Platinums Flashcards
Which of the following side effects is more frequently encountered with carboplatin administration than with cisplatin?
a. Nausea and vomiting
b. Renal injury
c. Auditory impairment
d. Myelosuppression
e. Hypersensitivity
d - Myelosuppression
Explanation: Generally, carboplatin offers a milder side effect profile than cisplatin. Myelosuppression, is however, more prominent than with cisplatin. Both thrombocytopenia and leukopenia can occur. Thrombocytopenia is cumulative and is most frequently encountered by the 4th or 5th cycle (in humans). [Chabner, pg 318-319]
In human patients, what biomarker may be used to guide treatment decisions with platinum-based agents?
a. CTR1
b. ERCC1
c. FAS
d. ABCB1
e. caspase 8
b - ERCC1
Explanation: ERCC1 is involved in the nucleotide excision repair (NER) pathway. The mRNA expression of ERCC1 in tumor tissues directly correlates with clinical resistance to platinum therapy. In humans, a specific polymorphism of ERCC1 (codon 118, if you care) was associated with reduced expression of ERCC1 (therefore increased sensitivity to platinums). In human patients with non-small cell lung cancer and colon cancer, expression of this polymorphism is used to guide the decision to institute platinum therapy. [Chabner, pg 314-315]
Which of the following options is contraindicated when attempting to decrease the risk of platinum-associated nephrotoxicity?
a. Pretreatment saline diuresis
b. Mannitol
c. Longer IV infusion (1-4 hours)
d. Dose calculations based on AUC
e. Furosemide
e - furosemide
Explanation: Furosemide decreases total body water, which would increase drug exposure per dose and therefore enhance toxicity. In humans, cisplatin is administered in normal saline after vigorous pre-hydration with saline and mannitol. Infusion duration is recommended between 1-4 hours (shorter infusions appear to have a greater risk of acute toxicity and longer CRIs are associated with reductions in efficacy). [Chabner, pg 317]
What is primarily responsible for the repair of the most common type of platinum-DNA lesions?
a. Mismatch repair pathway
b. Nucleotide excision repair
c. Nonhomologous end joining
d. Homologous recombination
b - Nucleotide excision repair
Explanation: NER is the DNA repair pathway that is primarily responsible for the repair of platinum-DNA lesions. Examples – ERCC1, XPA, XPF, XPB, XPD, and others. Cells deficient in NER (i.e. patients with xeroderma pigmentosa disorder) show extreme sensitivity to platinum damage. NEJ fixes ds DNA breaks but these are less common damages.
5Which phase of the cell cycle do platinum cross-links form with the greatest efficiency?
a. G1 phase
b. S phase
c. G2 phase
d. Mitosis
b - S phase
Explanation: Platinum agents are non cell cycle specific in terms of cell killing effects. Drugs that reduce the intracellular levels of purine and pyrimidine precursors needed for DNA replication or repair are synergistic with platinum agents.
Which of the following statements is true regarding the difference between cisplatin and carboplatin?
a. The cyclohexyl group of carboplatin alters the susceptibility of DNA repair pathways.
b. Cisplatin is less likely to induce emesis.
c. The leaving groups of carboplatin are more complex than cisplatin, which decreases its reactivity in aqueous solution.
d. Cisplatin is more stable at neutral pH
c
Regarding the affinity of cisplatin for intracellular targets, which is correct?
a. DNA>RNA>proteins
b. RNA>DNA>proteins
c. Proteins>DNA>RNA
d. DNA=RNA>proteins
b RNA>DNA>proteins
Chabner page 311
Which of the following would be expected to show a lack of synergism with cisplatin?
a. 5-fluoruracil
b. gemcitabine
c. paclitaxel
d. cyclophosphamide
d - cytoxan
Explanation: agents that deplete purine and pyrimidine precursors are synergistic with the platinums, as are agents that alter mitosis (so vincas also synergistic)
Which of the following would be least likely to confer platinum resistance to a cancer cell?
