Misc. Chemo

Question 1

A Bassett Hound is presented for general malaise. Five years ago, this patient was treated with CHOP-based chemotherapy and various rescue protocols for multicentric lymphoma. Today, his CBC reveals a severe leukocytosis of 91k/uL. A blood smear reveals circulating blast cells with multiple visible nucleoli. Flow cytometry demonstrates the following immunophenotype: CD34+/CD45+/CD3-/CD79-. What is your diagnosis, and what former chemotherapeutic is most likely to have caused this secondary malignancy?

i. Acute myeloid leukemia
ii. Chronic lymphocytic leukemia
iii. Cyclophosphamide
iv. Doxorubicin
v. Prednisone
a. i, iii
b. i, iv
c. ii, iii
d. ii, iv
e. ii, v

Answer 1

a.
Chemotherapy-related second malignancy is most frequently seen with mustard-type alkylators, nitrosureas, and procarbazine. The risk for leukemia increases with cumulative doses of alkylators, which should be considered when used long-term or at high doses. Second malignancies, although possible from doxorubicin, are far less likely seen than with alkylating agents. Also, the expression of CD34 can help differentiate AML (+) from CLL (-).

Question 2

Several administration techniques have been reported for cytosine arabinoside. Why might a continuous rate infusion be preferred over bolus dosing?

a. Cytosine arabinoside binds tubulin dimers.
b. Cytosine arabinoside is slowly metabolized.
c. Cytosine arabinoside causes nausea only when administered as a bolus.
d. Cytosine arabinoside is S-phase specific.

Answer 2

d.
Cytosar is cell-cycle-phase specific. If administered as a CRI compared to bolus therapy, a greater amount of tumor cells are exposed during the sensitive S-phase. Chabner reports improved therapeutic ratios for 5-FU, etoposide, ifosfamide and Cytosar when administered as an extended infusion.

Question 3

What drug has been shown to experimentally reverse the effects of the p-glycoprotein drug efflux pump in vitro?

a. Calcium-channel blockers
b. Cephalexin
c. Ondansetron
d. Azathioprine
e. Tyrosine kinase inhibitors

Answer 3

a.
Source = Chabner, and although not in our reading list, this article contains several great charts on the subject: Srivalli KMR and Lakshmi PK. Overview of P-glycoprotein inhibitors: a rational outlook. Brazilian Journal of Pharmaceutical Sciences. 2012; 48(3): 353-67. www.scielo.br/pdf/bjps/v48n3/a02v48n3.pdf
Explanation: P-glycoprotein effects can be reversed experimentally by administration of calcium-channel blockers, amiodarone, quinidine, various steroid hormones, and cyclosporine analogues. However, the results of in vitro studies are confounded by pharmacokinetic interactions of reversing agents and chemotherapy drugs.

Question 4

Which of the following are causes of resistance to cyclophosphamide?

i. increased intracellular thiol concentrations
ii. increased aldehyde dehydrogenase expression
iii. mutations in MSH6
iv. increased ABCB1 expression
v. increased methylguanine methyl transferase

a. i, ii
b. i, ii, iii
c. ii, iii, iv
d. ii, iv
e. i, iii, v

Answer 4

a.

Question 5

Which of the following is a mechanism of apoptosis suppression?

i. overexpression of bcl-2
ii. overexpression of caspase 8 and 9
iii. activation of PI3K
iv. down regulation of epithelial growth factor
v. activation of NF-KB
a. i, iv, v
b. i, ii
c. i, iii, v
d. ii, iii, v
e. ii, iv

Answer 5

c.
Bcl-2 is an antiapoptotic gene (direct suppression)
BRCA1/2 is a tumor suppressor genes (mutations are associated with inherited form of breast and prostate cancer)
Activation of PI3K, EGF, and NF-KB pathways are associated with indirect suppression of apoptosis

Question 6

What is the definition of dose intensity?

a. milligrams per m2 delivered per hour
b. milligrams per m2 delivered per week
c. milligrams per kg administered per week
d. milligrams per m2 per treatment cycle

Answer 6

b.

