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

Abstract

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.

Palladacycle (BPC) antitumour activity against resistant and metastatic cell lines: The relationship with cytosolic calcium mobilisation and cathepsin B activity

“…To further deepen the understanding of the molecular antitumour action of BPC, we evaluated the effectiveness of this complex against tumour cells using in vitro and in vivo systems. These studies demonstrated that BPC is effective in vivo against a specific isogenic melanoma tumour model and shows Saos-2 cell cytotoxicity, which is an osteosarcoma cell line that presents high chemotherapy resistance properties [45] due to a p53 gene expression impairment [28,46] and ABC protein expression [47]. Part of the BPC cytotoxicity to Saos-2 cells was caused by the cytosolic calcium mobilisation, LMP and a pro-apoptotic protein Bax translocation with caspase-3 activation.…”

Preoperative Localization of Abnormal Parathyroid Glands

“…However, 99m Tc-sestamibi is released much faster from thyroid than from parathyroid tissue, a pathophysiologic pattern possibly related to down-regulation in the parathyroid of the membrane-associated P-glycoprotein system related to multidrug resistance, a system for which 99m Tc-sestamibi is also a substrate. [58][59][60][61] This differential washout rate of 99m Tc-sestamibi from the thyroid relative to the parathyroid permits parathyroid scintigraphy to be performed with this single tracer, according to the so-called dual-phase 99m Tc-sestamibi acquisition protocol. As originally described by Taillefer et al, 54 planar imaging of the neck and thorax is acquired at 15 minutes, then 2-3 hours after the i.v.…”

Orthotopic murine model of a primary malignant bone tumor in the spine: functional, bioluminescence, and histological correlations

“…6,20 Although several animal models of primary malignant bone tumors have been described, 3,5,8,9,19,23 there are no animal models of any primary malignant bone tumor in the spine; therefore, none of them addresses the sequence of events …”