Antimicrotubule Agents

Question 1

Vinca alkaloid MOA

Answer 1

Vincas bind tubulin and inhibit polymerization to form microtubules

also antiangiogenic

Question 2

In which phase is the cell most sensitive to vincas?

When does chabner say mitosis is blocked? metaphase/anaphase transition

Answer 2

Lethally damaged cell may enter an ABORTIVE METAPHASE then lyse, BUT studies have shown that lethal toxicity for vinc/vbl occurs when cells are exposed during DNA SYNTH (S-PHASE), which is when formation of the mitotic spindle is initiated

When does chabner say mitosis is blocked? metaphase/anaphase transition

Question 3

What side effect is unique to vincristine amongst the vincas?

Answer 3

vincristine can cause SIADH!!

Question 4

Vincas are RADIOSENSITIZERS!!! Induce cell cycle block where?

Answer 4

G2/M phase

Question 5

Vinca multi-drug resistance conferred by _____ and _______

Answer 5

MDR1

MRP1

Question 6

How are vincas metabolized?

Answer 6

Hepatic cytochrom P450 CYP3A (t/f increased toxicity with CYP3A inhibitors like itraconazole, etc)

Question 7

What chemotherapeutic may reduce hepatic clearance of vincas? What is the recommendation?

Answer 7

Lspar. Which may increase toxicity.

Give VCR 12-24h BEFORE L-spar.

Question 8

Vincristine given with what type of inhibitors may lead to severe toxicity? Give examples.

Answer 8

CYP3A inhibitors.

Erythromycin, clarithromycin, itraconazole, posaconazole, voriconazole.

Question 9

What is the recommendation for vinc extravasation?

Answer 9

(chabner)

Stop infusion and aspirate.
Apply local HEAT - 60 min, 4x/d x 3-5 days
Hyaluronidase injection - SQ, 6 clockwise, 25g needle, new needle w each
Immediate surgical consult to consider early debridement

Question 10

5 vinca toxicities

Answer 10

1. Peripheral neurotoxicity (ileus, constipation) - axonal degeneration and decreased axonal transport dt interference w axonal mtb fxn
2. SIADH - directly affects hypothalamus, neurohypophyseal tract or post pituitary. Who at risk? Those receiving intensive hydration. Severe hypoNa secondary to SIADH which may result from seizures. Usually resolves.
3. Hand-food syndrome - RARE (navelbine)
4. Myalgia/arthralgia
5. Photosensitivity reactions (VBL) - corneal irritation

Question 11

Are the taxanes natural or synthetic?

Answer 11

Paclitaxel - natural

Docetaxel - semisynthetic

Question 12

Taxane MOA

Answer 12

Bind to tubulin and inhibit microtubule disassembly – > prevent normal growth and breakdown of MTBS reqd for cell division.

Question 13

When do the taxanes exhibit maximum toxicity?

Answer 13

Paclitaxel - increasing toxicity for cells as they pass S > G2 > M

Docetaxel - max toxicity in S phase

Question 14

Taxane metabolism?

Answer 14

mediated through cytochrome p450 (cytochrome P450 inducers)

agents that influence cytochrome P450 can modify clear/tox of taxanes (ie phenobarb can increase clearance and reduce toxicity)

Question 15

Where do taxanes block cells in cycle?

Answer 15

blocked from metaphase to anaphase (like vincas)

Question 16

What is different about taxane and vinca mtb dynamics?

Answer 16

in contrast to vincas, taxanes disrupt normal mtb dynamics by….

1. reducing critical tubulin concentration needed for MTB assembly &
2. promoting nucleation + elongation phases of polymeration reaction

**this stabilizes MTB against depolymerization and enhances polymerization

Question 17

Taxane resistance? (1)!

How reverse?

Answer 17

MDR phenotype - mostly MDR1 (Pgp) and MDR2

Can reverse with: calcium channel blockers, tamoxifen, cyclosporine A, antiarrhythmics

note: plasma concentrations of Cremophor EL can also reverse taxane resistance!

Question 18

Drug Interactions.

1. Taxanes induce _______ (enzyme) – > may increase metabolic activation of which chemotherapeutic?

Answer 18

thymidine phosphorylase

capecitabine

Question 19

CYP450 inducers (phenytoin, phenobarb, grapefruit juice, st johns wort, echinacea) may ______ metabolism of taxanes

Answer 19

ACCELERATE

Question 20

Name toxicities of the following:

paclitaxel - 1
docetaxel - 2
both - 2

Answer 20

Paclitaxel: arrhythmia,

docetaxel: skin toxicity, fluid retention syndrome (CUMULATIVE)

Both: peripheral neuropathy, hypersensitivity

How to prevent HSR?

1. Dexamethasone.
2. H1 receptor antag (diphenhydramine)
3. H2 receptor antag (cimet/famot/ranit)

Question 21

Vincas increase which cell cycle fraction?

Answer 21

G2/M

Question 22

Why should vinc be given before Lspar?

Answer 22

L-asparaginase may reduce hepatic clearance of vincas (esp VCR), which may result in increased toxicity•

Give VCR 12-24h before L-spar