Anticancer drugs Flashcards
What are methylating agents and give examples?
- Methylate guanine bases within major groove of DNA (N7 and O6 positions)
- Dacarbazine, procarbazine
What is darcabazine and how does it work?
What are the special storage conditions for it?
- 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
What is a caution with procarbazine?
Mild monoamine-oxidase inhibition effect may cause a disulfiram like reaction with alcohol ingestion
N+V, hangover effect
What provides the driving form for temozolamide MOA?
Does it penetrate BBB?
Production of small stable molecules (CO2, N2)
Yes, it penetrates BBB
How does temozolamide work?
- 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
Is there a test you can do to see if temozolomide will work in a particular patient?
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
What are alkylating agents?
- Alkylates N2 of guanine in minor groove
- Don’t see bone marrow suppression
Give an example of alkylating agent and MOA
- 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
Is there a test to see if a patient is suitable for ET-743 therapy?
- Patients overexpressing TCNER
Outline experimental PBD monomers for alkylating agents
Is it sequence selective?
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
Outline cross linking agents and the 9 types
Contains two alkylating moeities separated by various distances by linkers.
Interstrand and intrastrand
- Nitrogen mustards
- Mitomycin C
- Aziridines
- Epoxides
- Methanesulphates
- Nitrosureas
- Platinum complexes
- Carbinolamines
- Cyclopropranes
How do you monitor to see if cross-linking agents are working?
Single cell gel electrophoresis to see if there is a reduction in the comet tail (less fragmentation and stops the spread)
What are the 4 different types of nitrogen mustards?
- Aliphatic
- Aromatic
- Conjugated
- Oxazaphophorines
Outline the general principle of nitrogen mustards
- 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)
Outline aliphatic nitrogen mustards
Chlomethine (mustine) which attacks major groove
N7 - guanine on DNA
Forms cyclic aziridinium
SN2 reaction
Outline aromatic nitrogen mustards
- 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
Name 3 examples of aromatic nitrogen mustards
- Chlorambucil
- Melphalan - bone marrow toxicity so give every 6 weeks
- Tallimustine (binds to minor groove and is recognises 5-GAAT sequence)
What is cyclophosphoamide?
Oxazaphophorine nitrogen mustard
Theory that P=O would be cleaved by phosphoramides however in reality it is oxidised by liver enzymes
What is a side effect of cyclophosphoamide?
What can be done to avoid this?
- 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
What is estramustine phosphate?
Conjugated nitrogen mustard
Oestrogen and mustine joined via a carbamate linkage
Blocks 5-a reductase so has direct cytotoxic effect on prostate cancer cells
What are aziridines and give an example?
Why does it have a slower rate of action compared to nitrogen mustards?
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
What is mitomycin C?
- 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
Why are bioreductive agents useful in cancer treatment?
Bioreductive conditions can exist in centres of large tumours
Outline epoxides
Similar to aziridines
Ovastat
Outline methanesulphonates
Busulphan
Methanesulphonyloxy groups are leaving groups after attack by nucleophilic sites on DNA
Outline nitrosureas
Carmustine and Lomustine
Active in brain due to high lipophilicity
Can form mono adducts and interstrand cross links
Generation of chlorethyl carbonium ion
Outline platinum complexes
INTRASTRAND crosslinks
- Kinks DNA at adduct sites
- Cisplatin (transplatin has less antitumour activity)
- Carboplatin - better tolerated in terms of side effects
What is trimelamol?
Carbinolamines
Interstrand cross links
What are the only class of anti cancer agents that is known to interact with DNA via cycloproprane moeity?
Cyclopropanes
experimental duocarmycin agents
Outline intercalating agents
- 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
What are the 3 types of intercalating agents?
- Anthracyclines
- Anthracenes
- Phenoxazines
Outline anthracyclines
- 4 fused rings
- Doxorubicin - cardiotoxicity side effects (liposomal formulations help with this)
- Planar ring system inserting between DNA base pairs
Outline anthracenes
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
Outline phenoxazines
Dactinomycin
3 fused 6 memebered rings
Interacts with minor groove to inhibit DNA and RNA synthesis
GC preference with N2 amino groups
Outline topoisomerase inhibitors
- 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)
Outline topoisomerase I inhibitors
- Keeps chromosomes wound tight - cell cannot make proteins - cell death
Topotecan
Outline topoisomerase II inhibitors
Etoposide inhibits IIa and II beta
Drugs are derived from podophyllotoxin
Normally reversible double stranded DNA breaks are converted into lethal breaks
Outline DNA cleaving agents
What are the two examples?
Binds to DNA helix then cleaves double-stranded helix via radical production
- Bleomycin
- Enediymes
Outline bleomycins
Binds to DNA in a sequence selective manner followed by strand cleavage
ACCUMULATES IN SQUAMOUS CELLS SO GOOD FOR HEAD, NECK
What are the 3 componenets of bleomycins?
- Heterocyclic bithazole which inserts between DNA base pairs
- Glycopeptide proves additional stability
- Another component containing pyrimidine which forms iron (ii) complex - interacts with oxygen to generate free radicals
Outline enediymes
Calicheamicin
Binds in minor groove
Radical abstraction process (Bergman cyclisation)
What is the driving force for the MOA of enediymes?
Triple bonds rearrange to form aromatic ring