Question 7

Which of the following would be most likely to contribute to the development of a cancer’s resistance to doxorubicin chemotherapy?

i. increased drug efflux via upregulation of ABCB1 expression
ii. decreased drug uptake via decreased expression of the folate transporter
iii. altered drug target via changes to topoisomerase II
iv. increased detoxification via increased glutathione transferase
v. decreased recognition of damaged DNA via defects in mismatch repair

a. i and iii
b. ii, iii, and v
c. i, iii, and iv
d. i, ii, and iii

Answer 7

C

Question 8

A 12 year old female spayed mixed breed dog presents for an abdominal mass. Routine staging tests are clear, and on abdominal exploratory, a mass is found to be associated with the cecum. The mass cannot be completely excised, but the surgeon removes as much as possible. The histopathology report diagnoses a GIST.
The owners are willing to do anything necessary to best control this disease, and finances are not a concern. Which of the following is the best course of action?
a. No further therapy is needed for this tumor type, even when incompletely excised.
b. Carboplatin
c. Imatinib
d. Doxorubicin

Answer 8

c.
Answering correctly requires recognizing that this is a GIST. While Palladia is typically our treatment of choice, it is not a given option. Masitinib inhibits c-kit, but it is conditionally licensed for MCT, and hence cannot be used in this situation. Imatinib is therefore the best remaining choice. (Inspired by Chabner chapter 1, page 7, paragraph 2.)

Question 9

When attempting chemotherapeutic cytoreduction for a bulky tumor, which would be the most rational order of therapy? Ignore the chemoresponsiveness of specific tumor types and/or toxicity profiles, and base your answer solely on your knowledge of cell cycle kinetics.

a. Cytosar followed by chlorambucil.
b. Lomustine followed by cyclophosphamide.
c. Vincristine followed by lomustine.
d. Carboplatin followed by Paccal Vet.

Answer 9

d.
Bulky tumors have a large proportion of G0 or slowly dividing cells that are likely to be highly chemoresistant. Alkylators and platinums are effective in all phases of the cell cycle and therefore can be used to reduce tumor bulk. You can then follow with drugs that are most cell cycle specific (Cytosar – S phase; Vincas and taxanes – M phase). From Chabner Ch 1, page 6, paragraph 3.

Question 10

Which of the following chemotherapeutic agents is NOT considered to lack bone marrow toxicity?

a. Bleomycin sulfate
b. Vincristine sulfate
c. High dose methotrexate/leucovorin
d. Mechlorethamine

Answer 10

d.
Drugs such as vincristine sulfate, prednisone, bleomycin sulfate, L-aspariginase, high-dose methotrexate/leucovorin, and biological agents all lack bone marrow toxicity and are particularly valuable in combinations with traditional myelsuppressive agents.

Question 11

Choose from the list below which alkylating agents would be the most appropriate to use in a multi-agent protocol together.

a. Cyclophosphamide and melphalan hydrochloride
b. Cyclophosphamide and Ifosfamide
c. Mechlorethamine and procarbazine
d. Melphalan hydrochloride and chlorambucil

Answer 11

c.
Classic alkylating agents (cyclophosphamide, melphalan hydrochloride, nitrogen mustard) may share cross resistance related to enhanced DNA repair mediated by nucleotide excision repair enzymes and by increased levels of intracellular nucleophilic thiols, such as glutathione. Not all alkylating agents share cross resistance. Resistance to the nitrosourea, procarbazine, dacarbazine, and other methylating agents is mediated by increased levels of a different enzyme, methyl guanine methyl transferase. Thus, there is a clear rationale for combining different types of alkylators in a single regimen.

