B-35. Cancer chemotherapy III (Topoisomerase inhibitors. Inhibitors of mitotic spindle)

Question 1

Topoisomerase inhibitors drugs

Answer 1

1. Topoisomerase I inhibitors:
   
   1. Camptothecins: Topotecan, Irinotecan**
2. Topoisomerase II inhibitors:
   
   1. Anthracyclines: Doxo-, Dauno-, Ida-, and Epirubicin**
   2. Anthracenediones: Mitoxantrone
   3. Epipodophyllotoxins: Etoposide, Teneposide**

Question 2

Topoisomerase I inhibitor group?

Answer 2

Topoisomerase I inhibitors: camptothecins

Question 3

Topoisomerase I function

Answer 3

Topoisomerase I makes single-stranded “nicks” in DNA to relieve negative supercoiling of DNA that occurs due to separation / unwinding of double helix during replication, and then re-seals the nicks.

Question 4

Topoisomerase drugs

Answer 4

• Topoisomerase I inhibitors:
  
  1. Topotecan
  2. Irinotecan**

Question 5

Topoisomerase MOA and side effects

Answer 5

• MOA: inhibition → inability to reseal nicks → chromosomal breaks → cell death (in both S and G2 phase)
• Side effects:
  
  • Diarrhea- early form → tx with atropine / scopolamine; late form (2-10 days) → cholera-like, hard to treat
  • Flushing- of face / upper body
  • Myelosuppression- neutropenia, etc.

Question 6

Topotecan indications

Answer 6

Indication: 2nd line for ovarian cc. and SCLC

Question 7

Irinotecan indication and kinetics

Answer 7

• A prodrug
• Indication: DOC for colorectal (along w/ 5-FU + oxaliplatin, capecitabine, ) and lung cc.

Question 8

Topoisomerase II function

Answer 8

Topoisomerase II creates transient breaks in both DNA strands to relieve positive + negative supercoiling, and then re-seals the breaks it created.

Question 9

Topoisomerase II inhibitor MOA and kinetics

Answer 9

• MOA: inhibition → inability to reseal breaks → chromosomal breaks and free radical production → cell death
  
  • work in S phase as well as G2 phase (double-checking + repair) if some affected cells pass S phase
• Kinetics: are given as i.v. infusions

Question 10

Topoisomerase II inhibitor drug classes

Answer 10

1. Anthracyclines
2. Anthracenediones
3. Epipodophyllotoxins

Question 11

Anthracyclines (topoisomerase II inhibitor) drugs

Answer 11

• Topoisomerase II inhibitors:
  
  1. Anthracyclines: Doxo-, Dauno-, Ida-, and Epirubicin**
  2. Anthracenediones: Mitoxantrone
  3. Epipodophyllotoxins: Etoposide, Teneposide**

Question 12

Anthracyclines (topoisomerase II inhibitor) MOA and side effects

Answer 12

• MOA: inhibit topoisomerase II; Fe-dependent free radical formation; planar molecules → intercalate btwn BPs
• Side Effects:
  
  • Cardiotoxicity- dose-dependent, free radicals cause dilated cardiomyopathy (→ HF months after treatment); lower doses / acute form → arrhythmias, reversible with discontinuation
    
    • preventable with dexrazoxane (Fe chelator) treatment
  • Red urine - harmless, due to renal elimination of some of the drug
  • Myelosuppression, stomatitis / mucositis

Question 13

Doxorubicin, Daunorubicin, Idarubicin, and Epirubicin indication

Answer 13

• Doxorubicin - oldest anthracycline, widest indications
  • Indication: wide range of solid tumors, childhood tumors, lymphoma / leukemia
• Daunorubicin
  • Indication: mainly AML (less effective for solid tumors)
• Idarubicin - analog of dauno-
  • Indication: less effective for solid tumors; very effective in leukemias (esp. in combo with cytarabine)
• Epirubicin - newer, less sfx than doxorubicin

Question 14

Anthracenediones (Topoisomerase II inhibitor) drug

Answer 14

Mitoxantrone

Question 15

Mitoxantrone indications and side effects

Answer 15

• Indications: solid tumors (esp. prostate, breast); NHL and leukemias (AML); not commonly used
• Side Effects:
  
  • Cardiotoxicity- may cause cardiomyopathy, but less cardiotoxic than anthracyclines
  • Blue discoloration - of sclera and urine

Question 16

Epipodophyllotoxins (topoisomerase II inhibitor) drugs

Answer 16

Etoposide and Teniposide

Question 17

Etoposide and Teniposide

Answer 17

• Kinetics: given IV or oral (only 50% BA, so double dose)
  
  • excreted by kidney; ↓ dose in renal disease
• Indications:
  
  • Lung cancer - NSCLC or SCLC
  • Lymphomas- Hodgkins and NHLs
  • Gastric and testicular cc.
• Side Effects: mainly myelosuppression and alopecia

Question 18

Mitotic spindle inhibitor drugs

Answer 18

• Mitotic Spindle Inhibitors:
  
  1. Vinca alkaloids: Vincristine, Vinblastine, Vinorelbine
  2. Taxanes: Paclitaxel, Docetaxel

Question 19

• Vinca Alkaloids
  
  • MOA
  • Kinetics
  • Side effects

Answer 19

• Vinca Alkaloids:
  
  • MOA: inhibits tubulin polymerization → ↓ microtubule / mitotic spindle assembly → cell stuck in metaphase
  • Kinetics: metab’d by CYP450 (interaction with inhibitors)
    
    • given IV, low oral abs.
  • Side Effects:
    • Neurotoxicity- peripheral neuropathy (hand/foot), paresthesia; no CNS effect
    • Myelosuppression- mostly -blastine, -relbine; less with -cristine
    • ANS dysfunction - orthostatic hypotension, urinary retention + paralytic ileus (→ constipation)
    • Alopecia

Question 20

Vinca Alkaloids drugs and indication

Answer 20

• Vincristine
  
  • Indications: lymphomas (AML, ALL, MM, Hodgkins, NHL); childhood tumors (rhabdomyo-, Wilms, etc.)
• Vinblastine
  
  • Indications: testicular cc. (germ cell tumors); leukemia, lymphoma
• Vinorelbine
  
  • Indication: solid tumors (breast cc. )

Question 21

• Taxanes
  
  • Drugs
  • MOA
  • Indication
  • Kinetics
  • Side effects

Answer 21

Taxanes:

Paclitaxel and Docetaxel

• MOA: stabilize microtubules → ↓ mitotic spindle depolymerization → cell can not divide
• Indications:
  
  • Solid tumors - wide range; specifically hormone-insensitive prostate / breast cc.
• Kinetics: metabolized by CYP450
• Side Effects:
  
  • Hypersensitivity- esp. paclitaxel
  • Fluid retention - esp. docetaxel; treat with dexamethasone
  • Neuropathy- hand/foot
  • Myelosuppression