Reversal of P-glycoprotein-mediated multidrug resistance by XR9051, a novel diketopiperazine derivative

Abstract

Summary 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) was identified as a potent modulator of P-gtycoprotein-mediated multidrug resistance (MDR) following a synthetic chemistry programme based on a natural product lead compound. The Correspondence to: P Chartton has been well documented. but at present its role in solid tumours is less clear.A broad range of compounds has been identified that are able to rexverse the MDR phenotype by interacting with P-gp and blocking the efflux of cvtotoxics from cells. These compounds include peptides. steroids. calcium channel blockers. cardiox ascular drugys and immunosuppressix e and antifungal agents (reviewed by Ford. 1996). Their use has been limited bx the inabilitN to achiexe clinically effectixe plasma or tumour concentrations to inhibit P-gp function before non-specific. deleterious toxicities are encountered (Lum et al. 1993: Raderer and Scheithaeur. 1993). The requirement for more selectixe and potent agents as resistance modifiers has led to the identification of a number of secondgeneration modulators. such as a non-immunosuppressix e cxclosporin derivatixe SDZ PSC 833 (Boesch et al. 1991). an acridonecarboxamide derixatixe. GG918 (Hvafil et al. 1993). and a triazinoaminopiperidine derixitixe. S9788 (Pierre et al. 19921. These compounds are currentlx in clinical trial. The demonstration that potent modulators can oxercome resistance in P-gp-oxerexpressing cell lines and tumours is a vital step in answerinc the question of whether inhibition of P-gp function w ill be an effectix e therapeutic strategy.XR9051 (Figure 1) xas identified from a medicinal chemistrx programme based on a diketopiperazine originally isolated from the fermentation of a Streptomyces species. In this paper. we descnrbe the in X itro profile of XR905 1. wxhich illustrates its promise as a nexx drug for the treatment of MDR tumours. 885

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

“…The present in vivo studies with XR9051 have shown that this modulator is potent and welltolerated at effective doses. These results are in agreement with the in vitro results (Dale et al, 1998). Co-administration of XR9051 has shown clear dose-dependent enhancement of anti-tumour activity of five cytotoxic agents (vincristine, doxorubicin, epirubicin, Paclitaxel and etoposide) in mice bearing both murine and human tumour xenografts exhibiting multidrug resistance.…”

“…It restores sensitivity of syngeneic and human tumour xenografts to a range of cytotoxic agents at doses that are well-tolerated. The data reported here fully support our previous results demonstrating that XR9051 (300-500 nM) fully sensitized a panel of resistant cells to a broad range of cytotoxic drugs (Dale et al, 1998). Furthermore, the activity of XR9051 persisted in vitro for an extended period following removal from the culture medium.…”

“…have been extensively used for evaluating the efficacy of MDR modulators (Tsuruo et al, 1981;Shinoda et al, 1989;Boesch et al, 1991;Hyafil et al, 1993). We have shown in previous studies that in vitro co-exposure to XR9051 fully restored sensitivity of the resistant cells (P388/DX Johnson) to several cytotoxic agents (Dale et al, 1998). The in vivo studies with P388/P-sensitive cells implanted i.p.…”

“…In vitro, co-exposure to 300-500 nM XR9051 fully reverses resistance to a range of cytotoxic drugs in several murine and human P-gp-expressing cell lines (Dale et al, 1998). The present studies were performed to evaluate the in vivo efficacy and pharmacokinetic profile of XR9051.…”

In vitro and in vivo evaluation of WK‐X‐34, a novel inhibitor of P‐glycoprotein and BCRP, using radio imaging techniques

“…2,14 More recently, third generation modulators have been developed with reduced toxicities, increased specificity for Pgp and inhibition in the nanomolar range. 15,16 Unfortunately, to date clinical evaluations of many highly selective second and third generation modulators have resulted in conflicting results. 17 Their limitations to clinical applications include alterations in the pharmacokinetic profile of antineoplastic agents resulting in increased toxicities and inherent toxicities of the inhibitors themselves.…”