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Journal of Clinical Oncology, 2004 ASCO Annual Meeting
Proceedings (Post-Meeting Edition).
Vol 22, No 14S (July 15 Supplement), 2004: 2087
© 2004 American Society
of Clinical Oncology
Combined administration of hydrophilic antimitotic
desoxyepothilone B and vinorelbine induce PUMA, suppression of
microtubule dynamics, development of hypodiploidy and multinucleation,
cell cycle perturbation at G2/M and apoptosis in advanced breast
carcinoma (ABC) characterised by MDR-1 (Pgp),bcl-2 and mutant b-tubulin
G. N. John, J. Giannios, E.
Michailakis, S. Konstandinidou, G.
Xepapadakis, N. Alexandropoulos and T. Kononas
GSHA, Athens, Greece; BC, Athens, Greece; MH,
Athens, Greece; IH, Athens, Greece
2087
Introduction: Low aqueous solubility of VRL is a high
substrate for ATP dependent drug efflux proteins such as
MDR-1(Pgp) and MRP2(ABCC2) inserted in plasma membrane of
tumor cells.Furthermore,b-tubulin mutations are
cross-resistant to VRL. Methods: We treat with MTC
such as VRL and dEpoB advanced mammary carcinoma characterised by
overexpression of bcl-2,MDR-1(Pgp),MRP2(ABCC2) and mutant b-tubulin
according to PCR,WB and IHC analysis. MT polymerising agent
dEpoB is more soluble in aqueous solvents than VRL reducing affinity
for Pgp by being a poor substrate. Results:
Post-treatment,although VRL and dEpoB are structurally
unrelated,they bind to mutually exclusive sites on the
tubulin unit.After binding of MTCs to MT,there was
synergistic phosphorylation of bcl-2,overexpression of
bax,circumvention of expression of altered b-tubulin polypeptides,
MDR-1 and MRP-2 due to high hydrophilicity of dEpoB and
PUMA. Flow cytometry showed blockage of cell proliferation
at the metaphase-anaphase (G2/M) interface of the cell
cycle.There was an enhancement in hypodiploid population of
tumor cells,multinucleation,aberrant spindle
formation,nuclear convolution,suppression of MT-dynamics and
formation of MT bundling.Both drugs induced release of cyt-c from
isolated mitochondria after interaction of mitochondrial tubulin
with the voltage-dept anion channel of the permeability transition
pore.There was potent immunosuppression by inhibiting T-cell
proliferation.Methylene blue, BrdU and MTT exhibited inhibition
of tumor cell proliferation. We observed nuclear factor
kB-induced apoptosis displayed by features such as nuclear condensation
and fragmentation,Annexin V staining,cleavage of poly(ADP-ribose)polymerase
and activation of caspases. Conclusion: We observed
synergy between dEpoB and vinorelbine in potentiation of
apoptosis in advanced breast carcinoma circumventing chemoresistance.
No significant financial relationships to disclose.
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