Question 12

What is the name of the membrane glycoprotein that the MDR-1 gene codes for, in which promotes the efflux of many chemotherapeutic agents such as vinca alkaloids, anthracyclines, taxanes, actinomycin D, and even small molecules that target tysosine kinases?

a. P-170
b. P-180
c. G-120
d. G-190

Answer 12

a.

1. The most thoroughly studied and undoubtedly one of the most important mechanisms of multidrug resistance is increased expression of the MDR-1 gene. This gene codes for the P-170 membrane glycoprotein.
2. The multidrug resistance pump (P-glycoprotein) is a 170 kDa phosphorylated and glycosylated plasma membrane protein belonging to the ATP binding cassette superfamily of transport proteins encoded by the multidrug resistance genes (MDR), first described by Juliano and Ling in 1976

Question 13

Which of the following is paired appropriately the method of resistance and chemotherapy drug?

a. altered topoisomerase II : melphalan
b. decreased deoxycytidine kinase : cytosine arabinoside
c. increased glutathione : etoposide
d. increased O6- alkyl-guanine-alkyl transferase : 5-FU
e. amplified bcr-abl : bevacuzimab

Answer 13

b.

Question 14

Which of the following could contribute to the disruption of the fractional kill hypothesis in solid tumors with gross disease?

i. oxygenation and vascularity to the tumor
ii. all tumor cells are in the G1 phase
iii. S-phase specific chemotherapy agents target rapidly dividing cells which is not present in large, solid tumors
iv. a highly homogeneous cell population

a. i, ii
b. ii, iii
c. iii, iv
d. i, iii
e. ii, iv

Answer 14

d.

Question 15

A patient with chemotherapy and/or radiation-therapy induced leukemia is MOST likely to be diagnosed with which of the following:

a. chronic lymphocytic leukemia
b. acute lymphoblastic leukemia
c. polycythemia vera
d. primary thrombocytosis
e. acute myelomonocytic leukemia

Answer 15

e.

Question 16

Name 4 risk factors for developing sepsis during chemotherapy.

Answer 16

1. neutropenia (esp bacterial translocation
2. splenectomy
3. indwelling catheter or other implants

Question 17

Describe the changes that occur with ATLS:

K, Phos, uric acid, calcium

Answer 17

incr K
incr Phos
incr uric acid
decr calcium

Question 18

Name 4 risk factors for ATLS

Answer 18

high tumor burden
high pre-tx alk phos
rapid tumor response
pre-existing renal failure (or at least dehydration)

Question 19

Identify which of the following toxicities have been associated with L-asparaginase.

i. Pancreatitis
ii. Hypoglycemia
iii. Hypertension
iv. Decreased serum insulin
v. Elevated hepatic enzymes

a. ii, iii
b. i, ii, iii
c. i, iv, v
d. i, ii, iii, iv, v

Answer 19

c

Hyperglycemia and Hypotension actually occur instead. Decreased serum insulin occurs with hyperglycemia.

Question 20

Which drug has been shown to have its mechanism of action terminated with elspar?

a. Cyclophosphamide
b. Bleomycin
c. Vincristine
d. Methotrexate

Answer 20

d

The only well established drug interaction of L-ASP is its ability to terminate the action of methotrexate. The antagonism of asparaginase when given before methotrexate is possibly the result of inhibition of protein synthesis, with consequent prevention of cell entry into the vulnerable S phase of the cell cycle.

