Cancer Pharm: Natural Products

Question 1

What is the MOA of the vinca alkaloids, vinblastine, vincristine, and vinorelbine; specific to which phase?

Answer 1

• Inhibit tubulin polymerization by DISRUPTING assembly of microtubules; especially those involved in mitotic spindle
• M-phase specific: results in mitotic arrest in metaphase

Question 2

AE’s of vinblastine?

Answer 2

• N/V, bone marrow suppression (vin-blast-tine), and alopecia
• Potent vesicant (blistering)

Question 3

Vinblastine is used for what cancers?

Answer 3

Hodgkin’s and NHL’s, breast, and germ cell cancer

Question 4

Vincristine is similar to vinblastine but has a higher affinity for what?

Answer 4

Axonal microtubules

Question 5

What is the dose-limiting AE’s of Vincristine?

Answer 5

• Neurotoxicity –> Peripheral sensory neuropathy manifesting as:
• ANS dysfunction w/ orthostatic hypotension; urinary retention; paralytic ileus or constipation; CN palsies; ataxia; seizures; coma

Question 6

Which 2 vinca alkaloids are associated with SIADH as potential AE’s?

Answer 6

• Vincristine
• Vinorelbine

Question 7

List 4 AE’s associated with Vinorelbine?

Answer 7

• N/V
• Transient elevations in LFT’s
• Neurotoxicity
• SIADH

Question 8

Which vinca alkaloid can be used for pediatric tumors, rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, and Wilms tumor?

Answer 8

Vincristine

Question 9

Which 3 natural products work by binding to microtubules and enhancing tubulin polymerization causing cell death; which phase do they work in?

Answer 9

• Paclitaxel, Docetaxel, and Cabazitaxel (Taxanes)
• Work in the M phase

Question 10

Which 2 natural products are associated with hypersensitivity reactions as AE’s?

Answer 10

• Paclitaxel
• Docetaxel

Question 11

What are acute vs. delayed dose limiting toxicities associated with Paclitaxel?

Answer 11

• Acute = N/V, hypotension, arrhythmias, hypersensitivity
• Delayed = myelosuppression, peripheral sensory neuropathy

Question 12

Which form of paclitaxel is NOT associated w/ hypersensitivity rxns, has reduced myelosuppressive effects, and neurotoxicity more easily reversed?

Answer 12

Albumin-bound paclitaxel

Question 13

What are the acute vs. delayed toxicities assoc. w/ Docetaxel?

Answer 13

• Acute = hypersensitivity
• Delayed = neurotoxicity, fluid retention, myelosuppression w/ neutropenia

Question 14

Why is Cabazitaxel more useful in treating multi-drug resistant tumors than other taxanes?

Answer 14

Is poor substrate for P-glycoprotein

Question 15

How does Ixabepilone differ in its MOA from the taxanes?

Answer 15

Microtubule inhibitor that binds directly to β-tubulin subunits on microtubules —> dynamic inhibition of microtubule

Question 16

One of the benefits of Ixabepilone is due to its activity in tumors with what features?

Answer 16

Resistant tumors w/ tubulin mutations and overexpression of P-glycoproteins

Question 17

What are 2 unique AE’s of Ixabepilone?

Answer 17

• Hypersensitivity rxns
• Neurotoxicity in the form of peripheral sensory neuropathy

Question 18

Ixabepilon has been approved for tx of what cancer?

Answer 18

• Metastatic breast cancer as monotherapy
• Or in combo w/ capecitabine

Question 19

What is the MOA of Eribulin?

Answer 19

Inhibits microtubule function leading to a block in the G2-M phase

Question 20

Eribulin is used in which cancers; has activity in tumors with what features?

Answer 20

• Metastatic breast cancer
• Has activity in tumors that overexpress P-glycoprotein

Question 21

What is the MOA of the epipodophyllotoxin, Etoposide?

Answer 21

Forms complex w/ and inhibits activity of topoisomerase II and DNA

Question 22

What is the MOA of the camptothecins, Topotecan and Irinotecan?

Answer 22

Inhibit activity of topoisomerase I, the key enzyme for cutting and religating single DNA strands –> DNA damage

Question 23

What are 2 forms of diarrhea which may arise as AE of camptothecins, Topotecan and Irinotecan?

Answer 23

• Early form = occurs within 24-hrs of tx; cholinergic event; tx w/ atropine
• Late form = occurs 2-10 days after tx; can be severe and leads to electrolyte imbalances and dehydration

Question 24

Which camptothecin, topotecan or irinotecan, is more potent and why?

Answer 24

Irinotecan (prodrug) converted to SN-38 in liver, which is 1000-fold more potent topoisomerase I inhibitor