PHARM: Testicular Cancer

Question 1

What is the most common type of testicular cancer?

Answer 1

germ cell tumors (seminoma or nonseminoma)

Question 2

Which type of testicular germ cell tumor grows slowly and does not spread rapidly?

Answer 2

seminomas

Question 3

Where do non-seminomas spread?

Answer 3

liver, lungs, and brain (via blood)

Question 4

What is stage 1 testicular cancer?

Answer 4

cancer only in testicle

Question 5

What is stage 2 testicular cancer?

Answer 5

cancer has spread to lymph nodes in the abdomen

Question 6

What is stage 3 testicular cancer?

Answer 6

cancer has spread beyond the LNs in the abdomen

Question 7

What markers can be used to monitor seminomas in the follow-up period after treatment?

Answer 7

AFP, LDH, β-hCG

Question 8

How do you manage organ-confined testicular cancer?

Answer 8

surgery (removal of one of the testes)

Question 9

How do you manage stage 2 testicular cancer?

Answer 9

radiotherapy (treatment is repeated five days per week for approximately five to six weeks) and or chemotherapy are used in an adjunctive manner

Question 10

What is a common factor in ALL chemotherapeutic therapies for testicular cancer?

Answer 10

CISPLATIN (platinum agent)

Question 11

What are the 4 major divisions of the manners in which testicular cancer can become resistant to cisplatin?

Answer 11

Pre-Target Alterations
On-Target Alterations
Post-Target Alterations
Off-Target Alterations

(usually multifactoral!)

Question 12

What are some pre-target alterations that render testicular cancer resistant to cisplatin?

Answer 12

o Decreased influx
o Sequestration
o Increased efflux

Question 13

What are some on-target alterations that render testicular cancer resistant to cisplatin?

Answer 13

o Increased DNA repair

o Increased tolerance to lesions

Question 14

What are some post-target alterations that render testicular cancer resistant to cisplatin?

Answer 14

Defective activation and/or execution of cell death/ senescence

Question 15

What are some off-target alterations that render testicular cancer resistant to cisplatin?

Answer 15

Pro-survival antagonizing signals

Question 16

List the 3 top first line chemo combinations for testicular cancer?

Answer 16

1) Etoposide + Cisplatin
2) Bleomycin + Etoposide + Cisplatin
3) Etoposide + Mesna + Ifosfamide + Cisplatin

Question 17

What may be added to some “high dose” chemotherapy regimens?

Answer 17

peripheral stem cell infusions

Question 18

MOA: Binds DNA in presence of iron with ferrous oxide-mediated DNA strand breakage

Answer 18

Bleomycin

Question 19

MOA: Binds with high affinity to nuclear DNA (N7 sites) as well as interacting with mitochondrial DNA and proteins→Nuclear and mitochondrial damage + redox stress→ activation of pro-apoptotic BCL-2 members (BAK1 and KAB), opening of VDAC1, activating p53→ cell death and senescence

Answer 19

Cisplatin

Carboplatin (slower RXN with nuclear DNA)

Question 20

MOA: Stabilizes DNA and topo II complexes resulting in strand breakage

Answer 20

Etoposide

Question 21

MOA: Promotes microtubule assembly and stabilizes their formation by inhibiting depolymerizaiton

Answer 21

Paclitaxel

Question 22

MOA: Binds to low affinity sites on tubulin, resulting in splitting of the microtubules into spiral aggregates or protofilaments—leading to the disintegration of the microtubule

Answer 22

Vinblastin

Question 23

MOA: Alkylating agent that produces intra-and inter-strand DNA cross- links

Answer 23

Ifosfamide

Question 24

MOA: Forms acrolein-mesna thioester complexes that are inactive and eliminated in the urine

Answer 24

Mesna

Question 25

What drug is mesna used with? Why?

Answer 25

Ifosfamide (to prevent hemorrhagic cystitis)

Question 26

TOXICITY: Pulmonary Fibrosis and late-developing skin toxicities

Answer 26

Bleomycin

Question 27

TOXICITY: Renal toxicity, ototoxic (higher doses damage cochlea—via ROS), neurotoxic;

Answer 27

Cisplatin

Question 28

TOXICITY: Thrombocytopenia, less neruotox/ototox than other drug in class

Answer 28

Carboplatin

Question 29

TOXICITY: Leukopenia; hepatic toxicity after high dose treatment

Answer 29

Etoposide

Question 30

TOXICITY: Bone marrow suppression, peripheral neuropathy

Answer 30

Paclitaxel

Question 31

TOXICITY: Neuropathy

Answer 31

Vinblastine

Question 32

TOXICITY: Myelosuppression, neurotoxicity, Hemorrhagic Cystitis

Answer 32

Ifosfamide

Question 33

TOXICITY: Dysgeusia, soft stools and headache

Answer 33

Mesna

Question 34

What drug is given with paclitaxel to protect against bone marrow suppression?

Answer 34

Filgrastim

Question 35

What drugs is given with cisplatin to buffer adverse effects?

Answer 35

Amifostine

Question 36

True or false: cisplatin is actively pumped into renal and cochlear cells.

Answer 36

TRUE--cause of the nephrotoxicity and ototoxicity

Question 37

How does the accumulation of cisplatin in renal and cochlear tissues lead to adverse effects?

Answer 37

cellular stress causes a rise in ROS and depletion of cytoprotective oxidants

Question 38

What transporter takes cisplatin up into both normal and tumor cells?

Answer 38

Ctr1

Question 39

What transporter is expressed on only renal, cochlear, and nervous cells (with down-regulation on tumors)?

Answer 39

OCT2

Question 40

How might we prevent uptake of cisplatin into renal, cochlear and nervous cells?

Answer 40

specific inhibition of OCT2

Question 41

How does bleomycin injure lung epithelial cells?

Answer 41

produces ROS, chemokines and cytokines that enhance recruitment of leukocytes to sites of tissue injury

Question 42

How might you detect lung epithelial injury caused by bleomycin?

Answer 42

measuring NALP3

Question 43

What is the role of IL-1β in epithelial lung injury from bleomycin?

Answer 43

activates ROS-expressing neutrophils to cause damage and promotes TGF-β1

Question 44

What is the role of TGF-β1 in lung epithelial injury from bleomycin?

Answer 44

an important profibrotic cytokine that triggers fibroblast proliferation and activation (induces EMT and the formation of ECM producing myofibroblasts) and stimulates differentiation of Th17 cells