Vinca alkaloid-induced tubulin spiral formation correlates with cytotoxicity in the leukemic L1210 cell line

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.