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

• Published in: European journal of nuclear medicine and molecular imaging 2007-11, Vol.34 (11), p.1793-1803, Article 1793
• Main Authors: Gomes, Célia M F, Welling, Mick, Que, Ivo, Henriquez, Niek V, van der Pluijm, Gabri, Romeo, Salvatore, Abrunhosa, Antero J, Botelho, M Filomena, Hogendoorn, Pancras C W, Pauwels, Ernest K J, Cleton-Jansen, Anne Marie
• Format: Article
• Language: English
• Subjects: Animals; Bioluminescence; Bone cancer; Bone Neoplasms - diagnostic imaging; Cell Line, Tumor; Chemotherapy; Disease Models, Animal; Doxorubicin - administration & dosage; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Medical imaging; Mice; Mice, Inbred BALB C; Mice, Nude; Nuclear medicine; Osteosarcoma - diagnostic imaging; Osteosarcoma - drug therapy; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Sestamibi
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-007-0480-8

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 (99m)Tc-sestamibi. 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)Tc-sestamibi 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. 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 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. 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.