| Mechanisms involved in the potentiation of melphalan by the bioreductive compound THNLA-1 in vitro. | |
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MedLine Citation:
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PMID: 10803738 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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9-[3-(2-Nitro-1-imidazolyl)propylamino]-1,2,3,4-tetrahydroacridine hydrochloride (THNLA-1) is a 2-nitroimidazole-based, weakly DNA-intercalating bioreductive agent that significantly potentiates the toxic effects of commonly used antitumor drugs such as melphalan (L-PAM) or cis-DDP in sensitive or resistant cell lines in culture, as well as in solid tumors in mice. Potentiation in vitro was observed when cells were preexposed to THNLA-1 under hypoxic conditions before exposure to L-PAM under aerobic conditions. In this study we investigated possible mechanisms involved in the potentiation of L-PAM by THNLA-1 in V79 Chinese hamster cells. Limited depletion of glutathione with buthionine sulfoximine or THNLA-1 under hypoxic pretreatment conditions accounted for only 8.3% of the potentiation induced by THNLA-1. However, DNA, RNA, and protein synthesis were inhibited in a synergistic way in cells preexposed to THNLA-1 under hypoxic conditions (2 h, 37 degrees C) and then coexposed to various doses of L-PAM under aerobic conditions (1 h, 37 degrees C). Cell cycle analysis by flow cytometry showed a slow traverse through the S phase in the L-PAM-alone-treated cells. However, this phenomenon was more prominent in the THNLA-1 plus L-PAM-treated cells. Under aerobic co-incubation conditions with L-PAM, no difference was observed in the cell cycle of L-PAM-alone-treated cells vs. THNLA-1 plus L-PAM-treated cells. Significantly increased apoptosis was observed in the hypoxia-pretreated cells with THNLA-1, 12 and 24 h posttreatment. Comet and alkaline elution assay analysis showed increased DNA cross-links in the hypoxia-pretreated cells with THNLA-1 compared to the L-PAM-alone-treated cells. Finally, potential lethal damage repair was totally suppressed only in the hypoxia-pretreated cells with THNLA-1. In conclusion, DNA damage and hindrance in its repair are the most important mechanisms in the potentiation of L-PAM by THNLA-1, under hypoxic pretreatment conditions. |
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Authors:
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M V Papadopoulou; M Ji; S H Khan; W D Bloomer |
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Publication Detail:
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Type: Comparative Study; Journal Article |
Journal Detail:
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Title: Oncology research Volume: 11 ISSN: 0965-0407 ISO Abbreviation: Oncol. Res. Publication Date: 1999 |
Date Detail:
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Created Date: 2000-06-09 Completed Date: 2000-06-09 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9208097 Medline TA: Oncol Res Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 345-57 Citation Subset: IM |
Affiliation:
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The Radiation Medicine Institute, Evanston Northwestern Healthcare, IL 60201, USA. mvp499@anima.nums.nwu.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents, Alkylating / pharmacology* Apoptosis / drug effects Buthionine Sulfoximine / pharmacology Cell Cycle / drug effects Cell Hypoxia / drug effects Cell Line / drug effects Comet Assay Cricetinae Cricetulus DNA / biosynthesis, drug effects DNA Damage / drug effects DNA Repair / drug effects Drug Synergism Glutathione / metabolism Melphalan / pharmacology* Protein Biosynthesis Proteins / drug effects RNA / biosynthesis, drug effects Radiation-Sensitizing Agents / pharmacology* Tacrine / analogs & derivatives*, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Alkylating; 0/Proteins; 0/Radiation-Sensitizing Agents; 148-82-3/Melphalan; 163714-83-8/9-(3-(2-nitro-1-imidazolyl)propylamino)-1,2,3,4-tetrahydroacridine; 321-64-2/Tacrine; 5072-26-4/Buthionine Sulfoximine; 63231-63-0/RNA; 70-18-8/Glutathione; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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