Organ-Specific Modulation of Steady-State mdr Gene Expression and Drug Resistance in Murine Colon Cancer Cells

Dong, Zhongyun; Radinsky, Robert; Fan, Dominic; Tsan, Rachel; Bucana, Corazon D.; Wilmanns, C.; Fidler, Isaiah J.

doi:10.1093/jnci/86.12.913

Cited by 89 publications

(51 citation statements)

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“…In these models, tumour cells are selected in vitro for the MDR phenotype by exposure to anticancer drugs and then injected subcutaneously in the back or flank of nude mice. Although these models are adequate for specific assays, such as the rapid screening of new compounds, they cannot reproduce the physiological environment, which Results are expressed as mean ± SD of at least four mice MIBI 99m Tc-sestamibi, t 1/2 washout half-time, WR (%) percentage washout rate, T/NT 5 min tumour/non-tumour ratio at 5 min, T/NT 60 min tumour/ non-tumour ratio at 60 min *p<0.05 compared with 143B-luc + tumours without PSC833 **p<0.05 compared with MNNG/HOS-luc + tumours without PSC833 [45] demonstrated that the organ environment influences the Pgp expression in colon carcinoma cells, affecting their in vivo sensitivity to doxorubicin. The Pgp gene expression depends on a variety of host factors such as interaction with the extracellular matrix and environmental mitogenic signals [46,47].…”

Section: Discussionmentioning

confidence: 99%

Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi

Welling

Que

Henriquez

et al. 2007

Eur J Nucl Med Mol Imaging

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Purpose The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferaseexpressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with 99m Tc-sestamibi. Methods Doxorubicin-sensitive (143B-luc + ) and resistant (MNNG/HOS-luc + ) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a 99m Tcsestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of 99m Tc-sestamibi washout half-life (t 1/2 ), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio.Results A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t 1/2 of 99m Tc-sestamibi was significantly shorter (p<0.05) in drugresistant MNNG/HOS-luc + tumours (t 1/2 =87.3±15.7 min) than in drug-sensitive 143B-luc + tumours (t 1/2 =161.0±47.4 min) and decreased significantly with PSC833 (t 1/2 =173.0± 24.5 min, p<0.05). No significant effects of PSC833 were observed in 143B-luc + tumours. The T/NT ratio was significantly lower (p<0.05) in MNNG/HOS-luc + tumours than in 143B-luc + tumours at early (1.55±0.22 vs 2.14± 0.36) and delayed times (1.12±0.11 vs 1.62±0.33). PSC833 had no significant effects on the T/NT ratios of either tumour. Conclusion The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of 99m Tc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi

Welling

Que

Henriquez

et al. 2007

Eur J Nucl Med Mol Imaging

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“…siRNA has become a potential alternative for treating multi-drug resistant metastasis, which is the major cause of death in cancer patients [1]. Selective delivery of siRNA to metastatic tumors remains a major obstacle for siRNA based therapy.…”

Section: Introductionmentioning

confidence: 99%

Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles

Chono

Huang

2008

Journal of Controlled Release

139

133

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We have developed a nanoparticle (NP) formulation for systemically delivering siRNA into metastatic tumors. The NP, composed of nucleic acids, a polycationic peptide and cationic liposome, was prepared in a self-assembling process. The NP was then modified by PEG-lipid containing a targeting ligand, anisamide, and thus was decorated for targeting sigma receptor expressing B16F10 tumor. The activity of the targeted NP was compared with the naked NP (no PEGylation) and nontargeted NP (no ligand). The delivery efficiency of the targeted NP was 4-fold higher than the nontargeted NP and could be competed by excess free ligand. Luciferase siRNA was used to evaluate the gene silencing activity in the B16F10 cells, which were stably transduced with a luciferase gene, in a lung metastasis model. The gene silencing activity of the targeted NP was significantly higher than the other formulations and lasted for 4 days. While confocal microscopy showed the naked NP provided no tissue selectivity and non-targeted NP was ineffective for tumor uptake, the targeted NP effectively penetrated the lung metastasis, but not the liver. It resulted in 70-80% gene silencing in the metastasis model after a single i.v. injection (150 μg siRNA/kg). This effective formulation also showed very little immunotoxicity.

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“…Several lines of evidence indicate that the effect of antimetastatic agents can be differentially modulated by organ microenvironments, 21,22) because of, in part, a different host cell population and different pharmacokinetics. Therefore, it is important to explore whether MS-209 reverses the MDR of metastatic SCLC cells in various organs.…”

Section: Discussionmentioning

confidence: 99%

A New Quinoline Derivative MS‐209 Reverses Multidrug Resistance and Inhibits Multiorgan Metastases by P‐glycoprotein‐expressing Human Small Cell Lung Cancer Cells

Nokihara

Yano

Nishioka

et al. 2001

Japanese Journal of Cancer Research

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Organ-Specific Modulation of Steady-State mdr Gene Expression and Drug Resistance in Murine Colon Cancer Cells

Cited by 89 publications

References 0 publications

Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi

Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi

Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles

A New Quinoline Derivative MS‐209 Reverses Multidrug Resistance and Inhibits Multiorgan Metastases by P‐glycoprotein‐expressing Human Small Cell Lung Cancer Cells

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