Anti-microtubles Flashcards
What’s the MOA of the vinca alkaloids?
Prevents assembly of the microtubules –> mitotic arrest at the metaphase/ anaphase transition
What’s the MOA of taxens?
Prevents the disassembly of the microtubules
How does the tubulin binding affinity effect the anti-tumour activity?
It has no effect on anti-tumour activity
What’s the mechanism of resistance for the anti-microtubules?
- Multidrug resistance:
Innate or acquired
Ex. Pgp/MDR1 - Cross resistance:
Taxane, anthracycline, epipodophyllotoxins, actinomycin D - MRP1 (drug efflux)
- Structural alterations in tubulin
What are some known drug interaction with the vinca alkaloids?
- L-asparaginase
Reduce hepatic clearance VCR - Inhibitors of CYP3A
Erythromycin, itraconazole
Toxicity - Phenobarbital
Modulating clearance - Steroid
Induction of P450 metabolism
What some toxicities of vinca alkaloids?
- GI –> ileus
- peripheral neuropathy
- myelosuppression
- hyper/ hypo tension
- extravasation reaction: Hyaluronidase
and warm compress - SIADH
- Bladder atony
Which breed is more sensitive to vincristine? What’s the reasons?
Border Collie. In one study, it was found NOT to be related to ABCB1 mutation.
What’s the MTD for single agent vinblastine in dogs?
3.5mg/m2 IV q2 weeks
In a COP protocol for feline LSA, which vinca alkaloids had significant less GI side effects?
vinblastine, there was no difference in RR, PFI and MST
What’s the MTD of vinorelbine in cats?
11.5mg/m2 IV
(vs 15mg/m2 IV in dogs)
What’s the DLT of vinorelbine in cats?
Neutropenia
Vomiting
Nephrotoxicity ?
What are some mechanism of resistance for taxanes?
- MDR phenotype:
Pgp/MDR1
MRP1 lower level of resistance to taxanes than vincas - BSEP –> type of efflux pump that’s very specific to the taxanes
- Alterations in cytoskeleton, tubulin binding sites, microtubule
What’s the MOA of taxanes?
- Bind poorly to soluble tubulin
- High affinity to polymerized tubulin
- Stabilize the microtubules (prevents disassembly)
What’s the MTD of docetaxel when used in conjunction with cyclosporin A in cats? in dogs?
Cats: 1.75m/kg with 5mg/kg of cyclosporine
Dogs: 1.625mg/kg; DLT = GI
What are some known drug interactions with taxanes?
- depends on sequence of drugs: if given after cisplatin, more likely to have neutropenia (due to decrease in clearance of paclitaxel), but the reverse is fine
Also seen with cyclophosphamide, 5-FU, etoposide, ara-C - cardiotoxicity with doxorubicin
What are some toxicities of taxanes?
Paclitaxel:
- myelosuppression – nadir @ Day 5
- hypersensitivity reactions!
- GI
- peripheral neuropathy
- cardiotoxicity
Docetaxel:
- fluid retention (Due to increased capillary permeability and insufficient lymphatic drainage appear to be responsible)
- dermatopathy (dorsal hand-foot syndrome or rash, may occur in approximately 50% of patients)
Can paclitaxel be safely given SQ in dogs?
No hypersensitivity reaction by severe skin reaction at site of injection in 2/40 doses
2 dogs had grade V diarrhea :(
What’s the outcome of using docetaxel for cats with cancer?
- MTD 2.25 mg/kg IV q3w
- cats with oral SCC 6/9 SD
What’s the outcome of Paccal Vet for treatment of canine grade 2 or 3 nonresectable MCT?
in comparison to CCNU:
- ORR 7% v 1%
- BORR 23% vs 10%
- 33% of CCNU patients had to d/c due to hepatotoxicity, vs 2% on paclitaxel
What’s the response rate of paclitaxel for feline mammary tumours?
80%
What class of drugs can reverse the MDR/Pgp resistance in taxanes?
- calcium channel blockers,
- tamoxifen
- cyclosporine A
What are the major DLT for taxanes?
neutropenia and diarrhea
