In vivo evidence of complete circumvention of vincristine resistance by a new triazinoaminopiperidine derivative S 9788 in P388/VCR leukemia model

Cros, S.; Guilbaud, Nicolas; Berlion, Maryse; Dunn, Theresa; Regnier, G.; Dhainaut, A.; Atassi, Ghanem; Bizzari, Jean-Pierre

doi:10.1007/bf00685604

Cited by 16 publications

(6 citation statements)

References 10 publications

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“…It is twice as active and approximately seven times more potent than verapamil Pierre et al, 1992). In vivo, S9788 restored the anti-tumour activity of vincristine in a dosedependent manner in the P388/VCR leukaemia model (Cros et al, 1992).…”

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confidence: 91%

Multidrug resistance circumvention by a new triazinoaminopiperidine derivative S9788 in vitro: definition of the optimal schedule and comparison with verapamil

Julia

Roché²,

Berlion³

et al. 1994

Br J Cancer

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Summary The current work was undertaken to investigate the importance of exposure sequence and duration in achieving the maximum reversal action of S9788 on doxorubicin (DOX) cytotoxicity against cells that exhibit the (MDR) multidrug resistance phenotype: the MCF7/DOX cell line. Accumulation and release of DOX were examined in this cell line. The reversal effect was compared with that obtained with verapamil. S9788 activity was schedule dependent: when comparing incubation with S9788 before or after treatment with DOX, the best reversal factor was obtained in the case of a post-treatment incubation (65.6 ± 7.7 vs 20.8 ± 7.0). S9788 was a more potent modulating agent than verapamil, whatever the schedule of exposure of the cells to the reversal agent. The reversal of resistance after short-term DOX exposures was caused not only by prolonged cellular accumulation of DOX, but also by its prolonged retention after transfer of cells to DOX-free medium. A relationship was noted between cellular exposure to DOX and the cytotoxic effect, and so the reversal of resistance induced by S9788 appears to be directly linked to the level of cell exposure to DOX. This work provided a rationale for improving the schedule of administration of S9788 in clinical trials.

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confidence: 91%

Multidrug resistance circumvention by a new triazinoaminopiperidine derivative S9788 in vitro: definition of the optimal schedule and comparison with verapamil

Julia

Roché²,

Berlion³

et al. 1994

Br J Cancer

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“…Thereby, structure-activity relationship analyses (42) led to the development of new compounds, including the triazinoaminopiperidine derivative S9788 (9). This compound was efficient in several experimental models, in vitro and in vivo (8,26,39), and recently entered into clinical evaluation for the treatment of solid tumors (5).…”

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confidence: 99%

Influence of S9788, a new modulator of multidrug resistance, on the cellular accumulation and subcellular distribution of daunorubicin in p‐glycoprotein‐expressing MCF7 human breast adenocarcinoma cells

et al. 1995

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A triazjnoaminopiperidine derivative synthesized as a modulator of multidrug resistance, S9788, was investigated in the human breast adenocarcinoma MCF7"= cell line expressing P-glycoprotein. In addition to being less sensitive to daunorubicin, the resistant cell line showed dramatic alterations in the subcellular distribution of daunorubicin, as observed via fluorescence microscopy and quantified via tritiated daunorubicin nuclear distribution analysis. Compared to verapamil and cyclosporin A at 2 and 5 pmoyliter, S9788 proved to be more potent in restoring the cellular accumulation and the subcellular distribution of daunorubicin in the resistant cells. Significant activity of S9788 was observed at 2 FmoYliter, which is clinically achievable, and S9788 restored the nuclear distribution of the drug to the level observed in the parental sensitive cell line. Consequently, the restoration of the cytotoxicity of daunorubicin by S9788 was nearly complete (>!lo%) at 2 pmoyliter, whereas cyclosporin A reached this level of activity at 5 VmoVliter, and verapamil was always less active at both concentrations. These results suggest that the modulation of multidrug resistance by S9788 is not only related to the enhancement of the cellular accumulation but also especially by the restoration of the subcellular distribution of the drugs to their nuclear sites of action.

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“…The resistance factor of this cell line to vincristine was low (22-fold) compared to the cell line used in our studies (70-fold). Several second-generation MDR modulators have been reported to exhibit in vivo efficacy in murine tumour models including MS-209 (Sato et al, 1995), S9788 (Cros et al, 1992), the non-immunosuppressive cyclosporine A analogue, PSC 833, which showed significant oral activity (Boesch et al, 1991), GG918 (Hyafil et al, 1993) and LY335979 (Dantzig et al, 1996). However, direct comparison of the potency between modulators is difficult due to differences in tumour growth rates, treatment schedules and experimental design.…”

Section: Discussionmentioning

confidence: 99%

In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance

Mistry¹,

Plumb

Eccles

et al. 1999

Br J Cancer

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Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug resistance (MDR) in tumours. We have previously reported that XR9051 ( N -(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated the in vivo efficacy of this novel modulator in a panel of murine and human tumour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedules were well-tolerated. Following intravenous administration in mice, XR9051 is rapidly distributed and accumulates in tumours and other tissues. In addition, the compound is well-absorbed after oral administration. These data suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien. © 1999 Cancer Research Campaign

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In vivo evidence of complete circumvention of vincristine resistance by a new triazinoaminopiperidine derivative S 9788 in P388/VCR leukemia model

Cited by 16 publications

References 10 publications

Multidrug resistance circumvention by a new triazinoaminopiperidine derivative S9788 in vitro: definition of the optimal schedule and comparison with verapamil

Multidrug resistance circumvention by a new triazinoaminopiperidine derivative S9788 in vitro: definition of the optimal schedule and comparison with verapamil

Influence of S9788, a new modulator of multidrug resistance, on the cellular accumulation and subcellular distribution of daunorubicin in p‐glycoprotein‐expressing MCF7 human breast adenocarcinoma cells

In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance

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