B.31

Question 1

Drugs used in cancer treatment III (Topisomerase inhibitors. Inhibitors of mitotic spindle)

Answer 1

Topoisomerase 1 inhibitors: Irinotecan
Topoisomerase 2 inhibitors: Etoposide, Doxorubicin
Mitotic spindle inhibitors: Vincristine, Docetaxel

Question 2

3. Topoisomerase inhibitors

Answer 2

• Topoisomerase I inhibitor: Irinotecan
  
  • Topoisomerase II inhibitors:
    
    • Podophyllotoxin derivatives: Etoposide
    • Anthracyclines: Doxorubicin

Question 3

Irinotecan

Answer 3

MOA: G2-M phase specific.
Topoisomerase I inhibitor. The role of Topoisomerase I is to reduce the tension that comes from the supercoiled DNA by cleaving 1 DNA strand (→ the DNA can unwind and replication can happen), Topoisomerase inhibitors inhibit this process (→no DNA repair or replication);
IND: Colorectal cc, SCLC, pancreatic cc, liposomal irinotecan is used in metastatic pancreatic adenocarcinoma (after gemcitabine treatment);
SEs: myelosuppression, GI toxicity (cholera-like diarrhea - acute and delayed)

Question 4

Etoposide

Answer 4

MOA: S/G2 Phase specific.
Topoisomerase II inhibitor. (The role of Topoisomerase II is to reduce the tension that comes from the coiling of the DNA into superhelix by cleaving 2 DNA strands → DNA can unwind and replication can happen). Topoisomerase II inhibitors induce apoptosis;
IND: Solid tumors, (N)SCLC, testicular cc, leukemias, lymphomas;
SEs: myelosuppression, alopecia, hypotension

Question 5

Doxorubicin

Answer 5

MOA: S/G2 phase specific.
Topoisomerase II inhibitor (→no DNA replication), forming free radicals (→breakage of DNA strands), DNA intercalation (→breakage of DNA strands and inhibition of replication);
IND: Rhabdomyosarcoma, Thyroid, breast, lung, gastric, pancreatic, testicular, bladder, ovarian and endometrial cc, neuroblastoma, osteosarcoma, soft tissue sarcomas, hematologic malignancies;
SEs: Cardiotoxicity
(-acute form: arrhythmias - resolve spontaneously.
-Chronic form: dilatative cardiomyopathy),
increased risk of clonal hematopoiesis with intermediate potential, myelosuppression, alopecia, extravasation, infertility, Hand-foot syndrome; To prevent one of the
SEs: coadminister dexrazoxane to reduce cardiac SEs

Question 6

Vincristine

Answer 6

MOA: M-phase specific.
Mitotic spindle inhibitor. Vinca alkaloid. inhibits β-tubulin polymerization into microtubule→ prevention of the mitotic spindle formation→ mitotic arrest→ cell death;
IND: Solid tumors, leukemias, lymphomas;
SEs: neurotoxicity, paralytic ileus, bronchospasms, urate nephropathy, in case of extravasation(→irritation, local ulcers)

Question 7

Docetaxel

Answer 7

MOA: M-phase specific.
Mitotic spindle inhibitor. Taxanes. Inhibits depolymerization of microtubules→ hyperstabilization→ mitotic spindle is unable to break down→ mitotic arrest in metaphase;
IND: Solid tumors (breast, ovarian, prostate, gastric, head&neck, NSCLC, Kaposi-sarcoma);
SEs: Neuropathy, Hepatotoxicity, myelosuppression, Fluid retention, Bronchospasms, Urate nephropathy, Allergy, Onycholysis