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In Vitro and In Vivo Tracer Characteristics of an Established Multidrug-Resistant Human Colon Cancer Cell Line

Departments of Neuroanatomy and Nuclear Medicine, University Hospital Eppendorf, Hamburg, Germany

^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI) has been suggested as a tracer for the scintigraphic detection of multidrug resistance (MDR). The aim of this study was to compare MDR characteristics in vitro and in vivo by immunohistochemic and functional uptake assays in established tumor cell lines cultured and grown in severe combined immunodeficient (SCID) mice. Methods: The presence of MDR was assessed in vitro in drug-resistant HT-29^mdr1 colon carcinoma cells and in nonresistant HT-29^par cells by JSB-1 immunohistochemistry, uptake of the fluorescent dye Rhodamine 123, and quantitative measurement of ^99mTc-MIBI accumulation. For in vivo imaging, SCID mice bearing subcutaneous xenografts of these cell lines were injected with ^99mTc-MIBI and ¹⁸F-FDG for scintigraphic and PET examination. After imaging, tumors were analyzed by immunohistochemistry and electron microscopy. Results: All HT-29^mdr1 cells cultured in vitro exhibited distinct JSB-1 immunoreactivity, although to a variable degree, whereas HT-29^par cells were completely devoid of JSB-1 staining. Rhodamine 123 accumulated poorly in HT-29^mdr1 cells but strongly in HT-29^par cells. Accumulation of ^99mTc-MIBI was 0.05% ± 0.01% of the activity of the external medium in HT-29^mdr1 cells, but about eight times higher in HT-29^par cells (0.40% ± 0.09%), a very low percentage compared with other tumor cell lines. No difference in ²⁰¹TlCl accumulation was observed between both cell lines. In vivo, neither HT-29^par nor HT-29^mdr1 tumors grown in SCID mice could be detected by ^99mTc-MIBI scintigraphy. In FDG PET, both HT-29^mdr1 and HT-29^par tumors were clearly visible. FDG uptake was, however, markedly higher in HT-29^par than in HT-29^mdr1 tumors. Both tumor types were poorly vascularized, as shown histologically. JSB-1 immunoreactivity was absent in all HT-29^par tumors examined, whereas the majority of HT-29^par tumor cells were stained. Electron microscopy showed that HT-29^par tumors contained significantly less mitochondria than hepatocytes of the SCID mouse liver, which displayed high ^99mTc-MIBI uptake in our scintigraphy studies. Conclusion: Sufficient ^99mTc-MIBI uptake is the major prerequisite for distinguishing successfully between drug-resistant and sensitive cells. Negative ^99mTc-MIBI scintigrams are not necessarily associated with MDR expression. In some tumors, FDG may be an in vivo marker for MDR as suggested by PET.

Key Words: human HT-29 colon cancer cell line • electron microscopy • FDG • PET • immunohistochemistry • multidrug resistance • Rhodamine 123 • severe combined immunodeficient mouse • ^99mTc-methoxyisobutylisonitrile • ²⁰¹TlCl

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