Reversal of Multidrug Resistance with LY335979: Functional Analysis of P-glycoprotein-Mediated Transport Activity and Its Modulation in Vivo

Slapak, Christopher A.; Dahlheimer, Julie L.; Piwnica‐Worms, David

doi:10.1177/009127001773744134

Cited by 20 publications

(16 citation statements)

References 15 publications

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“…The exact mode of action of LY335979 in the reversal of MDR1-mediated MDR is unclear, although a noncompetitive inhibitory mechanism has been suggested. In animal experiments, LY335979 has been shown to significantly enhance survival and reduce tumor mass in mice engrafted with MDR-bearing human tumor cells [152].…”

Section: Third-generation Mdr Modulatorsmentioning

confidence: 99%

An Update on Overcoming MDR1-Mediated Multidrug Resistance in Cancer Chemotherapy

Takara

Sakaeda²,

Okumura

2006

CPD

216

179

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The intrinsic or acquired resistance to anticancer drugs remains one of the most significant factors impeding the progress of cancer chemotherapy. This phenomenon often involves simultaneous resistance to other anticancer drugs that differ in their chemical structure and mode of action and are not even used in chemotherapy. This phenotype has been called multidrug resistance (MDR). Although the cellular basis underlying MDR is not fully understood, several factors mediating therapy resistance in tumors have been proposed. One of the mechanisms leading to chemoresistance of tumor cells is the increased activity of transporter proteins. The best-characterized transporter protein is MDR1/P-glycoprotein, and a number of clinical investigations have suggested that its intrinsic or acquired overexpression resulted in a poor clinical outcome of chemotherapy. Various types of compounds and techniques for the reversal of MDR1/P-glycoprotein-mediated MDR have been developed, and efforts have concentrated on the inhibition of function and suppression of expression. This review summarizes the current state of knowledge of MDR1/P-glycoprotein and the modulation of MDR by targeting MDR1/P-glycoprotein.

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Section: Third-generation Mdr Modulatorsmentioning

confidence: 99%

An Update on Overcoming MDR1-Mediated Multidrug Resistance in Cancer Chemotherapy

Takara

Sakaeda²,

Okumura

2006

CPD

216

179

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“…Decreased uptake of 99m Tc-MIBI in resistant cells also has been attributed to a lower membrane potential and reduced mitochondrial density(8). Several groups have used 99m Tc-MIBI as a functional P-gp probe substrate in rodents and humans(9–12). Further investigations using cancer cells in culture revealed that 99m Tc-MIBI is a MRP1 substrate (13).…”

Section: Introductionmentioning

confidence: 99%

“…Coadministration of 99m Tc-MIBI with the P-gp inhibitors PSC833 and LY335979 resulted in prolonged hepatic exposure(9, 11, 12). 99m Tc-MIBI pharmacokinetics were altered in a cohort of cancer patients with common single nucleotide polymorphisms (SNPs) in ABCB1 exons 12 (C1236T) and 26 (C3435T); the elimination rate constant was significantly decreased(10).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of 99mTechnetium-Mebrofenin and 99mTechnetium-Sestamibi as Specific Probes for Hepatic Transport Protein Function in Rat and Human Hepatocytes

2010

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Purpose This study characterized 99mTc-Mebrofenin (MEB) and 99mTc-Sestamibi (MIBI) hepatic transport and preferential efflux routes (canalicular vs. basolateral) in rat and human sandwich-cultured hepatocytes (SCH). Methods 99mTc-MEB and 99mTc-MIBI disposition was determined in suspended hepatocytes and in SCH in the presence and absence of inhibitors and genetic knockdown of breast cancer resistance protein (Bcrp). Results The general organic anion transporting polypeptide (Oatp/OATP) inhibitor rifamycin SV reduced initial 99mTc-MEB uptake in rat and human suspended hepatocytes. Initial 99mTc-MIBI uptake in suspended rat hepatocytes was not Na+-dependent or influenced by inhibitors. Multidrug resistance-associated protein (Mrp2/MRP2) inhibitors decreased 99mTc-MEB canalicular efflux in rat and human SCH. 99mTc-MEB efflux in human SCH was predominantly canalicular (45.8±8.6%), and ~3-fold greater than in rat SCH. 99mTc-MIBI canalicular efflux was similar in human and rat SCH; basolateral efflux was 37% greater in human than rat SCH. 99mTc-MIBI cellular accumulation, biliary excretion index and in vitro biliary clearance in rat SCH were unaffected by Bcrp knockdown. Conclusion 99mTc-MEB hepatic uptake is predominantly Oatp-mediated with biliary excretion by Mrp2. 99mTc-MIBI appears to passively diffuse into hepatocytes; biliary excretion is mediated by P-gp. The SCH model is useful to investigate factors that may alter the route and/or extent of hepatic basolateral and canalicular efflux of substrates.

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“…One possible explanation for this observation may be the higher number of erythrocytes recognizable for destruction in the spleen, the major reticuloendothelial system (RES) organ, in the control group immediately after IV injection of the drug solution. The reduced intestinal uptake at 5 min (P < 0.01) can be explained by the reduced hepatobiliary excretion of the drug (Slapak et al, 2001).…”

mentioning

confidence: 94%

“…In addition, the minor expression of Pgp in a broad spectrum of tissues including adrenal glands, bladder, lungs, heart, spleen, esophagus, stomach and leukocytes has been reported (Chin et al, 1989;Schinkel et al, 1996;Wacher et al, 1998;Slapak et al, 2001;Brady et al, 2002). We used the pharmacological inhibition of Pgp in the present study to evaluate the possible effects of Pgp on the tissue uptake of indinavir.…”

mentioning

confidence: 99%

Role of P-glycoprotein in tissue uptake of indinavir in rat

Hamidi

2006

Life Sciences

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Reversal of Multidrug Resistance with LY335979: Functional Analysis of P-glycoprotein-Mediated Transport Activity and Its Modulation in Vivo

Cited by 20 publications

References 15 publications

An Update on Overcoming MDR1-Mediated Multidrug Resistance in Cancer Chemotherapy

An Update on Overcoming MDR1-Mediated Multidrug Resistance in Cancer Chemotherapy

Evaluation of 99mTechnetium-Mebrofenin and 99mTechnetium-Sestamibi as Specific Probes for Hepatic Transport Protein Function in Rat and Human Hepatocytes

Role of P-glycoprotein in tissue uptake of indinavir in rat

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