The effect of antimitotic agents on the intraneuronal distribution of lysosomes.
We previously showed that a single injection of colchicine into the lateral cerebral ventricle of the rat causes a redistribution of lysosomes from their normal localization in neuronal cell bodies into dendrites. In the present report we have examined the time course and specificity of this effect using a variety of microtubule poisons. Dipeptidylaminopeptidase II (Dpp II), a lysosomal marker enzyme, histochemistry was used to visualize lysosomes at the light microscopic level. Acid phosphatase, another lysosomal enzyme, histochemistry was used to confirm the Dpp II localization of lysosomes. Two h after an intracerebroventricular (i.c.v.) injection of colchicine, the distribution of neuronal lysosomes was drastically altered. Lysosomes in a number of neuronal populations were observed to move from the soma to the dendrites. This effect was maximal between 12 and 24 h and was partially reversed by 96 h. Injections of colcemid or podophyllotoxin, drugs that bind to tubulin rapidly, and much less tightly than colchicine, produced a much less pronounced alteration in the intraneuronal distribution of lysosomes. Injections of vinblastine or vincristine, whose binding kinetics range between that of colchicine and that of colcemid and podophyllotoxin, resulted in a redistribution of lysosomes which was less pronounced than the effects of colchicine but more pronounced than that caused by colcemid and podophyllotoxin. Likewise, treatment with other related compounds, 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone (A-C compound) and lumicolchicine, whose binding to tubulin is extremely rapid and reversible or non-existent, produced little or no alteration in the intraneuronal distribution of lysosomes. The results suggest that lysosome redistribution may be dependent upon a relatively slow dissociation rate constant of these drugs from tubulin, and this transport may occur when normal microtubule function is compromised.
Salk Institute, La Jolla, CA 92037.
V J
VJ
Roberts
C
C
Gorenstein
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000648:ultrastructure*; D003078:Colchicine / Q000494:pharmacology*; D003703:Demecolcine / Q000494:pharmacology*; D006651:Histocytochemistry; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D011919:Rats, Inbred Strains; D014747:Vinblastine / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014747:Vinblastine; D000135:Acid Phosphatase; D003078:Colchicine; D003703:Demecolcine