S. Lobert et al., Vinca alkaloid-induced tubulin spiral formation correlates with cytotoxicity in the leukemic L1210 cell line, BIOCHEM, 39(39), 2000, pp. 12053-12062
The ability of a class of C-20' modified vinca alkaloid congeners to induce
tubulin spiral formation was investigated relative to their ability to inh
ibit microtubule assembly, their cytotoxicity against a leukemic cell line,
L1210, and their measured and calculated partition coefficients. These stu
dies were prompted by the observation that the energetics of vinca alkaloid
-induced tubulin spiral polymers, or spiraling potential, is inversely rela
ted to their clinical dosage and are aimed at the long-term goal of develop
ing the ability to predict the cytotoxic and antineoplastic properties of a
ntimitotic drugs. We demonstrate here that vinca-induced tubulin-spiraling
potential is significantly correlated with cytotoxicity against L1210 cells
. This is consistent with the size of spirals formed being proportional to
the relaxation time for polymer redistribution, the lifetime of cell retent
ion, and effects on microtubule ends and dynamics. Spiraling potential also
correlates with calculated but not measured partition coefficients. Surpri
singly, spiraling potential does not correlate with the ability to inhibit
microtubule formation with purified tubulin or microtubule protein. For the
set of C-20' modified compounds studied, the largest inhibitory effects on
spiraling potential and cytotoxicity are caused by multiple sites of halog
en (-F, -Cl) substitution with the introduction of increased rigidity in th
e ring. This suggests the C-20' position interacts with a hydrogen bond acc
eptor or an electrophilic region on the protein that electrostatically disf
avors halogen substitutions. These studies are discussed in terms of the ce
llular mode of action of antimitotic drugs, particularly the importance of
microtubule dynamics during mitosis and thp factors that regulate those dyn
amics.