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Vinorelbine

Vinflunine

N' >T ^OCOCH3 H3CHO 'CO2CH3

Vinorelbine

Vinflunine

The Vinca alkaloids specifically block cells in mitosis with metaphase arrest, and hence are antimitotic drugs. Their biological activity is explained by their specific binding to the p subunit of tubulin dimers, in a region called the Vinca domain. Binding is fast and reversible, but it induces a conformational change in tubulin, increasing its affinity for itself and leading to the formation of paracrystal-line aggregates. This decreases the pool of free tubulin dimers available for microtubule assembly, resulting in a shift of the equilibrium toward disassembly and microtubule shrinkage. These phenomena result in microtubule depolymeri-zation and destruction of the mitotic spindles, as verified in HeLa cells at high (10-100 nM) concentrations (Fig. 8.2). As a consequence, dividing cells are blocked in mitosis with condensed chromosomes.

The mechanism described above led to the Vinca alkaloids being thought for many years to act solely as microtubule-depolymerizing agents. However, recent observations have shown that, at concentrations that are low but clinically relevant (0.8 nM in HeLa cells), the spindle microtubules are not depolymerized but mitosis is still blocked and cells die by apoptosis. This suggests that the block is due to suppression of microtubule dynamics rather than to microtubule depolymerization.

One of the drawbacks of Vinca alkaloids and their analogs is their neurotoxic-ity, which is probably related to the fact that microtubules are a key component of neurons. Another problem associated with the use of Vinca alkaloids is the easy development of resistance, normally mediated by the overexpression of the Pgp-170 transport protein (see Chapter 12).

Mitotic spindle

Microtubule

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