[In vitro characterization of S9788, a new modulator of multidrug resistance].

Abstract

S9788, a new triazinoaminopiperidine derivative, was 250-fold more active than verapamil in sensitizing DC-3F/AD cells to actinomycin D. This multidrug-resistance modulating activity of S9788 was confirmed on DC-3F/AD, P388/ADR-10, P388/VCR-20, KB/A1, K562/R, S1/tMDR, and COLO320DM cells, with respect to actinomycin D, doxorubicin, vincristine, vinblastine and etoposide. S9788 is 2-255-fold more active than verapamil, depending on the cell line and the cytotoxic agent used, potentiating preferentially the cytotoxicity of the vinca-alkaloid derivatives. S9788 only had a slight effect on vincristine accumulation and retention by parental sensitive cells, as well as on their sensitivity to cytotoxic drugs. S9788 fully restored vincristine accumulation and retention by S1/tMDR cells (S1 cells transfected by the mdr 1 gene) to a level similar to that measured in S1 cells, leading to a blockade in the G2 + M phase of the cell cycle. Therefore, S9788 enhances vincristine activity by restoring its cellular accumulation in resistant cells. After a short incubation period of cells with vincristine (4 h), a condition close to the clinical administration of this cytotoxic agent, a post-incubation for 20 hours more with 5 microM S9788, fully restored the sensitivity of S1/tMDR cells to vincristine. After an exposure of 4 hours at equal concentrations, the accumulation of S9788 was 13-fold that of verapamil in S1/tMDR cells, and 20 hours after the removal of the modulators, S9788 was retained at a concentration 20-fold that of verapamil. S9788 is therefore a powerful new modifier of the P-gp-mediated multidrug-resistance, which by its pharmacological properties (cellular kinetics and activity), might be used in combination with existing chemotherapy against tumors displaying the MDR phenotype.

• Authors: V Pérez, A Pierré, S Léonce, M Anstett, J F Prost, G Atassi
• Journal: Bulletin du cancer (Bull Cancer) Vol. 80 Issue 4 Pg. 310-25 (Apr 1993) ISSN: 0007-4551 [Print] France
• Vernacular Title: Caractérisation in vitro de l'activité du S9788, un nouveau modulateur de la résistance multidrogue.
• PMID: 8173185 (Publication Type: Comparative Study, English Abstract, Journal Article)

Chemical References

• Antineoplastic Agents
• Piperidines
• Triazines
• S 9788
• Verapamil

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Cycle (drug effects)
• Drug Resistance (genetics)
• Drug Screening Assays, Antitumor (methods)
• Humans
• In Vitro Techniques
• Mice
• Neoplasms (drug therapy)
• Neoplasms, Experimental (drug therapy)
• Phenotype
• Piperidines (pharmacology)
• Triazines (pharmacology)
• Tumor Cells, Cultured (drug effects)
• Verapamil (pharmacology)