Abstract | BACKGROUND: METHODS: Three human ovarian carcinoma cell lines of different sensitivity to TNF-alpha and/or CDDP were selected for the study and consisted of 222, a TNF/CDDP-sensitive line, 222TR (TNF-resistant), a TNF-resistant, CDDP-sensitive line, and AD10, a TNF-sensitive, CDDP-resistant line. Cytotoxicity was determined by the microculture tetrazolium dye assay. RESULTS: Synergy in cytotoxicity was achieved in all three lines treated with a combination of TNF-alpha and CDDP. Cytotoxicity by either TNF-alpha or CDDP or by both TNF-alpha and CDDP was inhibited in the presence of either Phe or BHA. Pretreatment of tumor cells with either Phe or BHA for up to 4 hours, washed and followed by the addition of the cytotoxic agents (alone or combined), resulted in no inhibitory effect. Pretreatment of the cells with the cytotoxic agent for up to 2 hours, washed and then followed by the addition of Phe, resulted in significant inhibition of cytotoxicity. In contrast to Phe, the addition of BHA as late as 12 hours post pretreatment of the cells with the cytotoxic agent(s) still inhibited cytotoxicity. These results demonstrated that free radicals are involved in cytotoxicity mediated by a single agent, and in synergy with both agents. Further, the results demonstrated that Phe acts at an early stage of the cytotoxic pathway and that BHA acts at both an early and a late stage of the cytotoxic pathway. CONCLUSIONS: These results demonstrated that both TNF-alpha and CDDP rapidly stimulate the induction of free radicals but a lag of several hours was necessary to initiate the irreversible program of cell death. Further, the studies demonstrated that synergy and reversal of drug resistance in ovarian tumor cells by TNF-alpha and CDDP, used in combination, share the same pathway of cytotoxicity as that mediated by TNF-alpha or CDDP used as a single agent.
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Authors | R Uslu, B Bonavida |
Journal | Cancer
(Cancer)
Vol. 77
Issue 4
Pg. 725-32
(Feb 15 1996)
ISSN: 0008-543X [Print] United States |
PMID | 8616765
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Antioxidants
- Free Radicals
- Multienzyme Complexes
- Oxazoles
- Pyrones
- Tumor Necrosis Factor-alpha
- phenoxan
- Butylated Hydroxyanisole
- Oxidoreductases
- Electron Transport Complex II
- Succinate Dehydrogenase
- NAD(P)H Dehydrogenase (Quinone)
- Cisplatin
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Topics |
- Antineoplastic Agents
(toxicity)
- Antioxidants
(pharmacology)
- Butylated Hydroxyanisole
(pharmacology)
- Cell Line
- Cell Survival
(drug effects)
- Cisplatin
(toxicity)
- Drug Synergism
- Electron Transport Complex II
- Female
- Free Radicals
- Humans
- Mitochondria
(metabolism)
- Multienzyme Complexes
(antagonists & inhibitors)
- NAD(P)H Dehydrogenase (Quinone)
(antagonists & inhibitors)
- Ovarian Neoplasms
- Oxazoles
(pharmacology)
- Oxidoreductases
(antagonists & inhibitors)
- Oxygen Consumption
- Pyrones
(pharmacology)
- Succinate Dehydrogenase
(antagonists & inhibitors)
- Tumor Cells, Cultured
- Tumor Necrosis Factor-alpha
(toxicity)
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