Treatment of Testicular Cancer

Question 1

T or F: the adverse effects of bleomycin and Cisplatin are direct effects of their MOAs?

Answer 1

True

Question 2

What are the 5 parts to the MOA of Cisplatin?

Answer 2

1. Platination of N7 purine sites
2. Platination of nucleophilic protein residues
3. Eliciting signal transduction via pro-apoptotic BCL-2, BAK1 and BAX
4. Eliciting signal transduction via voltage dependent ion channels
5. Acitivating p53

Question 3

What causes the reactions cause the renal and ototoxicy seen in Cisplatin?

Answer 3

**In kidney it is the redox stress of cisplatin that causes cell damage, oxidative stress is also believed to be the etiology of ototoxicity from cisplatin – administration of anti-oxidants (AMIFOSTINE) may help reduce oxidative stress in these tissues. OTC2 is the organic transporter that is believed to be behind the accumulation of Cisplatin in renal cells and cochlear cells.

Question 4

Bleomycin
- what are the steps to it causing lung fibrosis?

Answer 4

Bleomycin – Lung Fibrosis

Acts as an irritant (similar to silica, asbestos) by uric acid release from damage DNA leading to Nalp3 inflammasome activation. In the meantime irritants leads to formation of ROS. ROS and Inflammasome activation lead to production of IL-1beta and TNF-alpha by epithelial cells and macrophages. IL-1beta recruits neutrophils and elicits TGF-beta which leads to increased fibrosis.

Question 5

What 3 drugs all used in the treatment of testicular cancer have dose-limiting toxicities not related to bone marrow suppression?

Answer 5

Bleomycin, Cisplatin, and Vinblastine all have dose limiting toxicities not related to myelosuppressoin. These are dilated pulmonary fibrosis, renal toxicity, and peripheral neuropathy respectively.

Question 6

Bleomycin

• MOA
• AE

Answer 6

Bleomycin

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

AE: Skin rash (itchy, striae, etc.), DOSE LIMITING Pulmonary Fibrosis

Question 7

Cisplatin

• MOA
• AE

Answer 7

Cisplatin

MOA: Nuclear and mitochondrial damage + redox stress
AE: DOSE LIMITING Renal Toxicity; Ototoxicity, and peripheral neuropathy

Question 8

Carboplatin
MOA
AE

Answer 8

Carboplatin

MOA: Nuclear and Mitochondrial damage + redox stress, slower acting than cisplatin

AE: DOSE limiting Thombocytopenia, Renal, Oto, and peripheral neuropathy

Question 9

Etoposide
MOA
AE

Answer 9

Etoposide

MOA: Stabilizes TOPO II after it makes double stranded DNA breaks
AE: DOSE limiting Leukopenia, Hepatic toxicity at high doses

Question 10

Ifosfamide

• MOA
• AE

Answer 10

Ifosfamide

MOA: Metabolically activated Alkylating agent that does intra- and interstrand DNA cross-linking

AE: DOSE LIMTING myelosuppression, Neurotoxicity (SIEZURES, ATAXIA, COMA)

Question 11

Paclitaxel
MOA
AE
**What drug is often co-administered?

Answer 11

Paclitaxel

MOA: Stabilizes microtubules preventing disassembly

AE: DOSE LIMITING myelosuppression, peripheral Neuropathy (watch out for diabetics)
**Filgastrim often administered to recover bone marrow

Question 12

Vinblastin

• MOA
• AE

Answer 12

Vinblastine

MOA: Prevents microtubule polymerization
AE: DOSE LIMITING neuropathy (as with all vinca alkaloids)

Question 13

Mesna
MOA/Reason for giving it?
AE

Answer 13

Mesna

MOA: Binds acrolein (byproduct of cyclophosphamide/IFOSPHAMIDE responsible for hemorrhagic cystitis) by forming a thioester bond

AE: Dysgeusia (loss of taste), soft stools, and headache