Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

ESC > Anticancer drugs > Flashcards

Anticancer drugs Flashcards

1
Q

What are methylating agents and give examples?

A
  • Methylate guanine bases within major groove of DNA (N7 and O6 positions)
  • Dacarbazine, procarbazine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is darcabazine and how does it work?

What are the special storage conditions for it?

A
  • Methylating agent
  • Prodrug form of CH3+ ion and it converts into a methanediazonium which is very unstable
  • Results in CH3+ which alkylates N7 major groove guanine
  • Liable to photochemical decomposition so IV infusion bag should be protected from light
  • Metastatic melanoma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is a caution with procarbazine?

A

Mild monoamine-oxidase inhibition effect may cause a disulfiram like reaction with alcohol ingestion

N+V, hangover effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What provides the driving form for temozolamide MOA?

Does it penetrate BBB?

A

Production of small stable molecules (CO2, N2)

Yes, it penetrates BBB

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

How does temozolamide work?

A
  • Mismatch repair enzymes
  • Normally T hydrogen bonds with A. However, when you methylate G, it looks like A so T will bind to it creating a WOBBLE MISMATCH
  • MMR detects this and tries to replace T with C. However, because the methylated G looks like A. T will bind to it again.
  • Process repeats to the point where it triggers arrest of the cell via MMR- induced strand breaks
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Is there a test you can do to see if temozolomide will work in a particular patient?

A

Yes - if the MMR levels are high then they are a candidate for treatment

Also worth measuring ATases as there has been a development of resistance via O6 and N7 - alkylguanine DNA akyltransferases

So use only if ATase levels are low

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are alkylating agents?

A
  • Alkylates N2 of guanine in minor groove

- Don’t see bone marrow suppression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Give an example of alkylating agent and MOA

A
  • ET-743 (Trabectidin)
  • Bulky adduct that interferes with DNA processing and covalent bonds
  • Bends double helix towards major groove
  • Consists of 3 fused tetrahydroisoquinoline rings:

2 of them provide covalent interaction within minor groove

1 of them interacts with adjacent nuclear proteins proving cytotoxicity

Traps nucleuses in its adduct complex inducing single strand breaks in the DNA

  • Inhibition of DNA repair and cell cycle progression resulting in p53- INDEPENDENT APOPTOSIS

HOWEVER ALSO WORKS VIA P53 DEPENDENT APOPTOSIS:
Inhibits TCNER, a cell repair pathway

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Is there a test to see if a patient is suitable for ET-743 therapy?

A
  • Patients overexpressing TCNER
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Outline experimental PBD monomers for alkylating agents

Is it sequence selective?

A

Pyrrolobenzodiazepine

  • Sequence selective to AGA
  • Product based on anthramycin, which is a DNA monoalkylating agent that attacks 1 guanine
  • Chiral centre in PDBs give molecule right handed twist allowing it to follow the curvature of minor groove. This results in a guanine attack to form covalent bond
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Outline cross linking agents and the 9 types

A

Contains two alkylating moeities separated by various distances by linkers.

Interstrand and intrastrand

  1. Nitrogen mustards
  2. Mitomycin C
  3. Aziridines
  4. Epoxides
  5. Methanesulphates
  6. Nitrosureas
  7. Platinum complexes
  8. Carbinolamines
  9. Cyclopropranes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How do you monitor to see if cross-linking agents are working?

A

Single cell gel electrophoresis to see if there is a reduction in the comet tail (less fragmentation and stops the spread)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are the 4 different types of nitrogen mustards?

A
  1. Aliphatic
  2. Aromatic
  3. Conjugated
  4. Oxazaphophorines
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Outline the general principle of nitrogen mustards

A
  • Staples the two strands of DNA together via covalent interactions in major groove so replication is blocked
  • Forms mustard DNA adducts that block RNA polymerase
  • Mustard adducts also cause distortion of DNA around binding site and this can be transmitted through base pairs (telomeric effect)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Outline aliphatic nitrogen mustards

A

Chlomethine (mustine) which attacks major groove

N7 - guanine on DNA

Forms cyclic aziridinium

SN2 reaction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Outline aromatic nitrogen mustards

A
  • Reacts more slowly with DNA so less s/e
  • SN1 REACTION
  • AROMATIC RING DRAWS ELECTRONS FROM N ATOM so it discourages aziridinium ion formation
  • Chlorambucil
  • Melphalan
  • Tallimustine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Name 3 examples of aromatic nitrogen mustards

A
  1. Chlorambucil
  2. Melphalan - bone marrow toxicity so give every 6 weeks
  3. Tallimustine (binds to minor groove and is recognises 5-GAAT sequence)
18
Q

What is cyclophosphoamide?

A

Oxazaphophorine nitrogen mustard

Theory that P=O would be cleaved by phosphoramides however in reality it is oxidised by liver enzymes

19
Q

What is a side effect of cyclophosphoamide?

