Details

Autor(en) / Beteiligte

• Keilbaugh, Sue A.
• Prusoff, William H.
• Simpson, Melvin V.

Titel

The pc12 cell as a model for studies of the mechanism of induction of peripheral neuropathy by anti-HIV-1 dideoxynucleoside analogs

Ist Teil von

• Biochemical pharmacology, 1991-06, Vol.42 (1), p.R5-R8

Ort / Verlag

New York, NY: Elsevier Inc

Erscheinungsjahr

1991

Quelle

Elsevier Journal Backfiles on ScienceDirect (DFG Nationallizenzen)

Beschreibungen/Notizen

• The ability of DNA polymerase gamma to utilize ddNTPs+ as substrates, incorporating these chain terminators into DNA (see citations in[1]), has led us to propose that AZT-induced bone marrow suppression results from inhibition of mtDNA replication [1]. This could alter metabolism since mtDNA encodes proteins involved in ATP synthesis and mitochondrial ultrastructure. We have shown that AZT and some other ddNs used in AIDS therapy inhibit DNA replication by purified DNA polymerase gamma and by isolated mitochondria [1,2]. Moreover, proliferation of a hemopoietic cell, the Friend erythroleukemic cell, is strongly inhibited by AZT [2], and mitochondria from these cells show impairment of DNA replication++ [2]. Additional evidence comes from studies on the effect of ddC on the Molt-4F cell [3], and on the involvement of mitochondria in AZT-induced myopathy [4]. We propose that inhibition of mtDNA replication is also the primary step in ddC-induced [5], ddI-induced [6] and d4T-induced [7] peripheral neuropathy. We have found that a c-Ha-ras transformant of the PC12 cell, GS-ras-1+++, is a promising neuronal cell model for such studies. The PC12 cell line [8] is derived from a pheochromocytoma, an adrenal medullary tumor; cells of the adrenal medulla share their embryological origin with neuronal cells. When the PC12 cell is induced by NGF (or by dexamethasone in GS-ras-1) to differentiate, neurite outgrowth and increased synthesis of acetylcholine and other neuronal markers occur. We describe the effects of some ddNs on both the uninduced and the induced cell.