Chemotherapy

Question 1

Define therapeutic index

Answer 1

Ratio between toxic dose and therapeutic dose for a certain chemotherapy drug

Question 2

Define maximum tolerated dose (MTD)

Answer 2

Empirically derived value representing highest dose of a given drug that can be administered in the absence of unacceptable or irreversible side effects to a limited population.

Question 3

Define biologically effective dose (BED)

Answer 3

Measured response at a punitive target or surrogate that is related to the MOA of the agent.

Question 4

Define therapeutic gain.

Answer 4

Evaluated when combining two drugs or drug-RT combo and quantitatively described improved tumor response relative to increased normal tissue toxicity when agents are used in a planned schedule

Question 5

Describe the theory behind radiosensitization as it pertains to chemotherapy.

Answer 5

1. Enrichment of tumor population to a more sensitivity phase of cell cycle
2. Increased tumor oxygen through cytoreduction or alterations in tumor vascularization
3. Selective killing of radioresistant, hypoxic cells

Question 6

Describe four mechanisms of chemotherapy resistance

Answer 6

1. Decreased cellular drug levels (either from decreased uptake or increased efflux - ie ABCB1 expression)
2. Alterations of metabolic or detox pathways (ie CYP3A)
3. Mutations in target protein leading to decreased affinity of drug interaction via genetic/epigenetic changes
4. Alterations of DNA damage repair

Question 7

Chemotherapy drugs that utilize p-Gp

Answer 7

1. Vinca alkaloids
2. Doxorubicin
3. Taxanes
4. Etoposide
5. Decarbazine
6. Procarbazine
7. Topotecan

Question 8

What are the two most common types of chemotherapeutic drugs that cause febrile neutropenia in cats (Plerro et al, Vet Comp Onco 2017)?

Answer 8

CCNU and vinca alkaloids (lymphoma most common cancer)

Question 9

What are the two most common types of chemotherapeutic drugs that cause febrile neutropenia in dogs (Plerro et al, Vet Comp Onco 2017)?

Answer 9

Doxorubicin and vincristine

Question 10

Why was BSA-based dosing established?

Answer 10

certain studies indicated that drug elimination was proportional to metabolic rate for diff. species

Question 11

Does absorption of a drug correlate with body size?

Answer 11

No

Question 12

AUC is most important for which chemotherapies?

Answer 12

Alkylating and platinum agents

Question 13

What are the four main components of the emetic reflex?

Answer 13

1. Visceral receptors
2. Vagal and sympathetic afferent neurons
3. CRTZ in the postrema (brainstem)
4. Vomiting center in the reticular formation of the medulla oblongata (brainstem)

Question 14

_____ is a dopamine receptor (D2) antagonist that acts centrally on the vomiting center and peripherally to prevent emesis

Answer 14

Metoclopramide
- Vomiting center: D2 and 5-HT3 antagonist
- Peripherally: D2 antagonism via D2 and prokinetic (stomach and small intestine, no effect on colonic motility)

Question 15

____ is a 5HT3 serotonin antagonists

Answer 15

Ondansetron and dolasetron

Question 16

Ondansetron blocks 5HT3 receptors in the _____ (most important for cats) and gastric wall receptors that relay emetic impulses through the ____ (most imp. for dogs)

Answer 16

emetic center (most imp for cats) and gastric wall receptors (mucosal enterochromaffin cells)/vagal nerve (most imp for dogs)

Question 17

What is the mechanism of action of Cerenia?

Answer 17

Substance P antagonist that works along NK-1 receptors both centrally (vomiting center and CRTZ) and peripherally (vagal nerve)

Question 18

How do anti-histamine drugs effect emesis?

Answer 18

Block histamine receptors in the CRTZ and vestibular apparatus
- note: cats do not have histamine receptors in the CRTZ, therefore anti-histamines will not control their vomiting.

Question 19

What are the three major classes of anti-emetics currently available for the treatment of chemotherapy-induced nausea and vomiting

Answer 19

1. 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (ie zofran)
2. neurokinin1 (NK1) receptor antagonists (ie cerenia)
3. dopamine2 (D2) receptor antagonists (ie reglan)

Question 20

What are the two prodrug nitrogen-mustard alkylating agents that require activation in the liver?

Answer 20

Cyclophosphamide
Ifosfamide

Question 21

What is the maximum tolerated dose of oral cyclophosphamide in cats?

Answer 21

460 mg/m2 with an intertreatment interval of 2-3 weeks (Vet J 2020)

the MTD of IV cyclophosphamide in cats in 480 mg/m2 (2018)

Question 22

The increased production of ____ has been implicated in greater renal and bladder toxicity of ifosfamide (compared to cyclophosphamide)

Answer 22

chloroacetaldehyde

Can damage the proximal renal tubules leading to a Fanconi-type syndrome/azotemia

Question 23

The most commonly used drug to prevent sterile hemorrhagic cystitis caused by Acrolein (and chloroacetaldehyde) is ___

Answer 23

MESNA

MESNA (sodium salt 2-mercaptoethane sulfonate) is a thiol that conjugates the aldehyde functions of acrolein and chloroacetaldehyde in the bladder