Journal article
RELATIONSHIP BETWEEN CYTO-TOXICITY, DRUG ACCUMULATION, DNA DAMAGE AND REPAIR OF HUMAN OVARIAN-CANCER CELLS TREATED WITH DOXORUBICIN - MODULATION BY THE TIAPAMIL ANALOG RO11-2933
Cancer chemotherapy and pharmacology, Vol.25(2), pp.77-83
01/01/1989
DOI: 10.1007/BF00692343
PMID: 2598402
Abstract
The effect of N-(3,4-dimethoxyphenyl)N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride (RO11-2933), an analog of the calcium channel blocker tiapamil, on doxorubicin (DOX)-induced cytotoxicity and DNA damage in human ovarian cancer cells sensitive and resistant to DOX was investigated. A2780-DX2, A2780-DX3, and A2780-DX6 cell sublines were characterized by 7-, 26-, and 48-fold resistance after 2 h DOX exposure and 30-, 50-, and 500-fold resistance after 72 h DOX exposure, respectively. Increased drug efflux resulting in a lower intracellular drug accumulation, decreased DOX-induced DNA single-strand breaks (DNA SSBs), and rapid DNA repair correlated with the degree of resistance. In addition, DNA SSBs were rapidly repaired within 8 h in A2780-DX3 cells, whereas no significant repair of DNA SSBs was observed in sensitive cells. In comparison with verapamil, RO11-2933 was found to reverse DOX resistance at lower and nontoxic concentrations (2 μM as compared with 10 μM verapamil). This reversion was complete in cells with a low degree of resistance (A2780-DX1 and A2780-DX2) but partial in highly resistant cells (A2780-DX3 and A2780-DX6), and continuous exposure to RO11-2933 was essential for optimal reversal of drug resistance. Interestingly, RO11-2933 was found to inhibit the repair of DNA SSBs induced by DOX but not those induced by X-ray. These results suggest that the potentiation of DNA SSBs and the specific inhibition of DNA repair by RO11-2933 in multidrug-resistant cells could be of particular value in overcoming MDR in the clinic. © 1989 Springer-Verlag.
Details
- Title: Subtitle
- RELATIONSHIP BETWEEN CYTO-TOXICITY, DRUG ACCUMULATION, DNA DAMAGE AND REPAIR OF HUMAN OVARIAN-CANCER CELLS TREATED WITH DOXORUBICIN - MODULATION BY THE TIAPAMIL ANALOG RO11-2933
- Creators
- M. Abdellah Alaoui JamaliMing-biao Yin - Roswell Park Cancer InstituteAlessandra Mazzoni - Roswell Park Cancer InstituteIssam BankusliYoucef M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Cancer chemotherapy and pharmacology, Vol.25(2), pp.77-83
- Publisher
- Springer Nature
- DOI
- 10.1007/BF00692343
- PMID
- 2598402
- ISSN
- 0344-5704
- eISSN
- 1432-0843
- Number of pages
- 7
- Grant note
- CA 18420; CA 21071 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P01CA021071 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 01/01/1989
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359945002771
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