Question 21

What underlying cellular alteration is responsible for cell death in tumors sensitive to L-asparaginase?

a. Inhibition of cell membrane formation
b. Inhibition of protein synthesis
c. Depletion of purines
d. DNA damage

Answer 21

b

Question 22

Which of the following is true regarding L-asparaginase and L-asparagine?

a. Despite poor penetration of the blood brain barrier, antitumor affects of L-asparaginase are detectable within the CSF
b. Fewer hypersensitivity reactions are observed with the native, E. coli derived formulation of L-asparaginase compared to the pegylated formulation
c. NH2 is donated by glycine in order to form L-asparagine from L-aspartic acid within cells
d. The production of neutralizing antibodies to L-asparaginase is the primary mechanism of resistance

Answer 22

a

• CSF conc of asparagine falls rapidly with L-ASP admin and antileukemic effects is observed in the CNS despite poor penetration of the enzyme into the CSF
• L-aspartic acid is converted to L-asparagine intracellularly by L-asparagine synthetase. This reaction requires donation of NH2 group from L-GLUTAMINE (pg 412). However, L-asparagine does play a role as an NH2 group donor for glycine synthesis (pg 413).
• Elevated levels of asparagine synthetase within tumor cells is thought to be the main mechanism of resistance to L-asparaginase. Other mechanisms – neutralizing antibodies and defective induction of apoptosis.

Question 23

Which of the following could cause resistance to L-asparaginase?

a. up-regulation of asparaginase synthetase
b. down-regulation of asparaginase synthetase
c. up-regulation of glutamine transferase
d. down-regulation of glutamine transferase

Answer 23

A

Question 24

By what method do lymphoma cells die after exposure to L-asparaginase?

a. autophagy
b. necrosis
c. apoptosis
d. ferroptosis

Answer 24

C

Question 25

What is the advantage of the pegylated form of L-asparaginase compared to the native E. coli-derived preparations?

a. it is less immunogenic and has a longer half-life
b. more doses can be given before resistance develops
c. it has a lower risk of coagulopathy
d. it is better tolerated by patients with hepatic dysfunction

Answer 25

a.

Question 26

Which of the following may be a complication of treatment with L-asparaginase?

i. hemorrhage secondary to decreased vitamin-K dependent clotting factors
ii. thromboembolism secondary to decreased antithrombin
iii. bruising secondary to ADP-mediated platelet dysfunction

a. i
b. ii, iii
c. iii
d. i, ii

Answer 26

d.

Explanation: decreased protein synthesis can lead to both decreased clotting factors and decreased antithrombin. Patients treated with Elspar have platelet dysfunction in response to collagen but NOT ADP, arachidonic acid, or epinephrine.

Question 27

At what location do nitrogen mustards most commonly cause alkylation of DNA?

a. N2 position on adenine
b. N7 position on guanine
c. N3 position on cytosine
d. O6 position on guanine

Answer 27

B

Question 28

Which of the following chemotherapeutic drugs are primarily eliminated unchanged by the kidneys?

i. Carboplatin
ii. Vincristine
iii. 5-fluorouracil
iv. Bleomycin
v. Paclitaxel

a. i, iv
b. i, iii, iv, v
c. i, ii, v
d. iii, v
e. iv, v

Answer 28

Answer: a

Explanation: Carboplatin and bleomycin are eliminated unchanged by the kidneys. The others primarily undergo biliary excretion.

Question 29

Which of the following side effects occur at an increased frequency with pegylated liposomal doxorubicin compared to free doxorubicin?

a. Cardiotoxicity
b. Myelosuppression
c. Nausea
d. Hand-foot syndrome

Answer 29

Answer: d
Generally, the liposomal encapsulated doxorubicin has less side effects than free doxorubicin. However, hand-foot syndrome occur at an increased frequency with liposomal doxorubicin.

Question 30

A pharmacology study investigating a chemotherapeutic agent evaluated a group of patients in which severe toxicity was observed after administration of this drug. The investigators identified a genetic mutation of an enzyme located on chromosome 1p22. This mutation is thought to be the reason for the toxicity in these patients. Based on this description, identify what type of study this is.

a. Pharmacokinetic study
b. Pharmacodynamic study
c. Pharmacogenetic study
d. Bioavailability study

Answer 30

Answer: c

Pharmacokinetics is the study of the time course of drug and metabolite levels in different body fluids and tissues, including absorption, metabolism, and elimination.
Pharmacodynamics is the study of the relationship between drug effect and its concentration
Bioavailability refers to the amount of drug that is available after oral administration compared to that of IV administration
Pharmacogenetics refers to the study of how genetic features of the patient will influence response and toxicity. It seeks to explain phenotypic differences in response on the basis of differences in the activity of genes that are involved in drug metabolism and are related to specific mutations or polymorphisms.

