Wk 12: Alkylating + platinating agents (Nitrosoureas, platinum compounds etc.) Flashcards
What is thiotepa?
Thioplex
- Aziridine
- Less reactive than nitrogen mustards: more reactive at acidic pH
- For bladder cancer
- Oral or IV
How is thiotepa administered?
Directly into bladder by catheter:
- Dehydrate patient 8-12hrs
- 60mg thiotepa in 30-60ml sterile water
- Retaine for 2hr once a week for 4 wks
Give an example of an alkyl sulfonates
Busulfan - busulfex/myleran
How is busulfan administered?
- W/ phenytoin as it cross bbb + induces seizures
- IV: Sterile sol in 10ml ampule
- Tabs: 2mg for remission/maintenance
What is busulfan commonly used for?
Chronic myelogenous leukemia:
- Selective effect on bone marrow
- Little effect: lymphoid tissue + GI tract
What type of alkylating agent is busuflan?
Bifunctional:
- Sn2 mechanism
- Sulfonate group better leaving group than Cl on nitrogen mustards
- Reacts w/ thiol on aa
Give examples of nitrosoureas
- Lomustine
- Carmustine
- Streptozotocin
What is chloroethylnitrosoureas?
Carmustine:
- Bifunction
- Derivative of urea
- Cross links DNA (N-7, O-6 of guanine, N-3 of cytosine)
- Cross BBB
- Pro-drug
- Non-selective + very toxic (bone marrow depression)
What is lomustine?
- 40mg caps
- Used for: CNS tumours, hodgkin’s disease + lung cancer
Outline the mode of action of Carmustine
- Nitro + urea = bioactivated
- Prod isocyanate
- This reacts w/ lysine residues to produce protein that inactivates DNA repair enzymes
- 2 active prods: Chloroethyl diazonium ion OR chloroethyl carbonium ion - cross links DNA
What is Streptozotocin?
Zanosar:
- Naturally occuring nitrosourea
- From Streptomyces achromogenes
- MOA: formation of methyl diazonium ion + carbamylation of proteins (no cross links)
What is the mode of action of temozolomide + dacarbazine?
- Prodrugs
- Active prod: methyldiazonium ion
- DNA methylation of guanine bases O6 + N7
- Red activity of O6-alkylguanine-DNA-alkyltransferase
How are cisplatin similar to alkylating agents?
- Platinating agent
- Cross links DNA
- N-7 guanine + N-7 adenine involved
How is cisplatin administered?
- Slow IV
- Clear liquid in amber vile
- Opened: stable for 28 days from light
- Reacts w/ aluminium
What is the structure of cisplatin?
- Pt central atom surround by 2 Cl + 2 NH3 in cis position
- Tetra-coordinate transition metal w/ square planar geometry
What is the mode of action of cisplatin?
- Binds to DNA acting as bifunctional agent
- N-7 guanine favoured
- Binds N-7 purins + N-3 pyrimidines
- Cross links on single strand
- Unwinding at complexation site alters DNA structure preventing replication
- Water replaces Cl
- Resulting structure binds to N on DNA nucleotide
What size liposomes can enter tumour sites?
<400nm
What is lipoplatin?
- Reverse micelle btw cisplatin + DPPG converted to liposomes by interaction w/ PEG
- Minimise toxic exposure to normal tissue whilst maximising tumour uptake
- Targets primary tumours + metastases
What are the advantages of lipoplatin?
- Negatively charged DPPG molecule on surface = nanoparticles fusogenic properties
- Small size = passive extravasation to tumours
- Phagocytosis characteristic of tumour cells = enhances uptake of drug
- PEG coating = prolonged circulation time
What are the advantages of lipoplatin?
- Negatively charged DPPG molecule on surface = nanoparticles fusogenic properties
- Small size = passive extravasation to tumours
- Phagocytosis characteristic of tumour cells = enhances uptake of drug
- PEG coating = prolonged circulation time
