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Evaluation of S9788 as a potential modulator of drug resistance against human tumour sublines expressing differing resistance mechanisms In Vitro
Author(s) -
Hill Bridget T.,
van der Graaf Winette T. A.,
Hosking Louise K.,
De vries Elisabeth G. E.,
Mulder Nanno H.,
Whelan Richard D. H.
Publication year - 1993
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910550225
Subject(s) - p glycoprotein , cytotoxicity , vinblastine , verapamil , clonogenic assay , chemosensitizer , multiple drug resistance , pharmacology , cell culture , in vitro , drug resistance , vincristine , mtt assay , biology , medicine , biochemistry , chemotherapy , microbiology and biotechnology , genetics , calcium , cyclophosphamide
Significant activity has been identified using S9788, a triazineaminopiperidine derivative, as a new modulator of multidrug resistance against a series of drug‐resistant human tumour‐cell lines in vitro . Maximal non‐cytotoxic concentrations ( i.e. , those resulting in ≤ 10% cytotoxicity) of S9788 or verapamil were tested in combination with vinblastine, Adriamycin or vincristine and cytotoxicity was evaluated using a clonogenic assay, or the metabolic dye reduction MTT assay, or by monitoring growth inhibition. Under these conditions, the extent of resistance modulation by verapamil and by S9788 was comparable in the various tumour cell lines tested, although a definite concentration‐dependent modulation was noted with both compounds. The highest dose‐modification factors were noted in the highly vinblastine‐resistant classic multi‐drug‐resistant subline CEM/VLB 100, although resistance reversal was only partial. Resistance modulation by both verapamil and S9788 was noted in 4 drug‐selected resistant sublines and 4 “intrinsically” resistant human tumour cell lines, which all exhibited significant P‐glycoprotein expression. In contrast, in 2 drug‐resistant human tumour sublines (GLC4/ADR and CEM/ VM‐I) characterized by altered topoisomerase‐II activity and proving to be P‐glycoprotein‐negative, no resistance modulation relative to parental cells was observed. These data are consistent with the proposal that resistance modulation is mediated by interaction between S9788 and P‐glycoprotein and support its clinical evaluation in patients with P‐glycoprotein‐positive tumours.