Testicular Cancer -- ie conventional chemo review

Question 1

Bleomycin: MOA, AEs/DLT,

Answer 1

MOA: DNA strand breakage in presence of Fe (ferrous oxide mediated)

DL Tox: PULMONARY FIBROSIS
AEs: skin tox (rash/erythema, stiae, vesiculation, hyperpigmentation), interstitial pneumonitis

Question 2

Cisplatin / Carboplatin: MOA, AEs/DLT

Answer 2

Cisplatin
MOA: nuclear and mitochondrial DNA damage + ROS stress
DLT: RENAL TOXICITY (+ ototoxicity)
AEs: active accumulation in renal cells, inhibits breakdown of lipids to generate energy, neurotoxic, ototoxic, nausea

Carboplatin
MOA: slower rxn w/ nuclear DNA (larger dose than cis)
DLT: THROMBOCYTOPENIA
AEs: nausea, neurotoxicity, ototoxicity, nephrotoxity (less than cis)

Question 3

Etoposide: MOA, AEs/DLT

Answer 3

MOA: stabilizes DNA and Topoisomerase II complex –> strand breakage

DLT: leukopenia
AEs: nausea, vomiting, stomatitis, diarrhea, hepatic tox at high dose

Question 4

Ifosfamide/cyclophosphamide: MOA, DLT/AEs

Answer 4

MOA: alkylating agent = intra and inter strand DNA CROSS LINKING (must be metabolically activated)

DLT: MYELOSUPPRESSION (not hem cystitis)

AEs: neurotoxicity (coma/seizures), hemorrhagic cystitis

Question 5

Paclitaxel: MOA, DLT/AEs

Answer 5

MOA: stabilizes formed microtubules/inhibits depolymerization

DLT: BONE MARROW SUPPRESSION
AEs: peripheral neuropathy (esp pts with DM)

Question 6

Vinblastine/cristine: MOA, DLT

Answer 6

MOA: binds tubulin = splitting of microtubules/disintegration of microtubules

DLT: PERIPHERAL NEUROPATHY – esp vincristine!
AEs:

Question 7

Mesna

Answer 7

forms acrolein-mesna thioester = prevents hemorrhagic cystitis with ifosfamide use

AE: soft stools, HA, dysgeusia

Question 8

Amifostine

Answer 8

“kidney protective”, used with cisplatin

Question 9

MOA of cisplatin ototoxicity / renal toxicity?

Answer 9

– actively pumped into cochlear / renal epithelial / nervous system cells by copper transporter ATPases –> produce reactive oxygen species (ROS) –> trigger cell death

Cochlea = Ctr1 and 2, OCT2, MATE1 transporters
Renal = OCT2 transporter

• *Tumor cells generally down regulate OCT2 transporter = maybe a site to target to decrease toxicity
• • administering antioxidant therapy helps to dec toxicity

Question 10

MOA bleomycin pulmonary fibrosis?

Answer 10

Irritant (similar to asbestos / silica) –> increase ROS production, chemokine and cytokine production –> activate and recruit leukocytes

ILB1 –> activate neutrophil ROS production, increase TGFB1
TGFB1 –> profibrotic, inc Th17 differentiation, stimulate EMT/myofibroblasts

Question 11

Are bleomycin and cisplatin’s DLT’s related to their primary chemotherapeutic effects?

Answer 11

NO! – their toxicities are ancillary