Question 31

Identify the most correct statement in regards to the area under the curve in pharmacokinetics.

a. If the clearance of a drug declines, its AUC will decrease as well without an adjustment of dose, and this will result in a decrease of toxicity
b. A large distribution volume (Vd) indicates that drug is mainly distributed in plasma, rather than additional compartments such as tissue.
c. AUC= Clearance x rate of elimination
d. After one biological half-life the concentration of drug will have fallen to half of the initial concentration; After two biolog. half-lives it will have fallen to one quarter of the initial concentration and so on.

Answer 31

Answer: d

a. If the clearance of a drug declines, (e.g. in the setting of renal or hepatic dysfunction), its AUC will increase without an adjustment in dose, resulting in increased toxicities
b. The volume distribution represents a hypothetical volume of body fluid that would be required to dissolve the total amount of drug at the same concentration as that found in blood immediately after IV administration. Large distribution volume - not only heart but also in other tissues, larger distribution volume indicates drug has been distributed to additional compartments. Low Vd indicates that drug is mainly distributed in plasma
c. The AUC of a drug is related to its dose and clearance: AUC= Dose/Clearance
d. The half life of a drug is the time required for the drug concentration to decrease by half

Question 32

Identify the correct statement explaining the difference in how Vinca alkaloids and Taxanes work within the cell cycle.

a. These chemotherapeutics have the same mechanism of action as they both affect the microtubules within the cell
b. Taxanes inhibit microtubular disassembly, which then prevents normal growth and breakdown of microtubules that is required for cell division
c. Vinca Alkaloids inhibit microtubular disassembly, which then prevents normal growth and breakdown of microtubules that is required for cell division
d. Taxanes bind to the protein tubulin and inhibit its polymerization to form microtubules

Answer 32

Answer: b

Taxanes inhibit microtubular disassembly, which then prevents normal growth and breakdown of microtubules that is required for cell division
Vinca alkaloids bind to the protein tubulin and inhibit its polymerization to form microtubules

Question 33

The rate limiting step in 5-FU catabolism is mediated by what enzyme? A deficiency in this enzyme in patients receiving the drug would lead to an increased risk of severe toxicity.

a. Dihydropyrimidine dehydogrenase
b. Difluorohydrourase
c. Thymidylate synthase
d. Dihydrofolate reductase

Answer 33

Answer: a

Question 34

Identify the correct statement below:

a. Clearance of a drug is usually dependent on its dose.
b. The area under the curve (AUC) is defined as the dose times the clearance rate.
c. Volume of distribution will be greater than total body water for drugs that have poor tissue binding.
d. The α, β, and γ components of t1/2 can be used to characterize the clearance curve for the drug.

Answer 34

Answer: d.

(a) clearance is independent of dose unless a metabolizing enzyme becomes saturated. (b) AUC = dose/CL (c) Vd is greater than TBW if a drug is extensively tissue-bound.

Question 35

Which of the following alkylating drugs reacts primarily with thiol groups of amino acids and proteins, has selective effects on hematopoietic stem cells, and is eliminated via hepatic metabolism?

a. Ifosfamide
b. Carmustine
c. Busulfan
d. Dacarbazine

Answer 35

C - busulfan

Question 36

For which of the following drugs is cytotoxicity enhanced by the co-administration with leukovorin?

a. Methotrexate
b. 5-Fluorouracil
c. Gemcitabine
d. Dactinomycin

Answer 36

Answer: b.

