Binds to DNA + causes alkylation
2) Causes cross-linking
3) Can cause CG → AT transition
4) Basically prevents effective DNA replication and gene expression
- Info:
Oral admin
Most commonly used alkylating agent
Broad application (lymphoid/ breast/ lung/ ovary CA)
Used with other drugs to reduce resistance

16

Daunomycin

- Class = Antibiotic (polycyclin)
- Target = DNA template
- Mechanism = Non-covalent binding to DNA template
- Steps:
Inserts between adjacent base pairs
Intercalation → affects dimensions of major and minor grooves ⟶ affects DNA/RNA pol interactions ⟶ prevention of normal replication and transcription
Prevents DNA from being resealed

- Info:
Planar structure

17

D-cycloserine

- Class = Antibiotic
- Target = Cell wall biosynthesis
- Mechanism = Mimics D-ala
- Steps:
1) Inhibits L-alanine racemase
2) Inhibits D-ala D-ala synthase
3) Inhibits ligase (that joins to UDP-NAG)
- Info:
2nd class drug anti-TB

18

Erlotinib

- Class = Small molecule inhibitor (quinazoline derivative)
- Target = EGFR
- Mechanism = Inhibition
- Steps:
EGFR = RTK
Inhibition → ↓ proliferation and division
- Info:
Orally active
Potent
Selective
Toxicity → skin rashes + diarrhoea
Good in pancreatic and advanced NSCLC

19

Erythromycin

- Class = Antibiotic (Macrolide)
- Target = 50s ribosomal subunit
- Mechanism = Binds to polypeptide export tunnel on 50S → prevents elongation
- Steps:
1) Interacts with 23S rRNA in export tunnel
2) Allows 6-8 oligopeptidyl-tRNA build up before elongation is blocked
3) Causes premature termination
- Info:
Bacteriostatic or bacteriocidal (depends on dose + bacterial species/density)
-Resistance mechanism:
-methylation of adenine in 23S rRNA of 50S subunit by N-methyltransferase to prevent binding of macrolide antibiotics.

20

Etoposide

- Class = Topoisomerase II inhibitor
- Target = Topoisomerase II (human)
- Mechanism = Inhibition
- Steps:
Inhibition of type II topoisomerase in tumour cells ⟶ torsional stress on the DNA during DNA replication and transcription ⟶ genomic instability and impaired tumour cell proliferation
- Info:
Used in the treatment of lung cancer, testicular cancer, lymphoma

21

Fansidar

"- Class = Combination drug (sulfadoxin + Pyrimethamine)
- Target = Folate synthesis (DHPS + DHFR)
- Mechanism =
Sulfadoxin → inhibits DHPS
Pyrimethamine → inhibits DHFR
- Steps:
- Info:

"

22

Fluconazole

- Class = Triazole (antifungal)
- Target = Enzymes involved with ergosterol synthesis
- Mechanism = Inhibition
- Steps:
↓ ergoesterol → alters fluidity of membrane → alters permeability + activity of membrane associated enzymes
- Info:
-Resistance:
1) Alterations in the amount of enzymes involved with ergosterol synthesis
2) Efflux

23

Fosfomycin

- Class = Antibiotic
- Target = Cell wall biosynthesis
- Mechanism = Mimics phosphoenolpyruvate
- Steps:
1) Inhibits pyruvryl transferase
- Info:

24

Fusidic acid

- Class = Antibiotic
- Target = Elongation factors
- Mechanism = Inhibits protein synthesis
- Steps:
1) Binds to and inhibits elongation factor G
- Info:

25

Goseraline

- 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:

26

Imatinib

- 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

27

Isoniazid

- 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

28

Leucovorin

- 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

29

Lomustine

- 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

30

Melarsoprol

- 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