PubMed · 7375789
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P Niaudet. 1980-03-11. [Immunosuppressive agents].. https://pubmed.ncbi.nlm.nih.gov/7375789/
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The human lymphoblastoid cell lines TK6 (normal p53) and WI-L2-NS or WTK1 (mutant p53) differ in sensitivity to killing and induction of gene mutations and chromosome aberrations by ionizing radiation. This may be related to decreased apoptosis in the cells with mutated p53, such that more damaged cells survive. We compared the response of the two cell types to various chemicals. First, to ensure that the thymidine kinase deficiency does not increase the sensitivity of TK6 tk+/- cells to mutagens, we demonstrated that they were not hypersensitive to aberration induction by altered DNA precursor pools or DNA synthesis inhibition, by aphidicolin (APC), methotrexate, hydroxyurea (HU), cytosine arabinoside and thymidine. TK6 cells were then compared with WI-L2-NS or WTK1 cells. With APC, HU, methyl methanesulfonate (MMS), ethyl nitrosourea (ENU) and etoposide (etop), TK6 cells had more apoptosis in the first two days after treatment. Fewer aberrations were seen in normal p53 TK6 cells than the mutant p53 WI-L2-NS cells, ranging from very little difference between the two cell types with MMS to very large differences with ENU and etop. For MMS and ENU we followed cultures for several days, and found that WI-L2-NS cells underwent delayed apoptosis 3 to 5 days after treatment, in parallel with published observations with ionizing radiation. WI-L2-NS cells also had a delayed increase in aberrations (up to 5 days post-treatment) when no aberrations remained in TK6 cells. Colony forming efficiency was measured for APC, MMS and ENU, and was greater in the p53 mutant cells. Our results show that normal p53 function is required for rapid and efficient apoptosis in these lymphoblastoid cells with DNA synthesis inhibitors, alkylating agents and a topoisomerase II inhibitor, and support the hypothesis that induced levels of aberrations are higher in p53 mutant cells because of a failure to remove damaged cells by apoptosis.
N-chloroethyl derivatives of 7-hydroxy-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), or fluphenazine were microinjected into rat nucleus accumbens (Acc), and receptor binding quantified autoradiographically after 24 h. EEDQ reduced [3H]nemonapride (D2-like receptors) binding in Acc (by 84%) and islands of Calleja (IC; 44%), without affecting [3H](+)-7-OH-DPAT (D3); N-chloroethyl-7-OH-DPATs blocked both radioligands in Acc and IC (30%-70%); fluphenazine had no effect.
A specific and highly sensitive method has been developed for the determination of busulfan in plasma by gas chromatography-mass spectrometry using a deuterium-labeled busulfan (busulfan-d8) as internal standard. Plasma containing busulfan and busulfan-d8 were extracted with ethyl acetate and derivatized with 2,3,5,6-tetrafluorothiophenol prior to the monitoring of specific ions. The limit of quantification of the assay was 20 ng/ml and the calibration curve was linear over the range of 10 to 2000 ng/ml of derivatized busulfan. This method was in good agreement with the GC-MS assay using derivatization with sodium iodide and measuring diiodobutane. In addition, a pharmacokinetic study of busulfan was conducted in six children. The apparent oral clearance was 5.7+/-1.9 ml/kg/min and the volume of distribution was 1.0+/-0.4 l/kg and were similar to those previously reported in pediatric patients.