Anti-human immunodeficiency virus type 1 therapy and peripheral neuropathy: prevention of 2',3'-dideoxycytidine toxicity in PC12 cells, a neuronal model, by uridine and pyruvate.
A strategy for preventing or delaying the peripheral neuropathy induced by 2',3'-dideoxycytidine (ddC) therapy in patients with acquired immunodeficiency syndrome was suggested by findings, in two laboratories, that cultured avian and mammalian cells devoid of mitochondrial DNA continue to replicate at virtually normal rates, provided that the medium is supplemented with uridine and pyruvate. Inasmuch as it is likely that a depletion of mitochondrial DNA also takes place in neuronal cells exposed to ddC, we used PC12 cells, the neuronal model we have reported on previously, in an attempt to rescue these cells from the deleterious effects of ddC. We first show, using undifferentiated PC12 cells, that DNA replication is impaired in mitochondria isolated from cells grown in the presence of ddC. Then, using growth rate as a criterion of the well-being of the cells, we show that the addition of uridine and pyruvate to uninduced cells growing in the presence of ddC results in an average rescue efficiency of 51%, based on the uridine/pyruvate-treated control. This value increases considerably at substantially higher concentrations of uridine alone. Rescue efficiencies of differentiated cells, which do not proliferate, were assessed using neurite outgrowth and neurite survival as criteria. Here the rescue efficiency is 56%, based on the uridine/pyruvate-treated control. In addition, uridine and pyruvate prolong the viability of ddC-treated cells and maintain their healthy appearance; without these compounds, the ddC-treated cells have an abnormal morphology and die off quite rapidly.
Keilbaugh
S A
SA
Department of Biochemistry and Cell Biology, State University of New York, Stony Brook 11794-5215.
Hobbs
G A
GA
Simpson
M V
MV
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000502:physiology; D015497:HIV-1; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects; D016716:PC12 Cells; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000382:microbiology / Q000517:prevention & control*; D011773:Pyruvates / Q000627:therapeutic use*; D019289:Pyruvic Acid; D014529:Uridine / Q000627:therapeutic use*; D016047:Zalcitabine / Q000633:toxicity*
D004272:DNA, Mitochondrial; D011773:Pyruvates; D016047:Zalcitabine; D019289:Pyruvic Acid; D014529:Uridine