Evaluation of S9788 as a potential modulator of drug resistance against human tumour sublines expressing differing resistance mechanisms in vitro.
Significant activity has been identified using S9788, a triazineaminopiperidine derivative, as a new modulator of multi-drug resistance against a series of drug-resistant human tumour-cell lines in vitro. Maximal non-cytotoxic concentrations (i.e., those resulting in < or = 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/VLB100, 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-1) 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.
Hill
B T
BT
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, UK.
van der Graaf
W T
WT
Hosking
L K
LK
de Vries
E G
EG
Mulder
N H
NH
Whelan
R D
RD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000032:analysis; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D010880:Piperidines; D014227:Triazines; C077022:S 9788; D014750:Vincristine; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil