Comparative anabolism of azidothymidine (AZT) and didanosine (ddI) in human T-cell lines sensitive and resistant to AZT and human PBMC cells (Meeting abstract).

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Comparative anabolism of azidothymidine (AZT) and didanosine (ddI) in human T-cell lines sensitive and resistant to AZT and human PBMC cells (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A1982 1994. Unique Identifier : AIDSLINE ICDB/95603668
Periclou AP; Solorzano MM; Avramis VI; Division of Hem./Onc, USC/Childrens Hospital Los Angeles, Los; Angeles, CA 90027

Abstract: We have investigated the drug synergism between AZT and ddI in PBMC cells from pediatric patients with HIV-1 infection ex vivo and in T-cells in vitro. We investigated whether the drug anabolites, AZTTP and ddATP, could act synergistically intracellularly in both Jurkat T-cell lines and in freshly separated PBMC cells from healthy volunteers. PBMC cells or Jurkat T-cells were incubated with [3H]AZT and/or [3H]ddI for 1 hour, extracted with perchloric acid and the extracts were assayed with HPLC SAX-10 column. AZT (1 uM) anabolism in separated PBMC cells showed that AZTTP intracellular concentrations accumulated at 13.2 nM and 5.5 nM in mostly lymphocytes and monocytes, respectively. Anabolism of ddI in Jurkat T-cell lines sensitive (J/0) and resistant (J/AZT-10) to AZT showed no apparent difference in the accumulated ddATP cellular concentrations, 184.2 +/- 11.9 nM in J/0 vs 183.5 +/- 8.3 nM in J/AZT-10 (mean +/- SD), indicating possible collateral sensitivity between these drugs. DdI anabolism in J/0 T-cell lines showed that ddATP is 20% +/- 5% higher when co-cultured with 1 uM AZT. Experiments on sequential combination treatments of AZT and ddI and on the possible mechanism of augmentation of ddATP are in progress. DdI anabolism in PBMC cells showed ddATP concentrations of 149.6 +/- 16.7 nM, which are similar to the levels observed in T-cell lines. We conclude that the augmented ddATP concentrations in the presence of AZT could provide the biochemical rationale for the observed drug synergism between AZT and ddI.

Keywords: Biotransformation Cell Line Cells, Cultured Comparative Study Didanosine/ANALOGS & DERIVATIVES/*METABOLISM/TOXICITY Drug Resistance Drug Synergism Human Lymphocytes/DRUG EFFECTS/*METABOLISM T-Lymphocytes/DRUG EFFECTS/*METABOLISM Tumor Cells, Cultured Zidovudine/ANALOGS & DERIVATIVES/*METABOLISM/*TOXICITY ABSTRACT
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M9521049

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