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^99mTc-MIBI Imaging as a Predictor of Therapy Response in Osteosarcoma Compared with Multidrug Resistance-Associated Protein and P-Glycoprotein Expression

Zeynep Burak, MD¹, Jean-Luc Moretti, MD, PhD², Özden Ersoy, MD³, Ulus Sanl, MD⁴, Mehmet Kantar, MD⁵, Feyzi Tamgac, MD² and Gülçin Basdemir, MD³

¹ Department of Nuclear Medicine, Ege University Medical Faculty, zmir, Turkey
² Research Unit of Tumoral Tracers, Avicenne University Hospital, Paris North University, Paris, France
³ Department of Pathology, Ege University Medical Faculty, zmir, Turkey
⁴ Department of Medical Oncology, Ege University Medical Faculty, zmir, Turkey
⁵ Department of Pediatric Oncology, Ege University Medical Faculty, zmir, Turkey

In vitro studies have demonstrated that ^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI) is a transport substrate of multidrug resistance (MDR)-related proteins. The aim of this clinical study was to evaluate whether ^99mTc-MIBI scintigraphy was a functional imaging tool for in vivo detection of multidrug resistance-associated protein (MRP) expression in osteosarcoma and to investigate the role of MRP and ^99mTc-MIBI imaging to predict the clinical outcome. We also examined whether the scintigraphic parameters would help to distinguish the functional capacity of P-glycoprotein (Pgp) and MRP. Methods: Twenty-four patients with a diagnosis of osteosarcoma were studied before neoadjuvant chemotherapy. Tumor-to-background ratios of both early (10 min) and delayed (1 h) images and the percentage washout rate (WR%) of ^99mTc-MIBI were calculated. Immunohistochemical analysis of MRP and Pgp was performed on biopsy specimens, and the response to preoperative chemotherapy was assessed by histopathologic examination. Results: Fifteen of 24 osteosarcoma samples in our series (62.5%) showed significant expression of MRP. The level of MRP expression was significantly correlated with the WR% of ^99mTc-MIBI (r = 0.58, P = 0.003), and the WR% of ^99mTc-MIBI was significantly faster in patients with high MRP expression than in those with a low MRP score (P = 0.007). The clearance rate of ^99mTc-MIBI was significantly slower in tumor samples with negative or low expression of both Pgp and MRP (16% ± 6.2%) when compared with osteosarcomas with high expression of both proteins (31.7% ± 8.7%) (P = 0.001). There was not a significant difference between the WR% of ^99mTc-MIBI in tumors with coexpression of both proteins and in tumors with high expression of either Pgp or MRP. Both the rate of MRP expression and the WR% of ^99mTc-MIBI were significantly correlated with response rate. Conclusion: Our results suggest that the WR% of ^99mTc-MIBI is correlated with MRP expression. Both the WR% of ^99mTc-MIBI and MRP expression are correlated with therapy response. ^99mTc-MIBI can be used as a general probe for functional imaging of both Pgp and MRP; however, it is not capable of differentiating the functional status of either MDR-related glycoprotein.

Key Words: multidrug resistance • multidrug resistance-associated protein • P-glycoprotein • osteosarcoma • ^99mTc-methoxyisobutylisonitrile

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