Drug Resistance Flashcards
Which efflux pump needs to form a dimer in order to become a functional transporter?
a. ABCB-1
b. MRP-1
c. MRP-2
d. ABCG-2
Answer: d.
ABCG2 (aka BCRP or breast cancer resistance protein) cannot function alone, and like 3rd year oncology residents, must dimerize in order to become functional.
Which of the following drugs would you feel most comfortable giving to a long-haired Whippet on whom you had performed no genetic testing?
a. Topotecan
b. Methotrexate
c. Paccal Vet
d. Epirubicin
Answer: a.
explanation: you’re looking for something that is NOT a PGP substrate (long haired Whippets have a 65% chance of being either hetero or homozygous for MDR1-del1). Epirubicin (related to doxo) should be easily eliminated; Paccal Vet for the same reason. Methotrexate is also a PGP substrate, although we think about it less often because we don’t use it much. Topotecan is NOT a PGP substrate and could be given without knowing MDR status. Not much in the vet med literature, but it has been given to a few poor unsuspecting beagles. Page 447, table 19-2
A theoretical cell line over-expresses CTR1/SLC31A1. Which of the following chemo drugs is the cell line most likely to be hypersensitive to when compared to wild-type cells?
a. Palladia
b. Cisplatin
c. Vincristine
d. Gemcitabine
Answer: b.
Explanation: this is a transporter which is normally involved in copper uptake but also facilitates uptake of platinum drugs. Overexpression of the transporter should result in increased intracellular concentration and lethality.
Which of the following proteins being up-regulated would theoretically lead to resistance to doxorubicin?
i. ABCB1 ii. GSH S-transferase iii. DHFR iv. EGFR
a. i, ii
b. ii, iii
c. iii, iv
d. ii, iv
A
p-glycoprotein would increase efflux of doxorubicin, B) GSH S-transferase would increase antioxidant and decrease the reactive oxygen potential of this drug. C) increase would interfere with methotrexate and other anti-folates D) would be important for gefitnib and other antiEGFR inhibitors
A dog diagnosed with multiple myeloma has become resistant to melphalan therapy. The patient is mildly pancytopenic and has >30% plasma cells on bone marrow aspirate with a hypercellular and regenerative bone marrow. There is suspicion of cell-adhesion-mediated drug resistance in this patient. Which of the following could be used to inhibit the cell-adhesion-mediated drug resistance?
a. sunitinib b. gefitinib c. celocoxib d. bortezomib
Answer:
Explanation: Bortezomib is a proteasome inhibitor which has improved the prognosis in patients with MM. Myeloma cells are said to interact with the stroma in the bone marrow, leading to initiation of survival signals that are absent when the same cells are in suspension. They have found that extracellular matrix is needed to create resistance for these cells.
Which of the following would down-regulate a gene?
i. methylation of the CpG islands ii. demethylation of the CpG islands iii. acetylation of histones iv. deacetylation of histones
a. I, iii
b. ii, iv
c. I, iv
d. ii, iii
C
Which of the following is TRUE regarding multidrug resistance proteins (MRPs) and their role in chemotherapy resistance?
a. MRP1 was previously identified by the gene symbol ABCG2.
b. MRP1-mediated drug efflux of vincristine is dependent on cotransport of reduced GSH.
c. MRP2 and MRP4 are prevalent in human tumors and play an important role in drug sensitivity.
d. Overexpression of MRP1 would confer a higher level of resistance to paclitaxel than ABCB1.
e. MRP4-mediated transport is upregulated with co-administration of NSAIDs.
Answer: b
a) MRP1 = ABCC1. b) True. Reduced GSH is cotransported with vincristine and/or doxorubicin via MRP1 and MRP2. For drug metabolites, cotransport of GSH is not required. c) MRP2 and MRP4 are rarely found in tumor samples. d) Paclitaxel and vinblastine are more commonly affected by PGP; MRP1 only offers a low level of drug resistance. e) NSAIDs inhibit drug efflux via MRP4. MRP4 has a renal protective function.
You are evaluating tumor samples for multidrug resistance. You performed immunohistochemistry using the monoclonal antibody, C219. The tumor sample obtained after 2 cycles of chemotherapy stains for a greater proportion of C219 + cells than the sample obtained prior to treatment. Which of the following drug efflux pumps is over-expressed in your resistant cell population?
a. ABCC1
b. ABCB1
c. ABCC4
d. ABCG2
Answer: b
Explanation: Not from T&H but hopefully still relevant. C219 has been used to evaluate canine lymphoma samples for PGP-mediated drug resistance.
