Antimitotic and Biological response modifiers - Slides 1-23

Question 1

How do Antimitotic drugs work?

Answer 1

They either interfere with the mitotic process by altering spindle formation or degradation (M phase specific)
OR
Inhibition of the topoisomerase I or II enzyme, which is S-G2 phase specific.

Topoisomerase I breaks and reseals single stranded DNA
Topoisomerase II does the same on double stranded DNA

Question 2

Vinca’s block ________; Taxane’s block _______

Answer 2

Vinca’s block assembly

Taxane’s block disassembly

Question 3

How are Vinca alkaloids administered?

Answer 3

IV (does not enter CNS)

Vinorelbine has oral activity

Question 4

What is Vincristine used for?

Answer 4

Lymphomas
ALL
Hodgkin's
Part of MOPP's
Neuroblastoma
Wilm's tumor
Sarcoma's

Question 5

What is Vinblastine used for?

Answer 5

Testicular tumors
Hodgkin's
Breast
Part of ABVD therapy
Non-hodgkin's lymphoma

Question 6

What is Vinorelbine used for?

Answer 6

Breast

Non-small cell lung cancer (esp elderly)

Question 7

Toxicities for Vinca agents?

Answer 7

Common to all agents:
Rapid cytotoxic effects and cell destruction
Leads to hyperuricemia due to oxidation of purines to uric acid
(Give allopurinol to help prevent buildup)

Strong vesicants - if out of the vein, use heat or hyaluronidase to disperse the drug

Question 8

What is Hyalouronidase?

Answer 8

Used to disperse the Vinca agents if they escape the vein to prevent tissue damage

Question 9

Vincristine toxicities?

Answer 9

Dose limiting neurotoxicity
Peripheral neuropathies of hands and feet
May affect both sensory and motor nerves
Suppression of deep tendon reflexes
Cranial nerve damage
May cause jaw damage, face palsies
Muscle weakness, autonomic neuropathies, constipation

MINIMAL MYELOSUPPRESSION

Question 10

Vinblastine toxicities?

Answer 10

Dose limiting myelosuppression
Mild neurotoxicity
N/V/D, stomatitis

Question 11

Vinorelbine toxicities?

Answer 11

Myelosuppression
N/V/D
Least neurotoxicity of the vinca’s!

Question 12

How do Paclitaxel, Docetaxel work?

Answer 12

They cause cell division to stop in M phase, causes aptoptosis

Question 13

Indications for Paclitaxel, Docetaxel?

Answer 13

Metastatic ovarian, breast, lung, GI, bladder, head and neck, esophageal, prostate

Question 14

Name the taxanes

Answer 14

Paclitaxel
Docetaxel
Cabazitaxel

Question 15

Name the vinca’s

Answer 15

Vincristine
Vinblastine
Vinorelbine

Question 16

Toxicities with paclitaxel?

Answer 16

Myelosuppression
Hypersensitivity reactions due to diluent
Give H1/H2 and dexamethasone
Stocking-glove sensory neuropathy
Myalgia

Question 17

Toxicities with Docetaxel?

Answer 17

Neutropenia
Less severe peripheral neuropathy
Less hypersensitivit reactions
Fluid retention and edema, start dexamethasone 1 day prior

Question 18

Which drugs require dexamethasone pretreatment? Why?

Answer 18

Paclitaxel - bc of hypersensitivity rnxns

Docetaxel - bc of fluid retention and edema

Question 19

Indications for Cabazitaxel?

Answer 19

Metastatic hormone resistant prostate cancer

Increases survival 3 months over standard therapy but is very expensive - weigh risk/benefits

Question 20

Toxicities with Cabazitaxel?

Answer 20

Neutropenia
Anemia
Diarrhea
Fatigue
Nausea
Vomiting
Alopecia
Peripheral neuropathy

Question 21

What are Epothilones? What is the only agent available?

Answer 21

A new class of microtubule damaging compounds isolated from myxobacterium on Zambezi river in South Africa

Ixabepilone was FDA approved in 2007

Question 22

What is Ixabepilone used for?

Answer 22

Metastatic breast cancer after other treatments

Question 23

How is Ixapebilone administered?

Answer 23

IV

Question 24

What is the MOA of Ixabepilone?

Answer 24

Inhibits tubulin breakdown like taxanes but binds to a different site

Question 25

Toxicities of Ixabepilone?

Answer 25

Neutropenia
Peripheral sensory neuropathy
Fatigue
Diarrhea

Question 26

What are Epiodophyllotoxins?

Answer 26

Etoposide
Teniposide

They inhibit Topoisomerase II, causing strand breaks

Specific for S-G2

Question 27

How is Etopisode administered?

Answer 27

Oral and IV

Question 28

What is the difference in metabolism between Etoposide and Teniposide?

Answer 28

40% of Etoposide is excreted unchanged in the urine

Teniposide is extensively metabolized

Question 29

What is Etoposide used for?

Answer 29

Testicular, lung, non-Hodgkin’s lymphoma, breast, AML

Question 30

How is Teniposide administered?

Answer 30

IV

Question 31

What is Teniposide used for?

Answer 31

Acute lymphocytic leukemia in children

Neuroblastoma

Question 32

Toxicities for Etoposide AND Teniposide?

Answer 32

Both:
Alopecia
N/V
Dose limiting myelosuppression!!!!
Stomatitis

Question 33

Etoposide toxicities

Answer 33

Unusual non-lymphocytic leukemia due to alteration on chromosome 11, can occur 1-3 years after therapy for ALL in children treated with HIGH doses

Gene is MLL - mixed lineage leukemia gene, regulates proliferation of stem cells

Question 34

What are Irinotecan, Topotecan?

Answer 34

Camptothecins isolated from the Chinese happy tree

They inhibit topoisomerase I causing single strand breaks in DNA

Question 35

Irinotecan metabolism?

Answer 35

It’s a prodrug, metabolized and excreted in the bile

Question 36

Topotecan metabolism?

Answer 36

IV, Renal excretion

Question 37

Indications for Irinotecan?

Answer 37

Colorectal, breast, cervical, gastric, lung

Question 38

Indications for Topotecan?

Answer 38

Lung, ovarian

Question 39

Toxicities for Irinotecan, Topotecan?

Answer 39

Dose limiting myelosuppression (BOTH)
Diarrhea (Irinotecan more than Topotecan, give Loperamide)
Nausea, vomiting
Alopecia
Decreased cholinesterase activity (Irinotecan)