a. Increase in the ATP7A protein
b. Increased intracellular glutathione
c. Enhanced mismatch repair activity
d. Increased activity of ERCC1
c - enhanced MMR activity
Explanation: Apoptosis in response to cisplatin is mediated through the MMR complex (so would lead to more cell death/less resistance). All of the other answers would make the cell MORE resistant. (a) ATP7A contributes to drug efflux, so an increase in it would decrease the cell’s exposure to the drug. (b) Glutathione contains abundant sufhydryl groups, which can covalently bind the active moieties of the platinum drug and decrease drug effectiveness. (d) ERCC1 is an essential gene of the nucleotide excision repair pathway. Upregulation of the pathway can increase resistance by increasing the repair of damaged DNA.
Which of the following DNA lesions occurs most frequently following exposure to platinum drugs?
a. N7-d(GpXpG)-intrastrand adduct
b. N7-d(GpG) intrastrand adduct
c. N7-d(ApG)-instrastrand adduct
d. N7-d(X)-d(X)-interstrand cross link
b - N7-d(GpG) intrastrand adduct
Explanation: p311-312, Table 15.2, (see figure 15-3 for pictures of the adducts)
The N7-d(GpG) and N7-d(ApG) instrastrand adducts account for more than 80% of total platinum-DNA damage that forms after an exposure of cisplatin to isolated DNA.
What is the only orally active platinum analogue?
a. Cisplatin
b. Oxaliplatin
c. Satraplatin
d. Transplatin
c - satraplatin
Explanation: A potentially promising new analog of cisplatin is satraplatin. It is an orally active platinum analogue, which has preclinical activity in tumor cell lines resistant to cisplatin, taxanes, and/or anthracyclines. p. 319
Selting, et al. Evaluation of satraplatin in dogs with spontaneous occurring malignant tumors. JVIM 2011
Which of the following drugs is most likely to cause severe ototoxicity?
a. Cisplatin
b. Carboplatin
c. Oxaliplatin
d. Satraplatin
a - cisplatin
Explanation: Auditory impairment can be overt, with clinically dramatic reductions in auditory acuity after several cycles of cisplatin-based therapy, or they can be more subtle. Severe ototoxicity appears to occur less frequently with carboplatin or with oxaliplatin. p. 316
Which of the following breeds would be MOST likely to have a genetic basis for carboplatin resistance when being treated for a mammary tumor?
a. Labrador Retriever b. German Shepherd Dog c. Shih Tzu d. Yorkshire Terrier e. Pomeranian
C - Shih Tzu
Explanation: This is based on current usage in humans and veterinary patients. The other important factor here is Shih Tzus are known to have BRCA1 mutations causing an increase in BRCA1 expression. This can lead to improved repair of dsDNA breaks. English Springer Spaniels also have documented BRCA mutations.
Which of the following is thought to be MORE sensitive to platinum analogue toxicity?
a. distal renal tubule b. proximal renal tubule c. renal collecting duct d. renal glomerulus e. juxtaglomerular cells
A - distal renal tubule
Chabner - page 315
Which of the following is/are TRUE regarding platinum agents?
i. carboplatin requires esterase activity to expose the reactive arms for covalent binding
ii. Carboplatin can safely be administered in 0.9% NaCl without change to stability
iii. Cisplatin causes rigid bond angles within DNA where carboplatin does not
iv. Passive diffusion is the only mechanism of cellular influx for both platinums
v. the active forms of platinum agents occur in the cis conformation
a. i, v
b. ii, iii
c. iii, iv
d. I, iii, v
e. ii, iii, iv
A - i, v
page 311-312
Explanation: ii) Benaji et al J Clin Pharm Ther 1994 states that in the presence of chloride ions, carboplatin is converted to cisplatin; therefore, not stable iii) aside from the initial step to create an active compound, all platinum agents have a subcellular mechanism that is the same. Both compounds create rigid angles that do not allow bend in the DNA. Bifunctional alkylating agents allow the adducts to conform to the DNA iv) specific transmembrane transport proteins (e.g. CTR1, ATP7A, etc) help mediate the transport.
