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

Julia, Anne Marie; Roché, H.; Berlion, Maryse; Lucas, Catherine; Milano, G.; Robert, Jacques; Bizzari, Jean-Pierre; Canal, Pierre

doi:10.1038/bjc.1994.168

Cited by 16 publications

(8 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, this study shows that, using this schedule, effective concentrations of S9788 can be reached at nontoxic doses in patients. The high total body clearance and short initial half-life of S9788 that we found support the rationale for prolonged infusion over bolus infusion of S9788, as was suggested by others (Perez et al, 1993;Julia et al, 1994;Soudon et al, 1995). Compared with treatment with doxorubicin alone, patients treated with doxorubicin plus S9788 experienced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia, but not in the occurrence or severity of other toxicities.…”

Section: Discussionsupporting

confidence: 85%

“…Structurally, S9788 does not belong to any of the classes of compounds known to reverse MDR. It increases the intracellular accumulation and retention of doxorubicin, vincristine and vinblastine in resistant cell lines displaying the Pgp-mediated MDR phenotype Efferth et al, 1993;Hill et al, 1993;Huet et al, 1993;Julia et al, 1994;Merlin et al 1994). These studies also showed that modulation of resistance is obtained in both drug-selected and inherently resistant cell lines, and that S9788 is more potent than verapamil at equimolar concentrations.…”

mentioning

confidence: 98%

“…It has been hypothesized that, in addition to P-gp binding, S9788 may also act by altering the intracellular drug distribution (Merlin et al, 1994;Sebille et al, 1994). Although the optimum schedule has not yet been defined, a prolonged infusion of S9788 starting before and maintained after the administration of chemotherapy appears to be more effective than a single-bolus infusion (Perez et al, 1993;Julia et al, 1994;Soudon et al, 1995). S9788 has been shown not to interfere with doxorubicin plasma pharmacokinetics (de Valeriola et al, 1997).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer

Punt

Voest²,

Tueni³

et al. 1997

Br J Cancer

Self Cite

View full text Add to dashboard Cite

Summary S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m-2 over 30 min followed by doxorubicin given at 50 mg m-2 as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m-2 in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24-or 48-h Holter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severe cardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results administered in combination with doxorubicin.Inherent or acquired multidrug resistance (MDR) is an important cause of failure of cancer chemotherapy. Several mechanisms responsible for MDR have been described, and the most extensively investigated is the expression of the product of the MDRJ gene, P-glycoprotein (P-gp) or P-170 (Roninson, 1992). This protein acts as an efflux pump for a number of commonly used cytotoxic agents, e.g. doxorubicin, vincristine, vinblastine and actinomycin D. Different compounds have been shown to reverse P-gp-mediated MDR, including calcium channel antagonists (verapamil), calmodulin inhibitors (quinine, quinidine), oestrogen receptor antagonists (tamoxifen), steroids and immunomodulators (cyclosporin A). The mechanisms by which these drugs influence MDR have not always been identified. The clinical use of these MDR modulators is hampered by the toxic side-effects that occur when the suprapharmacological doses required to achieve significant reversal of MDR are used (Pennock et al, 1991;Raderer and Scheithauer, 1993

show abstract

Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 98%

mentioning

confidence: 99%

See 1 more Smart Citation

Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer

Punt

Voest²,

Tueni³

et al. 1997

Br J Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…MCF7/DOX cells (Julia et al 1994) were obtained from Dr F Pinguet (CRLC, Montpellier, France). Monolayer cell cultures were grown in Ham's F-12/Dulbecco's modified Eagle's medium (1:1) (F12/DMEM) supplemented with 10% foetal calf serum (FCS) (Life Technologies, Cergy-Pontoise, France) and antibiotics.…”

Section: Plasmids Containing P21mentioning

confidence: 99%

Oestrogen receptor alpha increases p21(WAF1/CIP1) gene expression and the antiproliferative activity of histone deacetylase inhibitors in human breast cancer cells

Margueron¹,

Licznar²,

Lazennec³

et al. 2003

Journal of Endocrinology

View full text Add to dashboard Cite

We analysed the antiproliferative activity of various histone deacetylase (HDAC) inhibitors such as trichostatin A (TSA) on human breast cancer cells. We observed a lower sensitivity to HDAC inhibition for oestrogen receptor negative (ER ) versus positive (ER+) cell lines. This differential response was associated neither with a modification of drug efflux via the multidrug resistance system nor with a global modification of histone acetyltransferase (HAT)/HDAC activities. In contrast, we demonstrated that in ER+ breast cancer cells the p21 WAF1/CIP1 gene was more sensitive to TSA regulation and was expressed at higher levels. These differences were observed both in transient transfection experiments and on the endogenous p21 WAF1/CIP1 gene. The Sp1 transcription factor, which was shown to interact in vitro with both class I and class II HDACs, is sufficient to confer the differential sensitivity to TSA and participated in the control of p21 WAF1/CIP1 basal expression. Finally, re-expression of ER following adenoviral infection of ER breast cancer cells increased both p21WAF1/CIP1 protein accumulation and the growth inhibitory activity of TSA. Altogether, our results highlight the key role of ER and p21 WAF1/CIP1 gene expression in the sensitivity of breast cancer cells to hyperacetylating agents.

show abstract

“…This triazineaminopiperidine derivative has no structural similarities to other known MDRmodulating agents. In vitro, S9788 has been shown to effectively reverse MDR-dependent resistance to doxorubicin, vincristine and a variety of cytotoxic drugs [19,20]. At a concentration of 5 uM it was 2.5-317 times more potent than verapamil in reversing MDR [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

Stupp¹,

Bauer²,

Pagani³

et al. 1998

Annals of Oncology

View full text Add to dashboard Cite

SummaryBackground; S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity.Patients and methods: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m 2 on the 30 minutes infusion, and to 144 mg/m 2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined.Results: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788

show abstract

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

Cited by 16 publications

References 26 publications

Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer

Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer

Oestrogen receptor alpha increases p21(WAF1/CIP1) gene expression and the antiproliferative activity of histone deacetylase inhibitors in human breast cancer cells

Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

Contact Info

Product

Resources

About