What can be done to avoid this?

A
  • Haemorrhagic cystitis due to byproduct acrolein
  • Acrolein alkylates nucleophiles in bladder epithelium creating lesions

Using MESNA reduces this as it acts as the nucleophile acrolein alkylates. It forms a non-reactive water soluble product

20
Q

What is estramustine phosphate?

A

Conjugated nitrogen mustard

Oestrogen and mustine joined via a carbamate linkage

Blocks 5-a reductase so has direct cytotoxic effect on prostate cancer cells

21
Q

What are aziridines and give an example?

Why does it have a slower rate of action compared to nitrogen mustards?

A

Thiotepa

Aziridine ring is already incorporates into their structure to bypass the intermediate

Ring opening is slower as they are not fully charged like nitrogen mustards

22
Q

What is mitomycin C?

A
  • Antitumour antibiotic
  • Bioreductive agent and cross-linking
  • Contains an aziridine ring

INTERSTRAND CROSS LINK OF GUANINE N2 GROUPS IN MINOR GROOVE

Delayed bone marrow toxicity so administer every 6 weeks

23
Q

Why are bioreductive agents useful in cancer treatment?

A

Bioreductive conditions can exist in centres of large tumours

24
Q

Outline epoxides

A

Similar to aziridines

Ovastat

25
Q

Outline methanesulphonates

A

Busulphan

Methanesulphonyloxy groups are leaving groups after attack by nucleophilic sites on DNA

26
Q

Outline nitrosureas

A

Carmustine and Lomustine

Active in brain due to high lipophilicity

Can form mono adducts and interstrand cross links

Generation of chlorethyl carbonium ion

27
Q

Outline platinum complexes

A

INTRASTRAND crosslinks

  • Kinks DNA at adduct sites
  • Cisplatin (transplatin has less antitumour activity)
  • Carboplatin - better tolerated in terms of side effects
28
Q

What is trimelamol?

A

Carbinolamines

Interstrand cross links

29
Q

What are the only class of anti cancer agents that is known to interact with DNA via cycloproprane moeity?

A

Cyclopropanes

experimental duocarmycin agents

30
Q

Outline intercalating agents

A
  • Interaction of the drug in between base pairs on DNA, perpendicular to axis
  • Held in place via H bonding and van der waals forces
  • Minor/major/both (if both, threading agents)
  • Many are GC specific
  • Others have the ability to trap complexes between topoisomerase and DNA enzymes resulting in strand cleavage
31
Q

What are the 3 types of intercalating agents?

A
  1. Anthracyclines
  2. Anthracenes
  3. Phenoxazines
32
Q

Outline anthracyclines

A
  • 4 fused rings
  • Doxorubicin - cardiotoxicity side effects (liposomal formulations help with this)
  • Planar ring system inserting between DNA base pairs
33
Q

Outline anthracenes

A

Mitoxantrone

  • 3 fused rings
  • Rich in oxygen and nitrogen substituents giving it stability of intercalated adduct via H-bonding interactions
  • GC preference
  • Dose related cardiotoxicity
34
Q

Outline phenoxazines

A

Dactinomycin

3 fused 6 memebered rings

Interacts with minor groove to inhibit DNA and RNA synthesis

GC preference with N2 amino groups

35
Q

Outline topoisomerase inhibitors

A
  • Works on S phase as topoisomerase levels are at a maximum here
  • Some also work by intercalating
  • Drug causes strand breakage which alerts p53 pathway
  • Topoisomerase catalyses winding and unwinding of supercoiled DNA during DNA synthesis Made up of Class I and II (cuts one and two strands respectively)
36
Q

Outline topoisomerase I inhibitors

A
  • Keeps chromosomes wound tight - cell cannot make proteins - cell death

Topotecan

37
Q

Outline topoisomerase II inhibitors

A

Etoposide inhibits IIa and II beta

Drugs are derived from podophyllotoxin

Normally reversible double stranded DNA breaks are converted into lethal breaks

38
Q

Outline DNA cleaving agents

What are the two examples?

A

Binds to DNA helix then cleaves double-stranded helix via radical production

  1. Bleomycin
  2. Enediymes
39
Q

Outline bleomycins

A

Binds to DNA in a sequence selective manner followed by strand cleavage

ACCUMULATES IN SQUAMOUS CELLS SO GOOD FOR HEAD, NECK

40
Q

What are the 3 componenets of bleomycins?

A
  1. Heterocyclic bithazole which inserts between DNA base pairs
  2. Glycopeptide proves additional stability
  3. Another component containing pyrimidine which forms iron (ii) complex - interacts with oxygen to generate free radicals
41
Q

Outline enediymes

A

Calicheamicin

Binds in minor groove

Radical abstraction process (Bergman cyclisation)

42
Q

What is the driving force for the MOA of enediymes?

A

Triple bonds rearrange to form aromatic ring

ESC (6 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions