Topoisomerase and Spindle Inhibitors

Question 1

Drug classes for mitotic spindle inhibitors

Answer 1

1. Vinca alkaloids

2. Taxanes

Question 2

Drug classes for topoisomerase inhibitors

Answer 2

1. Camptothecin analogs
2. Podophyllotoxins
3. Anthracyclins

Question 3

Drugs in vinca alkaloid class

Answer 3

1. Vincristine
2. Vinblastine
   M phase arrest

Question 4

Mechanism for vinca alkaloids

Answer 4

Bind to beta-tubulin to block alpha-beta polymerization of microtubules form the + end –> causes M phase arrest

Question 5

Unique toxicities of vinca alkaloids

Answer 5

1. Leukopenia with vinblastine

2. Significant neurotoxicity due to disrupted microtubule formation (worse with Vincristine)

Question 6

Unique mechanism of resistance for vinca alkaloids

Answer 6

Mutation of beta-tubulin structure

Question 7

Drugs in taxane class

Answer 7

1. Paclitaxel
2. Docataxel –> semi-synthetic, less hypersensitivity
   M phase specific

Question 8

Mechanism for taxanes

Answer 8

Binds to microtubules (B-tubulin) and prevents disassembly –> disrupts mitotic spindle

Question 9

Taxane IV infusion

Answer 9

1. Paclitaxel –> cremaphor
2. Docataxel –> Polysorbate 80
   Co-administer with antihistamines and steroids to prevent hypersensitivity

Question 10

Unique toxicities of taxanes

Answer 10

Blood dyscriasis and peripheral neuropathy

Question 11

Neurotoxicity or nerve axons and/or dorsal root ganglion of sensory nerves caused by?

Answer 11

1. Vincas
2. Taxanes
3. Platinum drugs

Question 12

Drugs in camptothecin analog class

Answer 12

1. Topotecan

2. Irinotecan

Question 13

Camptothecin analog mechanism

Answer 13

Stabilizes DNA topoisomerase I cleavable complex leading to single and double stranded DNA breaks

Question 14

Unique toxicity of irinotecan

Answer 14

Metabolized by Phase II glucuronidation so some patients can receive toxic dose if they have mutations in UDP-glucuronosyltransferase 1A1 gene

dose limiting toxicity is diarrhea believe it or not

Question 15

Drug in podophyllotoxin class

Answer 15

Etoposide (VP-16)

Question 16

Mechanism of etoposide

Answer 16

Binds to the DNA-topoisomerase II complex and prevents religation of DNA –> strand breaks and apoptosis

Question 17

Drugs in anthracyclines class

Answer 17

1. Doxorubicin
2. Daunorubicin
3. Idarubicin

Question 18

Mechanism of anthracyclines

Answer 18

1. DNA intercalation
2. Stabilize DNA-topoisomerase II complex
3. Generate free radicals

Question 19

Unique toxicities of anthracyclines

Answer 19

Cardiotoxicity (primarily doxorubicin)
Acute: tachycardia, arrhythmia, hypotension
Chronic: CHF
Dilated, flabby heart

Question 20

Ways to reduce toxicity of anthracyclines

Answer 20

1. Co-administer dexrazoxane to prevent free radical damage

2. Liposomal formulations of doxorubicin (less cardiotoxic)

Question 21

Do both Vinca Alkaloids cause leukopenia?

Answer 21

No, Vincristine does not

Question 22

How are Vinca Alkaloids excreted?

Answer 22

Hepatically

Question 23

What can occur with Vinca Alkaloids upon IV administration?

Answer 23

Extravasational Necrosis, local tissue necrosis if the drug escapes the vasculature into the surrounding tissues

Question 24

How must the Taxanes be administered?

Answer 24

IV infusion with cermaphor or polysorbate (both surfactants). Taxanes are very insoluble by themselves

Question 25

What physical exam findings would you look for if concerned about taxane peripheral neuropathy?

Answer 25

1) loss of deep tendon reflex (patellar) | 2) inability to get up out of a chair without using arm muscles

Question 26

Are taxanes and vincas cell cycle specific?

Answer 26

Yes, both are only effective during mitosis

Question 27

Mechanism of bleomycin

Answer 27

Bleomycin-Fe complex oxidizes deoxyribose on nucleotides causing single and double strand breaks

Question 28

Unique toxicities of tretinoin

Answer 28

Dry skin, bone tenderness, hyperlipidemia, cheilitis (inflammation of lips)

Question 29

Mechanism of pegaspargase

Answer 29

Asparagine supply broken down so protein synthesis is halted

Question 30

Unique toxicities of pegaspargase

Answer 30

Necrotic pancreatitis (THIS), immune suppression, and poor regulation of blood sugar

Question 31

Lenalidomide mechanism

Answer 31

1. Inhibits tumor cell proliferation 2. Inhibits tumor cell adhesion 3. Inhibits angiogenesis 4. Enhances NK cell activity

Question 32

Unique toxicities of lenalidomide

Answer 32

Peripheral neuropathy, sedation, constipation, arterial/venous embolism

Question 33

Mechanism of tretinoin

Answer 33

High dose of tretinoin binds to PML-RAR cancer fusion protein and releases it from co-repressors allowing promyelocytes to mature and stop proliferating

Question 34

Unique toxicities of tretinoin

Answer 34

Dry skin, bone tenderness, hyperlipidemia, cheilitis

Question 35

Rules for combination therapies

Answer 35

1. No two drugs act through same mechanism 2. Drugs with overlapping toxicities are avoided 3. Proven activity against the tumor type

Question 36

Dose limiting toxicity of Irinotecan

Answer 36

Diarrhea

Question 37

Cell Cycle specificity of Etoposide?

Answer 37

Late S/Early G2

Question 38

Indications for Doxorubicin

Answer 38

Solid tumors, especially breast

Question 39

Problem with administering liposomal Doxorubicin?

Answer 39

It causes Hand Foot Syndrome

Question 40

Unique mechanism of resistance to Doxorubicin?

Answer 40

Increased Glutathione Peroxidase expression

Question 41

Cell cycle specificity of Bleomycin?

Answer 41

Early G2

Question 42

Problem with administration of Pegaspargase?

Answer 42

Some people have hypersensitivity reactions to it, Aspargase generated from bacteria

Question 43

What is Chemo-Fog??

Answer 43

Impaired verbal/visual memory, attention deficits, concentration problems, issues with speech, multitasking, and organization post chemotherapy... Cytotoxic therapy releases lots of TNF-a which crosses the BBB and can permanently damage brain by production of reactive Nitrogen Species

Question 44

pharmacogenomic risk factor of toxicity w/ Irinotecan

Answer 44

Gilbert's syndrome