Mechanisms involved in the potentiation of melphalan by the bioreductive compound THNLA-1 in vitro.

Abstract

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.

• Authors: M V Papadopoulou, M Ji, S H Khan, W D Bloomer
• Journal: Oncology research (Oncol Res) Vol. 11 Issue 8 Pg. 345-57 ( 1999) ISSN: 0965-0407 [Print] United States
• PMID: 10803738 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antineoplastic Agents, Alkylating
• Proteins
• Radiation-Sensitizing Agents
• 9-(3-(2-nitro-1-imidazolyl)propylamino)-1,2,3,4-tetrahydroacridine
• Tacrine
• Buthionine Sulfoximine
• RNA
• DNA
• Glutathione
• Melphalan

Topics

• 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)