See: Bergman PJ, Ogilvie GK, Powers BE. Monoclonal antibody C219 immunohistochemistry against P-glycoprotein: sequential analysis and predictiveability in dogs with lymphoma. JVIM 1996;10(6):354-9.
Which of the following drugs may have enhanced uptake within a hypoxic tumor with a low extracellular pH?
a. Doxorubicin
b. Vincristine
c. Melphalan
d. Paclitaxel
e. Bleomycin
Answer: c
Melphalan and chlorambucil are weak acids. Therefore, extracellular acidity may enhance their uptake. Conversely, doxorubicin, vincristine and bleomycin are all weak bases. They will have a greater proportion of molecules in the charged form under acidic conditions, which decreases their ability to cross the plasma membrane. Paclitaxel is not ionizable and thus drug distribution should not be affected by pH.
Also see: Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Molecular pharmaceutics. 2011;8(6):2032-2038. doi:10.1021/mp200292c.
A wide range of changes in the properties of tumor cells may lead to resistance to specific drugs. Identify the most appropriate match up for the mechanism of resistance that occurs along with the drug this mechanism is most commonly associated with.
a. Increase in drug catabolism: Cisplatin
b. Increased DNA repair: Anthracyclines
c. Decreased ability to undergo apoptosis: TKIs
d. Decreased uptake: Vinca Alkaloids
Answer: b
The following is a list of mechanisms by which drug uptake occurs within a cell. All mechanisms allow for drug entry into cells down a concentration gradient. Identify which one of these can also lead to transport against a concentration gradient.
a. Passive diffusion
b. Facilitated diffusion
c. Binding of drug to cell surface receptor that is then internalized
d. Active transport
Answer: d
Passive diffusion is when the drug enters the cell by an energy and temperature independent process without interacting with specific constituents in the cell membrane
Facilitated diffusion is when the drug interacts in a chemically specific manner with a transport carrier the cell membrane and is translocated into the cell in an energy and temperature independent manner
Active transport is when the drug is actively transported by a carrier mediated process that is both temperature and energy dependent.
Drug uptake into cells occurs by many mechanisms and all of these mechanisms allow for drug entry into cells down a concentration gradient. Identify the most accurate definition for the one mechanism that can also lead to a transport against a concentration gradient.
a. when the drug enters the cell by an energy and temperature independent process without interacting with specific constituents in the cell membrane
b. when the drug interacts in a chemically specific manner with a transport carrier the cell membrane and is translocated into the cell in an energy and temperature independent manner
c. when the drug is actively transported by a carrier mediated process that is both temperature and energy dependent
d. when the drug binds to a cell surface receptor and is then internalized
Answer: c
Explanation: the key here is to know that the answer is active transport and then you have to be able to identify the differences between the mechanisms so that you would be able to identify which answer choice was describing active transport.
Which of the following is true?
a. An inactivating mutation in dihydropyrimidine dehydrogenase would decrease efficacy of 5-FU
b. Verapamil can reverse resistance of a variety of drugs due to p-glycoprotein expression
c. Vincristine efficacy can be decreased by transfection of cells with glutathione S-transferase
d. Increased expression of folypolyglutamyl synthase would decrease toxicity of MTX
Answer: b.
(d) FPG synthase polyglutamates MTX and makes it more effective
Which of the following small molecule inhibitors is least likely to develop a resistance mechanism related to drug efflux?
a. Erlotinib
b. Imatinib
c. Gefitinib
d. Sunitinib
Answer: d.
Sunitinib and sorafenib are not effluxed efficiently by ABC transporters and do not rely on SLC proteins for cellular entry. Resistance with these SMIs is less likely than with drugs, but still possible with chronic use.
Which of the following species has been shown to have defective ABCG2 transport of mitoxantrone?
a. Humans
b. Dogs
c. Cats
d. Mice
Answer: c.
2015 (VCO) Lewis et al. Comparison of chemotherapeutic drug resistance in cells transfected with K9 ABCG2 or feline ABCG2
- Cells transfected with k9 ABCG2 had greater survival than feline ABCG2 transfected cells
o Presumptively d/t amino acid change in ATP binding domain
- No resistance was conferred to doxorubicin, vinc, or toceranib with either ABCG2
- K9 ABCG2 transfected cells conferred resistance to carboplatin, which has not been shown in other species
