SDZ 280-446, a novel semi-synthetic cyclopeptolide: in vitro and in vivo circumvention of the P-glycoprotein-mediated tumour cell multidrug resistance

Abstract

Summary SDZ 280-446 is a semi-synthetic derivative of a natural cyclic peptolide. Its ability to sensitise in vitro tumour cells whose resistance is due to P-glycoprotein-mediated anticancer-drug efflux was shown using four different pairs of parental drug-sensitive (Par-) and multidrug-resistant (MDR-) cell lines, from three different species (mouse, human, Chinese hamster) representing four different cell lineages (monocytic leukaemia, nasopharyngeal epithelial carcinoma, colon epithelial carcinoma, ovary fibroblastoid carcinoma), and using four different drug classes (colchicine, vincristine, daunomycin/doxorubicin and etoposide). By measuring its capacity to restore normal drug sensitivity of MDR-cells in culture in vitro, it appeared that SDZ 280-446 belongs to the same class of very potent chemosensitisers as the cyclosporin derivative SDZ PSC 833: both are about one order of magnitude more active than cyclosporin A (CsA), which is itself about one order of magnitude more active than other known chemosensitisers (including verapamil, quinidine and amiodarone which have already entered clinical trials in MDR reversal). Low concentrations of SDZ 280-446 could also restore cellular daunomycin retention in MDR-P388 cells to the levels found in the Par-P388 cells. SDZ 280-446 was also effective as a chemosensitiser when given orally in vivo. In a syngeneic mouse model, combined therapy with vinca alkaloids given i.p. and SDZ 280-446 given per os for 5 consecutive days significantly prolonged the survival of MDR-P388 tumour-bearing mice, when compared with mice receiving vinca alkaloids alone. Another protocol, using three cycles of i.p. doxorubicin at 4 day intervals, could also not increase MDR-P388 tumour-bearing mouse survival unless the mice received SDZ 280-446 orally 4h before each doxorubicin injection. Though only very few combined therapy treatment protocols have been tested so far, clear increases in survival time of MDR-tumour-bearing mice were regularly obtained, leaving hope for major improvement of the therapy using other dosing schedules.

Growth inhibition, cytokinesis failure and apoptosis of multidrug-resistant leukemia cells after treatment with P-glycoprotein inhibitory agents

“…9 The calcium channel blocker verapamil was the first agent that was shown to modify MDR in vivo and in vitro, 10 but unfortunately the MDR modulating activity required concentrations that are associated with severe cardiac toxicity in patients. 11 Therefore, a new generation of highly specific and potent Pgp Correspondence: G Lehne, Department of Clinical Pharmacology, Rikshospitalet, The National Hospital of Norway, N-0027 Oslo; Fax: 47 22 11 19 87 Received 28 September 1998; accepted 28 December 1998 inhibitors with less toxic potential have been developed including the non-immunosuppressive cyclosporin SDZ PSC 833, 12 the cyclopeptolide SDZ 280-446, 13 and the cyclopropyldibenzosuberane LY 335979.…”

A novel bioassay for P-glycoprotein functionality using cytochalasin D

“…The chemosensitizers were mainly compounds with a high potency to reverse P-gp-MDR (10,(20)(21)(22)27,32,39,45), and some of them additionally with a lower one to overcome MRP-MDR (38,51). One compound (probenecid) was included as a classic MRP modulator ineffective in P-gp-MDR (51).…”

“…(8,21,22,27,39,45,51). Additionally some of the P-gp modulators (VP, cyclosporin A, SDZ PSC 833) had been described to reverse also MRP-MDR, although to a much lower extent as compared to P-gp-MDR (38,51).…”

Discovery of Potent Inhibitors for Breast Cancer Multidrug Resistance

“…Another variant to these structures includes the cyclodepsipeptides. Several cyclodepsipeptides including the analogues of cyclosporine have been demonstrated to exhibit relatively high chemo-sensitizing potency Kurome, Takesako et al, 1998;Loor et al, 1992;Stratmann et al, 1994). The chiral α-hydroxy acid equivalents of the respective α-amino acids are readily available and can be incorporated accordingly into solid-phase synthesis using the tBoc strategy .…”