Drugs that Interrupt Mitosis/Cytotoxic Drugs Flashcards
What are the two main groups of drugs that interrupt mitosis?
- Vinca alkaloids
- Epilones
- Taxanes
Drugs that interrupt mitosis - CCS or CCNS?
CCS - M phase
-Act as mitotic spindle proteins
What drugs are vinca alkaloids?
Vinblastine, Vincristine, Vinorelbine
What are the epilones?
Ixabepilone
What are the taxanes?
Cabazitaxel, Docetaxel, Paclitaxel
What is the difference in toxicity between Vincristine and Vinblastine?
Vincristine = CNS Vinblastine = Bone Marrow suppression
What are the classes of plant alkaloids?
- Camptothecans
- Epipodophylotoxin
- Taxanes
- Vinca alkaloids
What drug is an epipodophylotoxin?
Etoposide
What drugs are a Camptothecins?
Irinotecan, Topotecan
What is the MOA for Vinca Alkaloids?
- Vinblastine, vinorelbine, vincristine
- Bind to tubulin at the forming end of microtubules and TERMINATE spindle assembly
- Minor changes in structure can result in significant changes in toxicity and anti-tumor activity
What resistance has developed against Vinca alkaloids?
- Dec. accumulation of drug via INCREASED P-GLYCOPROTEIN expression –> MDR
- Changes in target proteins
- –Mutations to tubular that prevent binding
- Cross reactivity among vinca alkaloids is not absolute
What is the therapeutic use of vinca alkaloids?
-Routinely used in combination therapy because of distinct mechanisms of action and toxicities
What regimens is Vincristine involved in?
(Oncovin)
- MOPP for Hodgkin’s disease
- CHOP for non-Hodgkin’s lymphoma
What regimens is Vinblastine involved in?
- ABVD for Hodgkin’s disease
- PVB for testicular cancer
What toxicities are caused by vinca alkaloids as a class?
- Bone marrow suppression
- Neurotoxicity
What are the different degrees to which Vinblastine and Vincristine cause toxicity?
Vincristine = more CNS toxicity (more lipid soluble) --> fatal if given intrathecally Vinblastine = more Bone marrow suppression
What are other toxicities of vinca alkaloids?
- BMS (greater for Vinblastine)
- Nausea and vomiting (greater for Vinblastine)
- Alopecia
What is important about the neurotoxicity seen in vinca alkaloids?
- Prominent because of the requirement for microtubules
- Common symptoms:
- –Motor: loss of reflexes
- –Autonomic: constipation, paralytic ileus, orthostatic hypotension
- –Sensory: paresthesias (“pins and needles”)
What would cause you to decrease the dose of a vinca alkaloid?
- Depression of deep tendon reflexes occurs within 2-3 weeks in 100% of patients – this is used as an indication of sufficient dose
- This can be followed by severe paresthesias and mild to moderate sensory loss - this is used as an indication to decrease the dose
What is the mechanism of action for taxanes?
-Bind in tubulin and ENHANCE AND STABILIZE spindle assembly
What resistance has developed against taxanes?
-Decreased accumulation via increased P-glycoprotein expression –> MDR
What is the pharmacokinetics for taxanes?
Excessive CYP450 metabolism
When you think paclitaxel. what should you think?
Drug interactions
What are the toxicities for taxanes?
- Bone marrow suppression
- Hypersensitivity/Allegic reactions
- –An albumin-bound formulation of PACLITAXEL has been developed that has significantly reduced toxicity
- Peripheral neuropathy
- Nausea and vomiting
- Hypotension, arrhythmias
What is the MOA of IXABEPILONE (Epilone)?
-Binds to tubulin and ENHANCES AND STABILIZES spindle assembly (similar to PACLITAXEL)
What is Ixabepilone used with?
Capecitabine - for treatment of breast cancer (3rd line treatment)
Where is Ixabepilone metabolized?
in the liver
What side effects can Ixabepilone cause?
- Bone marrow suppression, peripheral neuropathy and cardiac arrhythmias
- Hypersensitivity
Like other natural product drugs, Vinca alkaloids and taxanes lead to the development of. . .
. . .multidrug resistance due to increased expression of P-glycoprotein
What drug is used for breast cancer patients who have failed anthracycline antibiotic and taxane treatments? Why?
Ixabepilone
-It does not produce MDR
