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Cross-Resistance to Cisplatin in Cells Resistant to Photofrin-mediated Photodynamic Therapy¹

Ontario Cancer Treatment and Research Foundation, Hamilton Regional Cancer Centre, and Department of Pathology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

This study shows that a Photofrin-induced photodynamic therapy-resistant variant (RIF-8A) of a radiation-induced fibrosarcoma-1 cell line (RIF-1) is cross-resistant to cis-diamminedichloroplatinum(II) (cisplatin). This is the first study to show cross-resistance to cisplatin in photodynamic therapy-resistant variants in vitro. Resistance does not appear to be the result of elevated glutathione levels since neither the resistant variant (RIF-8A) nor the parental line (RIF-1) varied in total glutathione levels. However, cisplatin-DNA adduct levels differed significantly between the two cell types. Immediately following a 1-h exposure to cisplatin (50 µM), RIF-1 cells contained 44.6 ± 2.0 (SEM) pg platinum/µg DNA while RIF-8A cells contained 24.8 ± 6.3 pg platinum/µg DNA. In addition, the resistant variant had decreased plasma and mitochondrial membrane potentials. The plasma and mitochondrial membranes of the resistant variant accumulated 3- and 3.6-fold less rhodamine 123, respectively. The difference in rhodamine 123 accumulation could not be attributed to elevated P-glycoprotein expression because both the parental line and the variant contained similar amounts of P-glycoprotein. In conclusion, alterations in the plasma and/or mitochondrial membrane potentials may provide cells with a survival advantage when challenged with either photodynamic therapy or cisplatin in vitro. This appears to be a novel mechanism of resistance.

¹ Supported by a grant from the Medical Research Council of Canada (MA-10409) and NIH Program Grant (Project 3) CA 43892 to G. S.

² Present address: Ontario Cancer Institute, Toronto, Ontario, Canada, M4X 1K9.

³ To whom requests for reprints should be addressed, at Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, Ontario, Canada, L8V 5C2.

Received 3/ 7/94. Accepted 4/ 5/94.

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