Immunofluorescence study of the action of navelbine, vincristine and vinblastine on mitotic and axonal microtubules.
Among the various non-naturally-occurring Vinca alkaloid compounds, nor-anhydro-vinblastine (Navelbine, NVB) exhibits in preliminary clinical studies broader anti-tumor activity and lower neurotoxicity than vinblastine (VBL) and vincristine (VCR). The action of these 3 Vinca alkaloids on axonal and mitotic microtubules has been studied experimentally in a specific model, the tectal plate anlage of mouse embryos at the earliest stages of neuronal differentiation. Post-implantation embryos were cultured in toto in a medium containing increasing concentrations of drugs. Microtubules were stained using immunofluorescence with a tubulin-specific polyclonal antibody in semi-thin sections after embedding in high-molecular-weight polyethylene glycol. All drugs induced depolymerization of mitotic interpolar microtubules and cell metaphase block at the same concentration. Increasing the concentrations led to progressive depolymerization of kinetochore microtubules. However, NVB was the only drug to induce complete microtubule depolymerization. The activity of the 3 compounds on axonal microtubules was identical: depolymerization of a labile pool of microtubules. This was observed at higher concentrations with NVB than with the 2 other Vinca alkaloids. Our results show that, in this model, NVB is as active on mitotic microtubules as VCR and VBL, and less active on axonal microtubules. None of the 3 drugs modified microtubule length but all appeared to induce disruption of the labile microtubule pool without altering the stable pool.
Laboratoire d'Anatomie, UER Biomédicales des St-Pères et Broussais-Hôtel-Dieu, Paris, France.
S
S
Binet
E
E
Chaineau
A
A
Fellous
H
H
Lataste
A
A
Krikorian
J P
JP
Couzinier
V
V
Meininger
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000187:drug effects / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D014750:Vincristine; D014747:Vinblastine; D000077235:Vinorelbine