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[Pharmacological properties of S9788, a new modulator of multidrug resistance]
Abstract:
S9788, a triazinoaminopiperidine derivative, is a new multidrug resistance (MDR) modulating agent. S9788 activity was investigated on 12 tumoral cell lines, either sensitive or resistant, with respect to different cytotoxic agents: adriamycin (ADR), daunorubicin (DNR), viscristine (VCR) and vinblastine (VLB). S9788 is 1.5 to 30 times more active than verapamil and 1.2 to 119 times more active than cyclosporin, depending on both the cell line and the antitumoral agent. Reversion of resistance to ADR was nearly complete in K562R at 5 microM S9788 (F Res = 30; F Rev = 20). In MCF7/ADR cell line, highly resistant to ADR, S9788 (1 microM) partially reversed the resistance (F Res = 917; F Rev = 110). S9788, when associated with either ADR or vinca-alcaloïds, had a slight effect on ovarian carcinoma (OVCCR1, NIHOVCAR3, SKOV3, IGROV1), sarcoma (SARCCR2) and breast adenocarcinoma (CAL51, CAL85-1/2) cell lines which poorly expressed P glycoprotein (F Rev = 1-3). In K562R cells, S9788 (5 microM) restored DNR accumulation (measured by flow cytometry) to a level similar to that measured in sensitive cells K562S. A novel method of microspectrofluorimetry showed that S9788 modified the kinetic and the intracellular distribution of cytotoxic agent, leading to its accumulation in resistant cell nuclei. Concomitant incubation of S9788 and cytotoxic agent, followed by a postincubation with S9788 alone, significantly increased MDR reversion. Therefore, S9788 should be used as an adjuvant of polychemotherapy against tumors displaying MDR phenotype.
Insights
S9788, a novel multidrug resistance modulator, effectively reverses resistance to chemotherapy agents like adriamycin and vinca-alkaloids in various cancer cell lines. This agent enhances drug accumulation in resistant cells, showing promise as an adjuvant therapy.
Area of Science:
- Pharmacology
- Cancer Biology
- Drug Discovery
Context:
- Multidrug resistance (MDR) significantly limits the efficacy of chemotherapy.
- Novel agents are needed to overcome MDR in cancer treatment.
- S9788 is a new triazinoaminopiperidine derivative investigated for its MDR modulating properties.
Purpose:
- To evaluate the efficacy of S9788 in reversing multidrug resistance in various cancer cell lines.
- To compare S9788's activity with existing MDR modulators like verapamil and cyclosporin.
- To elucidate the mechanism of action of S9788 in restoring sensitivity to cytotoxic agents.
Summary:
- S9788 demonstrated significant MDR modulating activity across 12 sensitive and resistant cell lines against adriamycin, daunorubicin, viscristine, and vinblastine.
- Its potency exceeded verapamil and cyclosporin, with nearly complete resistance reversion in K562R and MCF7/ADR cells.
- S9788 restored daunorubicin accumulation in resistant cells and altered drug distribution to cell nuclei, suggesting a novel mechanism.
Impact:
- S9788 shows potential as an adjuvant therapy to enhance polychemotherapy effectiveness against MDR tumors.
- The findings support the clinical investigation of S9788 for improving cancer treatment outcomes.
- This research contributes to understanding and overcoming chemotherapy resistance mechanisms.