TS inhibition (by FdUMP) depends on a cofactor that combines with TS and FdUMP. If excess cofactor is present, the complex does not dissociate as rapidly. Leucovorin is a prodrug of this cofactor – if I understood this correctly? (a) Leucovorin rescues from methotrexate toxicity; it is a reduced folate so bypasses the blockade induced by methotrexate.

Question 37

What is the active metabolite of cyclophosphamide?

a. SN38
b. acrolein
c. phosphoramide mustard
d. L-phenylalanine mustard

Answer 37

c - phosphoramide mustard

Question 38

Based on expression levels of 45 bitches for growth factors in canine mammary tumors, which of the following targeted therapies would be indicated based on the high expression level?

a. bevacizumab
b. traztuzumab
c. cetuximab
d. gefitnib

Answer 38

Answer: D

Explanation: Queiroga, F. L., et al. “Quantification of epidermal growth factor receptor (EGFR) in canine mammary tumours by ELISA assay: clinical and prognostic implications.” Veterinary and comparative oncology (2015).
a) monoclonal antibody for VEGF-A, b) HER-2 monoclonal antibody, c) monoclonal antibody for EGFR

Question 39

Which of the following is true regarding platinating agents?

a. Transplatin will produce DNA binding and is more potent than cisplatin because it creates 2 adjacent binding sites.
b. The leaving groups of carboplatin are 4 chloride ions.
c. The leaving groups of platinating agents are replaced by hydroxyl groups
d. the preferred site of binding for cisplatin is the 5 position for cytosine and thymine.

Answer 39

Answer: C

Explanation: a) cisplatin is more potent because both leaving chloride groups are in the cis form leading to intrastrand crosslinking due to cis positioning, b) most of the platinum agents that we have are 2+ oxidative states with 2 leaving groups They can exist with 2+ or 4+ oxidation, with 4 or 6 bonds linking the platinum atom. d) the preferred site is the 7 positions of guanine and adenine bases.

Question 40

Which of the following drugs requires enzymatic activation to induce cytotoxic effects?

i. Capecitabine
ii. 5-FU
iii. Cytosine arabinoside
iv. Cisplatin
v. Etoposide

a. i, ii, iv
b. ii, iii, v
c. i, ii, iii
d. iii, iv

Answer 40

C

Question 41

Which of the following is true regarding the similarities and differences of ara-C and gemcitabine?

a. Gemcitabine is less effective than ara-C in DNA chain termination
b. Ara-C has prolonged retention intracellularly compared to gemcitabine
c. Ara-C inhibits ribonucleotide reductase in addition to other intracellular effects
d. Both Ara-C and gemcitabine are non-cell cycle specific chemotherapeutics

Answer 41

A

Question 42

Which of the following chemotherapeutic agents is correctly matched with the enzyme responsible for degradation and/or inactivation of the active compound?

a. Cyclophosphamide – dihydropyrimidine dehydrogenase
b. 5-FU – aldehyde dehydrogenase
c. Irinotecan – uridine diphosphate glucuronosyltransferase-1A1
d. Methotrexate – dihydrofolate reductase

Answer 42

Answer: c.

Explanation: UDG1A1 inactivates SN-38 (active metabolite of irinotecan) by glucuronidation to form SN-38G. Other answers are incorrect because cyclophosphamide is inactivated by aldehyde dehydrogenase, 5-FU is inactivated by dihydropyrimidine dehydrogenase, and methotrexate’s mechanism of action is to bind and inhibit DHFR.

Question 43

Choose the correct definition of the therapeutic index when referring to anticancer drugs.

a. The dose required for 50% probability of anti-tumor effect (complete or partial response).
b. The dose required for

Answer 43

Answer: d
The therapeutic index can represent any pre-determined number (e.g., 5% probability of severe toxicity; 15% probability). Any probability may be used.

