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 luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with 99mTc-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 99mTc- sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of 99mTc-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 99mTc-sestamibi was significantly shorter (p<0.05) in drug-resistant 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 99mTc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma. © 2007 Springer-Verlag.