Drugs that Interrupt Mitosis - Fitz

Question 1

What are the 3 vinca alkaloids?

Answer 1

1. Vinblastine
2. Vincristine
3. Vinorelbine

Question 2

What are the 3 taxanes?

Answer 2

1. Cabazitaxel
2. Doxetaxel
3. Paclitaxel

Question 3

What is the epilone drug that interrupts mitosis?

Answer 3

Ixabepilone

Question 4

What are the 4 plant alkaloid groups we’ve learned?

What do you worry about with these?

Answer 4

1. Irontecan, topotecan
2. Etoposide
3. Taxanes: Paclitaxel, Capazitaxel, Docetaxel
4. Vinca alkaloids: Vinblastine, Vincreistine, Vinorelbine

**worry about resistance of decreased accumulation via increased P- glycoprotein

—–>MDR

Question 5

MOA of vina alkaloids?

Answer 5

Bind to tubulin at forming end of microtubules and TERMINATE spindle formation

Minor changes in structure –>significant changes in toxicity and anti-tumor activity

Question 6

Resistance of vina alkaloids (vincristine and vinblastine)?

What if you get resistance to vincristine, will you be resistant to vinblastine too?

Answer 6

1. decreased accumulation from increased P-glycoprotein expression

—–>MDR

2. Change in target proteins :: Tubulin

**Cross reactivity among vinca alkaloids is NOT absoulte :)

(wouldn’t have asked if it was)

Question 7

Therapeutic uses:

Vincristine?

Vinblastine?

Answer 7

*used in combo therapy b/c of distinct MOA and toxicities

Vincristine: Hodgkin’s disease and non-Hodgkin’s lymphoma

Vinblastine: Hodgkin’s disease and testicular (balls) cancer

Question 8

Specific Toxicity of:

Vincristine?

Vinblastine?

Answer 8

Vincristine: More CNS toxicity –> fatal if given intrathecally :(

Vinblastine: more bone marrow suppression

Both cause some BMS and neurotoxicity

Question 9

Toxicity of vina alkaloids as a class?

Answer 9

1. Bone marow suppression (more in vinblastine)
2. Nausea and vomiting (more in vinblastine)
3. Vesicant –>blisters
4. Neurotoxicity (more in vincristine)

Question 10

Common symptoms of neurtoxicity from Vincristine?

Answer 10

* occur b/c you need microtubules in axon transport

Motor: loss of reflexes (2-3 weeks in 100% of pts) **indication of sufficient dose!

Autonomic: constipation, paralytic ileus, orthostatic hypotension

Sensory: paresthesia –>sensory loss and severe paresthesia –> indicaiton to decrease dose, por favor!

Question 11

MOA of Taxanes:

(Capazitaxel, Docataxel, Paclitaxel)

While we are at it, what’s the resistance of Taxanes?

PK?

Answer 11

Bind to tubulin and ENHANCE and STABILIZE spindle assembly

Resistance = hmm, it’s a plant alkaloid/natural product

-Decreased accumulation via increased P-glycoprotein expression –>MDR

*side bar: extensive CYP450 metabolism

Question 12

Toxicity of Taxanes?

Answer 12

• Bone marrow suppression
• Hypersensitivity/allergic reactions
  
  • albumin-bound formulation of Paclitaxel developed to significanlty reduce toxicity
• Peripheral neuropathy
• N/V
• Hypotension, arrhythmias

Question 13

Ixabepilone MOA:

Toxicity:

Answer 13

MOA: binds tubulin and enhances and stabilize spindle assembly

Use with capecitabine (5-FU) for breast cancer

Toxicity: BMS, peripheral neuropathy, cardiac arrhythemias, hypersensitivty

Question 14

Ixabepilone is soooo similiar to Paclitaxel (MOA and toxicity) ….

Why do we use it/like it?

Answer 14

Ixabepilone does not produce MDR

-use in breast cancer patients who have failed Doxorubicins and Paclitaxel

3rd line treatment