Question 44

In regards to toxicity to the bone marrow from chemotherapy, identify which cell line would show the slowest substantial decrease in the number of mature cells.

a. White blood cells
b. Red blood cells
c. Platelets
d. These are all affected equally

Answer 44

Answer: b
A substantial decrease in the number of mature cells is common for granulocytes because their lifetime is only 1-2 days, less common for platelets (a few days) and rare for red blood cells (~ 120 days). Red blood cells have a long lifetime, which usually prevents the rapid development of anemia following initiation of chemotherapy.

Question 45

Which class of drugs is most commonly implicated as the cause of a second malignancy in human patients treated with chemotherapy, and/or the addition of radiation therapy?

a. Vinca alkaloids
b. Platinums
c. Alkylating agents
d. Small molecule inhibitors

Answer 45

Answer: c
Many of the second malignancies are acute leukemias, and their most common time of presentation is 2-6 years after initiation of chemotherapy. Drugs that target topoisomerase II (e.g. doxorubicin, mitoxantrone, etc) have also been identified as causes of treatment related leukemia.

Question 46

What neurotransmitters are most commonly involved in transmitting signals involved in producing nausea and vomiting, especially from chemotherapy?

i. Substance P
ii. Dopamine
iii. GABA
iv. Serotonin (5-HT3)
v. Acetylcholine

a. i, ii, v
b. ii, iii, iv
c. iv, v
d. i, iv
e. iii, iv

Answer 46

Answer: d
Several neurotransmitters, such as Serotonin (5-HT3) and Substance P are involved in transmitting signals involved in producing nausea and vomiting. Medications have been developed that inhibit nausea and vomiting after chemotherapy. The most effective are serotonin antagonists (ondansetron) which block 5-HT3 receptors, and the neurokinin 1 receptor antagonists which block substance P.

Question 47

You develop an experiment to investigate a new drug which may work synergistically with radiation therapy. Cells are placed in cell culture with increasing concentrations of the drug and static 4Gy radiation therapy to the cells. Which of the following would be best to quantify the cells?

a. terminal deoxynucleotidul transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling
b. annexin V
c. methyl thiazole tetrazolium
d. propidium iodide

Answer 47

Answer: C

Explanation: A and B label for cells undergoing apoptosis which does not always occur with cells undergoing radiation therapy. MTT depends on the reduction of tetrazolium-based compound to a blue formazan product by living, but not dead, cells. Propidium iodide labels cells DNA and used in flow cytometry to determine the fluorescent intensity of the DNA

Question 48

Therapeutic index (TI) is defined as:

a. The ratio of the drug dose required for a 5% level of probability of severe toxicity to that required for 50% probability of antitumor effect.
b. The ratio of the drug dose required for a 50% level of probability of severe toxicity to that required for 50% probability of antitumor effect.
c. The ratio of the drug dose required for 50% probability of antitumor effect to that required for a 5% level of probability of severe toxicity.
d. The ratio of the drug dose required for 50% probability of antitumor effect to that required for a 50% level of probability of severe toxicity.

Answer 48

Answer: A

Question 49

An experiment is designed where human melanoma xenografts are implanted in severe combined immunodeficiency mice. The mice are divided into a canine tyrosinase DNA vaccine group and a non-treatment group; the treatment group is vaccinated every 2 weeks until tumors reach 1 cm^3. There is no statistical difference in time to euthanasia nor number of pulmonary metastases. What would explain this discrepancy?

a. There is nothing wrong with this experiment.
b. The rate of growth and metastatic capabilities are limited with these xenografted mice due to the serially transplanted nature of the grafts
c. The presence of the stroma in the xenograft negates the immune response by the host
d. Immuno-compromised mice may not mount an immune response to the tumor which is required by this vaccine.

Answer 49

Answer: D

Explanation: B) The rate of growth of xenografts derived from serially transplanted human tumor cell lines is often very rapid compared with that of primary human tumors C)the stromal component of a xenograft is not human and difficult to evaluate the effect of the microenvironment on drug response or to evaluate drugs such as monoclonal antibodies.

