MT L2 Mitotic spindle poisons Flashcards
What are microtubules?
responsible for maintaining structure of the cell and for separating sets of chromosomes during mitosis.
Interfering with formation and remodeling inhibits mitosis and therefore the proliferation of cancer cells
microdubules are assembalies of …………
each has….
tubulin dimers
one alpha and one beta subunit
how do tubulin dimers work
spiral strucutre onto a base plate - remodelled by the loss of pull of free tubulin dimers and growing and shrinking dynamic equillibrium,
microtubules are in dynamic equillibrium with tubulin dimers
What do mitotic spindle poisons interfer with
the dynamic equillibrium of microtubules with individul tubulin dimers
name 4 vinka alyaloids
vinblastine
vincristine
vindesine
Vinorelbine
how do vinca alkyloids work (3 steps)
- bind strongly to tubulin dimers causing conformatoional change and preventing binding to microtubules
- also bind to individual tubulin dimers to stop them adding on
- individual complexes of vinca alkyloid and tubuin dimer condense into paracrystlline aggregates - irriversible process
(le chatelier’s principle applies - microtubules shrink)
What cancers can we use Vincristine for
Leukaemias Lymphomas Mammary carcinoma Neuroblastoma Rhabdomyosarcoma
What cancers can we use Vinblastine for
Lymphomas Testicular carcinomas Ovarian carcinomas Bladder carcinomas Hodgkin’s lymphoma
What cancers can we use Vindesine
Leukaemias
Lymphomas
What cancers can we use Vinorelbine
Non-small-cell lung carcinoma
Mammary carcinoma
additional way vinblastine works?
caps off the +ve end ff micro tubule, prevetting new tubulin dimers adding
name two taxol/taxol like drugs
Paclitaxel (taxol)
Docetaxel (taxotere)
What is paclitaxel used for?
mammary and ovarian carcinoma
what is docetaxel used for
prostate mammary ovarian and lung (all carcinomas)
Action of taxoles
Taxols bind to taxol-binding sites on the inside surface of the microtubule, preventing disassembly as dimers cannot dissociate off the end.
The microtubule cannot grow/shrink therefore inappropriate microtubules remain.
Concerntration of free tubulin dimers decreases so new microtubultes cannot be formed
name two colchicine like drugs
colchicine and Combretastatin A-4
When is colchcine used
no currently approved for cancer
approved for gout
when is combretastatin a-4 used
in clinical trials for cancer
what is the mode of action of BOTH colchicine like drugs?
binds at colchicine-binding sites on b-tubulin in MICROTUBULES disfavours disassembly of inappropriate microtubules.
AND
binds to colchicine-binding sites on the b-tubulin SUBUNITS, disfavouring assembly of protofilaments.
bulkiness of the drug stops subunit binding. Fowls up assembly and stops association