Platinum Analogues Flashcards
Pharmacokinetic differences between cisplatin and analogs are dt differences in what?
LEAVING GROUPS
Describe the structure of the platinum analogues in regard to oxidation state
Platinum drugs exist in 2+ (II) or 4+ (IV) oxidation state (with 4 and 6 bonds respectively) – > all used now are platinum II compounds which exhibit a PLANAR structure with FOUR attached chemical groups
The chemical groups dictate the efficacy and pharmacokinetics of the compound
Two of the groups are CARRIERS (chemically inert) and the other two leaving groups are for SUBSTITUTION and REACTION w molecules such as DNA
Cisplatin -
- what molecule is the leaving group?
- what is preferred site for binding of cisplatin to DNA?
- chlorine atom
2. 7 positions of guanine and adenine bases
Cisplatin -
Stereochemistry critical for cytotoxicity. Binds to ___ sites on DNA and 95% of binding produces _____ crosslinks (usually GG or GA)
Binds TWO sites on DNA
95% INTRASTRAND crosslinks
Cisplatin is rapidly and _______ bound to ______ ________ upon administration
rapidly and IRREVERSIBLY bound to PLASMA PROTEINS
Carboplatin has a substitution of _______ for chloride leaving groups on cisplatin
cyclobutanedicarboxylate leaving groups
Is carboplatin excreted changed or unchanged by kidneys?
What can predict amount of carbo excreted?
UNchanged
Creatinine clearance
Oxaliplatin has a substitution of _________ for the amine carrier groups
DACH = diaminocyclohexane
3 methods of platinum resistance
- Reduced platinum-DNA adduct formation
- Increased repair/tolerance of adducts
- Increased binding of drug to intracellular scavengers (ie glutathione, metallothionine)
Platinum Toxicity:
1. Cisplatin can lead to this uncommon hematologic toxicity:
- cisplatin – > anemia
Carbo in particular reduces this cell line
carbo – > thrombocytopenia
Cisplatin can cause these two unusual side effects – >
Cisplatin – > damage to nerves and ear – > hearing loss
other platinums can also cause NEUROTOX but less frequently
Oxaliplatin can cause this specific toxicity – >
Oxaliplatin – > CUMULATIVE SENSORY NEUROTOXICITY – > marked sensitivity to cold (particularly in oropharynx)
Are the platinums water or lipid soluble?
highly WATER soluble
Analogs in the ____ configuration are clinically active. Analogs in the ___ configuration are not.
CIS are active. TRANS are not.
All clinically active platinum analogs form _____ DNA adducts; this type of damage appears to be responsible for the cell-killing effect of these analogs
BIFUNCTIONAL DNA adducts responsible for cytotoxicity
Which 2 intrastrand adducts are responsible for > 80% of total platinum-DNA damage from cisplatin?
N7-d(GpG) and N7-d(ApG)
These two adducts – > severe kinking of DNA helix (dt rigid bond angles w/in cisplatin molecule
What types of cells are most sensitive to cisplatin?
Cells deficient in DOUBLE-STRAND BREAK REPAIR (BRCA-1 or BRCA-2) — > these accumulate single or double strand crosslinks…and eventually double strand breaks…and die.
Is cisplatin and other platinums synergistic with any anti-cancer agents?
Synergistic w agents that reduce intracellular levels of purine/pyrimidine precursors needed for DNA replication/repair, including 5-FU and GEMCITABINE
Platinums additive or synergistic w agents that ALTER MITOSIS (PACLITAXEL) and with inhibitors of DNA repair (PARP) and with downregulation or inhibition of ERCC1
Are platinums cell cycle specific or not?
Relatively non-cell cycle specific.
BUT cross-links do form with greatest efficacy during S-PHASE
Is cisplatin a radiosensitizer?
Is carbo?
Cisplatin YES
Carbo NO
Platinums form bulky compounds (platinum-DNA adducts) with DNA, which are repaired by __1___. Cells deficient in __1__ show extreme sensitivity to platinum damage.
___2__ is useful in determining patients that would benefit from platinum chemo bc this is a biomarker for activity of ___1___, which is the DNA repair path primarily responsible for repair of platinum-DNA lesions
- NER - increased NER, increased platinum resistance
2. ERCC1
Upregulation of _______ or ________ will inactivate drug before it reaches nucleus
metallothioneins, glutathione (sulfhydryl-containing groups)
When ______ is inactivated in cells, cellular accumulation of drug is significantly reduced
copper transporter CTR1
Resistance to apoptosis in response to cisplatin mediated through _____, _______, and ________
MMR, p53, bcl/bax
Loss of which minerals may occur after platinums?
HypoMg and HypoCa - may be symptomatic
Also decreased Zn, Se
Dose carbo based on ____, which is eliminated primarily by renal clearance
AUC
_______ administered IV may inactivate platinums systemically
__________ may also inactivate, but preferentially healthy tissues
- thiosulfates
2. amifostine
