Platinum Analogues

Question 1

Pharmacokinetic differences between cisplatin and analogs are dt differences in what?

Answer 1

LEAVING GROUPS

Question 2

Describe the structure of the platinum analogues in regard to oxidation state

Answer 2

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

Question 3

Cisplatin -

1. what molecule is the leaving group?
2. what is preferred site for binding of cisplatin to DNA?

Answer 3

1. chlorine atom

2. 7 positions of guanine and adenine bases

Question 4

Cisplatin -
Stereochemistry critical for cytotoxicity. Binds to ___ sites on DNA and 95% of binding produces _____ crosslinks (usually GG or GA)

Answer 4

Binds TWO sites on DNA

95% INTRASTRAND crosslinks

Question 5

Cisplatin is rapidly and _______ bound to ______ ________ upon administration

Answer 5

rapidly and IRREVERSIBLY bound to PLASMA PROTEINS

Question 6

Carboplatin has a substitution of _______ for chloride leaving groups on cisplatin

Answer 6

cyclobutanedicarboxylate leaving groups

Question 7

Is carboplatin excreted changed or unchanged by kidneys?

What can predict amount of carbo excreted?

Answer 7

UNchanged

Creatinine clearance

Question 8

Oxaliplatin has a substitution of _________ for the amine carrier groups

Answer 8

DACH = diaminocyclohexane

Question 9

3 methods of platinum resistance

Answer 9

1. Reduced platinum-DNA adduct formation
2. Increased repair/tolerance of adducts
3. Increased binding of drug to intracellular scavengers (ie glutathione, metallothionine)

Question 10

Platinum Toxicity:

1. Cisplatin can lead to this uncommon hematologic toxicity:

Answer 10

1. cisplatin – > anemia

Question 11

Carbo in particular reduces this cell line

Answer 11

carbo – > thrombocytopenia

Question 12

Cisplatin can cause these two unusual side effects – >

Answer 12

Cisplatin – > damage to nerves and ear – > hearing loss

other platinums can also cause NEUROTOX but less frequently

Question 13

Oxaliplatin can cause this specific toxicity – >

Answer 13

Oxaliplatin – > CUMULATIVE SENSORY NEUROTOXICITY – > marked sensitivity to cold (particularly in oropharynx)

Question 14

Are the platinums water or lipid soluble?

Answer 14

highly WATER soluble

Question 15

Analogs in the ____ configuration are clinically active. Analogs in the ___ configuration are not.

Answer 15

CIS are active. TRANS are not.

Question 16

All clinically active platinum analogs form _____ DNA adducts; this type of damage appears to be responsible for the cell-killing effect of these analogs

Answer 16

BIFUNCTIONAL DNA adducts responsible for cytotoxicity

Question 17

Which 2 intrastrand adducts are responsible for > 80% of total platinum-DNA damage from cisplatin?

Answer 17

N7-d(GpG) and N7-d(ApG)

These two adducts – > severe kinking of DNA helix (dt rigid bond angles w/in cisplatin molecule

Question 18

What types of cells are most sensitive to cisplatin?

Answer 18

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.

Question 19

Is cisplatin and other platinums synergistic with any anti-cancer agents?

Answer 19

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

Question 20

Are platinums cell cycle specific or not?

Answer 20

Relatively non-cell cycle specific.

BUT cross-links do form with greatest efficacy during S-PHASE

Question 21

Is cisplatin a radiosensitizer?

Is carbo?

Answer 21

Cisplatin YES

Carbo NO

Question 22

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

Answer 22

1. NER - increased NER, increased platinum resistance

2. ERCC1

Question 23

Upregulation of _______ or ________ will inactivate drug before it reaches nucleus

Answer 23

metallothioneins, glutathione (sulfhydryl-containing groups)

Question 24

When ______ is inactivated in cells, cellular accumulation of drug is significantly reduced

Answer 24

copper transporter CTR1

Question 25

Resistance to apoptosis in response to cisplatin mediated through _____, _______, and ________

Answer 25

MMR, p53, bcl/bax

Question 26

Loss of which minerals may occur after platinums?

Answer 26

HypoMg and HypoCa - may be symptomatic

Also decreased Zn, Se

Question 27

Dose carbo based on ____, which is eliminated primarily by renal clearance

Answer 27

AUC

Question 28

_______ administered IV may inactivate platinums systemically

__________ may also inactivate, but preferentially healthy tissues

Answer 28

1. thiosulfates

2. amifostine