Cisplatin and analogues Flashcards
what cells are more susceptible to the toxicity effects of chemotherapy
cells with a high turnover rate, hair, GI and blood cells
how does cisplatin work in treating cancer
- direct consequence of the damage caused by their reaction with DNA
- Majority of adducts involve cross-linking of two nucleotides, preferentially guanine and adenine
- Formation of platinum-DNA adducts activates various signal transduction pathways including those involved in DNA-damage recognition/repair, cell cycle arrest and programmed cell death/apoptosis
what cancers are susceptible to cisplatin treatment
testicular
what platinum-DNA adducts are susceptible to cross lines
guanine-guanine
gunaine-adenonine
cis configuration causes _
- Significanlty greater anti-tumour activity
- Decrease formation of more cytotoxic DNA crosslinks or adducts
what is the rate limiting step in the reaction of platinum compounds with biomolecules
intracellular hydrolysis
Describe the differences between cisplatin and carboplatin
- Carboplatin has approximately 100x lower interaction rate with DNA than cisplatin due to slow loss of second arm of bidentate ligand
[Less toxic as less reactive] - Major difference between cisplatin and carboplatin is in kinetics of adduct formation, not the nature of the reaction with DNA
Explain the breakdown of adduct formation
normally (90%) intrastand cross links
10% interstrand and DNA protein cross links
why are testicular cancer ‘hypersensitive’ to cisplatin
- reduced DNA-repair capacity in response to platinum-DNA adducts
- low constitutive nucleotide-excision repair (NER) pathway
- low DNA-repair capability leads to increased cisplatin-induced apoptosis
describe the development of cisplatin treatment
- Introduction of cisplatin-containing regimens in the 1970’s (with vinblastine and bleomycin) increased cure rates for metastatic testicular cancer from 5% to 60%
- Further improvement to 80% following subsequent substitution of vinblastine with etoposide
How can a tumour become resistance to platinum agents
- Intrinsic (already resistant or insensitive)
- Acquired (initially good response from medication however tumour cells fight back
How is a tumour resistant to platinum agents
- Reduced access of drug to target DNA = decreased uptake into tumour cells, changes in tumour vasculature, intracellular inactivation (e.g. GSH, metallothioneins)
- Increased repair or tolerance of DNA damage
How can insufficient DNA binding causes resistance to cisplatin mechanism
□ generally related to decreased drug uptake (plasma membrane transporter CTR1); smaller role played by efflux proteins (ATP7A/7B)
□ increased levels of cytoplasmic thiol-containing species, e.g. glutathione, metallothioneins (binding of platinum to sulphur) / possible role of GSTs
How is resistance to cisplatin mediated after DNA binding
- Increased DNA-repair capacity (NER is the major DNA-repair pathway known to remove cisplatin lesions from DNA)
- Increased tolerance to platinum-induced DNA damage through loss of function of MMR pathway, leading to decreased apoptosis linked to unsuccessful DNA repair cycles
- Decreased expression of apoptotic signalling pathways, e.g. p53
What are the possible mechanisms which may cause cisplatin resistance
□ Increase efflux in ATP7A/7B
□ Reduce influx by modulating CTR1
□ Bound to either metallothionein or glutathione
How can cisplatin resistance be circumvented
○ Uses lipids or liposome as a protectant vesicle for deliver (However the drugs aren’t release therefore too well protective)
○ Modulators (Using the knowledge of resistance to give combinations or drugs [TLK286 and decitabine])
○ Developing drugs to get around resistance (Most weren’t licensed)
○ Combining platinum drugs with molecularly targeted agents
How can cisplatin drug delivery be improved
using nanoparticles
- Can give lower concentrations of drug to recue the side effects
- Using equivalent concentration, the one with nano particles delivery system is 6 times more effective
what are the toxicities involved with cisplatins
Neohrotoxicity, neurotoxicity, ototoxicity (blindness), nausea and vomiting
What is the clinical activity of carboplatin
FDA approval in 1989
Germ cell tumours, ovarian cancer, childhood cancer
- uses in high dose chemotherapy regimens
what are the toxicities surrounding carboplatin
Haematological toxicities = thrombocytopenia, neutropenia (can harvest WBC and return them for treatment)
Nausea and vomiting
what are the pharmacokinetic principles which can be applied to platinum agents
Measurements of ultrafilterable (free) platinum and total platinum
- Ultrafilterable platinum: non-protein bound drug thought to represent platinum species with anti-tumour and toxic properties
- Total platinum: protein bound and ultrafilterable platinum species
Platinum compounds commonly administered by _ with variable infusion times from a few minutes up to 24 hours
Intravenous infusion
Exposure to total drug is higher in _, but when measuring free drug _ has high exposure as its less protein bound
cisplatin
carboplatin
A high AUC means what ?
better response
