The Clinical Relevance of Multidrug Resistance

Bellamy, William; Dalton, William S.; Dorr, Robert T.

doi:10.3109/07357909009012080

Cited by 52 publications

(19 citation statements)

References 82 publications

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“…P-glycoprotein (P-gp), a 170 kDa transmembrane protein found in a variety of tumor cell lines (Juliano & Ling, 1976), probably contributes to resistance, e.g. in osteosarcoma, leukaemias and neuroblastoma (Bourhis et al, 1989;Bellamy et al, 1990;Marie et al, 1991;Baldini et al, 1995). In vitro studies showed that P-gp can transport a wide range of hydrophobic, amphipathic compounds (reviewed by Gottesman & Pastan, 1993).…”

Section: Introductionmentioning

confidence: 99%

Substantial excretion of digoxin via the intestinal mucosa and prevention of long‐term digoxin accumulation in the brain by the mdrla P‐glycoprotein

Mayer

Wagenaar

Beijnen

et al. 1996

British J Pharmacology

265

204

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We have used mice with a disrupted mdrla P‐glycoprotein gene (mdrla (—/—)mice) to study the role of P‐glycoprotein in the pharmacokinetics of digoxin, a model P‐glycoprotein substrate. [3H]‐digoxin at a dose of 0.2 mg kg−1 was administered as a single i.v. or oral bolus injection. We focussed on intestinal mucosa and brain endothelial cells, two major pharmacological barriers, as the mdrla P‐glycoprotein is the only P‐glycoprotein normally present in these tissues. Predominant faecal excretion of [3H]‐digoxin in wild‐type mice shifted towards predominantly urinary excretion in mdrla (—/—) mice. After interruption of the biliary excretion into the intestine, we found a substantial excretion of [3H]‐digoxin via the gut mucosa in wild‐type mice (16% of administered dose over 90 min). This was only 2% in mdrla (—/—) mice. Biliary excretion of [3H]‐digoxin was not dramatically decreased (24% in wild‐type mice versus 16% in mdrla (—/—) mice). After a single bolus injection, brain levels of [3H]‐digoxin in wild‐type mice remained very low, whereas in mdrla (—/—) mice these levels continuously increased over a period of 3 days, resulting in a ∼200 fold higher concentration than in wild‐type mice. These data demonstrate the in vivo contribution of intestinal P‐glycoprotein to direct elimination of [3H]‐digoxin from the systemic circulation and to the pattern of [3H]‐digoxin disposition, and they underline the importance of P‐glycoprotein for the blood‐brain barrier.

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Section: Introductionmentioning

confidence: 99%

Substantial excretion of digoxin via the intestinal mucosa and prevention of long‐term digoxin accumulation in the brain by the mdrla P‐glycoprotein

Mayer

Wagenaar

Beijnen

et al. 1996

British J Pharmacology

265

204

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“…1 Resistance to chemotherapy is an important impediment constraining the successful treatment of patients. 2 Multidrug resistance (MDR) may be either an inherent resistance to a broad spectrum of chemotherapeutic drugs (intrinsic resistance) or 'acquired' (ie the mechanism of resistance may be procured during the course of treatment), which in both cases result in acutely resistant forms of cancer at relapse. 3 The molecular steps implicated in the induction of this resistance remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein

et al. 2001

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The appearance of multidrug-resistant (MDR) proteins or the acquisition of a defective apoptotic programme are major drawbacks in the treatment of cancers since both induce a resistance to classical chemotherapy. However, a link between the two mechanisms has not, as yet, been clearly established. In this study, HL-60 cells cultured in the continual presence of a sub-lethal dose of doxorubicin (dox; HL-60/Dox) were used as a model to study acquired chemoresistance. During the induction of chemoresistance, the appearance of a functional P-glycoprotein (P-gp), in addition to the expression of anti-apoptotic Bcl-2, Bcl-XL and pro-apoptotic Bax proteins was assessed. Parental cells which are sensitive to dox, have no P-gp activity and express Bcl-2 and Bax. After 4 weeks of treatment, a functional P-gp was detected in HL-60/Dox cells. In addition, the synthesis of Bcl-2 appeared to be replaced by Bcl-XL while that of Bax remained unchanged. These cells were also resistant to apoptosis induced by both P-gp and non-P-gp substrates. This inability to induce apoptosis could have resulted from the induction of the expression of the inhibitor of apoptosis protein (XIAP). Our data show that acquired chemoresistance could involve a parallel induction of P-gp and an impairment of the apoptotic pathway. Leukemia (2001) 15, 1377-1387.

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“…This problem is further exacerbated by the observation that these emerging tumours are often cross-resistant to other chemotherapeutic agents, even though these drugs were not used in the initial treatment, belong to unrelated structural classes and have different mechanisms of action. This phenomenon is widely known as 'multidrugresistance' (MDR) (Bellamy et al, 1990;Moscow & Cowan, 1990).…”

mentioning

confidence: 99%

“…However, this cannot be done in vivo since in clinical practice, cancer patient treatments are already performed with ACD regimens close to the maximal tolerated dose (MTD). As a consequence, MDR-tumours cannot be treated by some of the most effective ACD available today, since the doses required to reach cytostatic levels are unacceptably toxic if not lethal to the patient (Bellamy et al, 1990;Moscow & Cowan, 1990).…”

mentioning

confidence: 99%

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

Loor

Boesch²,

Gavériaux³

et al. 1992

Br J Cancer

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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.

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The Clinical Relevance of Multidrug Resistance

Cited by 52 publications

References 82 publications

Substantial excretion of digoxin via the intestinal mucosa and prevention of long‐term digoxin accumulation in the brain by the mdrla P‐glycoprotein

Substantial excretion of digoxin via the intestinal mucosa and prevention of long‐term digoxin accumulation in the brain by the mdrla P‐glycoprotein

Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein

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

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