Question 50

Which of the following chemotherapeutics would be most likely to increase the risk of developing a secondary malignancy?

a. Vincristine
b. Epirubicin
c. 6-Mercaptopurine
d. Carboplatin

Answer 50

Answer: b.
Although alkylators are the poster child for secondary malignancies, drugs targeting TOPO II can also cause treatment related leukemias with a relative risk of 1.5 compared to patients who did not receive the drug.

Question 51

What is the primary rationale for not giving a myelosuppressive chemotherapeutic in the face of existing chemotherapy-induced neutropenia or thrombocytopenia?

a. Treatment with additional chemotherapy could cause immediate worsening of the cytopenia
b. The second chemotherapy will be less likely to be effective due to immune suppression
c. There is increased likelihood of damage to reserve bone marrow stem cells
d. The cytopenia indicates that other high-grade toxicities (e.g. GI or liver) may occur with cumulative administration.

Answer 51

Answer: c.

If cytopenias are present, the bone marrow stem cells are likely actively dividing to resolve the cytopenia, and will be more susceptible to depletion while they are actively dividing.

Question 52

Which of the following is true regarding assessment of cell damage?

a. Methyl thiazole tetrazolium (MTT) reduction can be used to measure the number of metabolically active cells.
b. Assays for apoptosis give results comparable to those from colony-forming assays.
c. Sulforhodamine B (SB) uptake assesses cell viability but not metabolic activity.
d. TUNEL staining measures the number of cells undergoing both necrosis and apoptosis.

Answer 52

Answer: a.

(b) because chemo and RT kill cells via methods other than apoptosis, apoptosis assays correlate poorly with CF assays. (c) SB measures metabolic activity. (d) TUNEL staining assesses the number of cells in apoptosis.

Question 53

Which of the following choices most accurately describes RNA interference screening?

a. mRNA is extracted from cells or tissues and then converted to cDNA with reverse transcriptase for analysis of gene expression
b. Complete DNA sequencing of cells or tissue
c. Double stranded RNA sequences are introduced → endogenous Dicer digests RNA into short sequences → RNA silencing complexes are used to bind and ID complementary mRNA → gene knockdown
d. Following RNA isolation, electrophoresis is used to separate RNA based on size and hybridization probe complementary to gene target is applied

Answer 53

Answer: c.

A is describing basic microarray, B is describing DNA sequencing, and D is describing Northern blotting.

Question 54

Which of the following is a proteasome inhibitor?

a. Bortezomib
b. Olaparib
c. ABT-737
d. Dasatinib

Answer 54

Answer: a.
Bortezomib has reversible inhibition of proteosome. Another SMI called carfilzomib can irreversibly bind and is more potent than bortezomib. 26S proteasome is responsible for degradation of proteins, which is important for cell cycling and completing mitosis. Proteasome inhibition leads to ER stress with activation of unfolded protein response, inhibition of NF-KB, increased ROS, and activation of Caspase 8 and apoptosis. Olaparib is PARP inhibitor, ABT-737 is a binds BCL-2, and dasatinib binds ABL kinase among other off target sites.

Question 55

By what primary mechanism does rituximab induce cell death?

a. Prevents ligand binding and intracellular signaling.
b. Promotes antibody- and complement-mediated cytotoxicity.
c. Fusion of the liposome with cell membrane allows for internal delivery of the cytotoxic compound
d. Directly activates the death receptor pathway and inducing caspase mediated apoptosis.

Answer 55

Answer: b.
Monoclonal antibodies can bind to and block the protein function of the receptor, as with bevizumab (binds VEGF preventing it from binding rec), or can target cells by binding to a specific cell marker and promote immunogenic elimination of target cell, as is seen with rituximab (binds CD20). They can also be used to enhance drug delivery to target cell or radionuclides as well.