Oestrogen potentiates topoisomerase-II-mediated cytotoxicity in an activated subpopulation of human breast cancer cells: Implications for cytotoxic drug resistance in solid tumours
✍ Scribed by R. J. Epstein; P. J. Smith; J. V. Watson; C. Waters; N. M. Bleehen
- Publisher
- John Wiley and Sons
- Year
- 1989
- Tongue
- French
- Weight
- 811 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Primary resistance to chemotherapeutic agents is a major problem in the management of advanced cancer. By using oestrogen to modulate the topoisomerase II content of T-47D human breast cancer cells, we show here that cell subpopulations resistant to the topoisomerase-ll-interactive drug VP 16 (etoposide) can be identified and quantified using singlecell analytical techniques. lmmunohistochemical studies reveal topoisomerase II to be present in approximately 10% of control cells compared with 30% of oestrogen-stimulated cells, and this difference is reflected in the proportions of cells exhibiting VP 16-induced cell-cycle delay. This moderate increase in overall cell sensitivity is accompanied by massive enhancement of clonogenic cell kill, suggesting that oestrogen enhances VP I6 cytotoxicity by recruiting a clonogenic cell subpopulation characterized by increased topoisomerase II content. Flow cytometry confirms that the increase in topoisomerase II is localized to an activated G,-phase cell subset. We conclude that (i) single-cell analysis of cellular topoisomerase II content is predictive of VP 16 chemosensitivity; (ii) the existence of resistant tumour-cell subpopulations does not necessarily indicate the presence of phenotypically divergent subclones; and (iii) rational strategies for eliminating tumour resistance may be based on biological manipulation of specific cytotoxic drug targets.