IN-VIVO IMAGING AND SPECIFIC TARGETING OF P-GLYCOPROTEIN EXPRESSION IN MULTIDRUG-RESISTANT NUDE-MICE XENOGRAFTS WITH [I-125] MRK-16 MONOCLONAL-ANTIBODY

Multidrug resistance (MDR) in tumors is associated with P-glycoprotein (Pgp) expression. In vivo quantitation of Pgp may allow MDR to be eva luated noninvasively prior to treatment planning. The purpose of this study was to radiolabel MRK-16, a monoclonal antibody that targets an external epitope of P-glycoprotein, and perform in vivo quantitation o f P-glycoprotein in a MDR xenograft nude mouse model. MRK-16 was label ed with I-125 by the iodogen method, with subsequent purification by s ize exclusion chromatography. Groups of 10 Balb/c mice were each xenog rafted with colchicine-resistant or -sensitive neuroblastoma cell line s, respectively. Whole body clearance and tumor uptake over time was q uantitated by gamma camera imaging, and biodistribution studies were p erformed with [I-125]MRK-16 and an isotype matched control antibody, A 33. Quantitative autoradiography and immunohistochemistry analysis of tumors was also evaluated to confirm specific targetting of [I-125]MRK -16. Peak tumor uptake was at 2-3 days post-injection, and was signifi cantly greater in resistance compared to sensitive tumors (mean % inje cted dose/g +/- SD) (18.76 +/- 2.94 vs 10.93 +/- 0.96; p < 0.05). Quan titative autoradiography verified these findings (19.13 +/- 0.622 vs 1 2.08 +/- 0.38, p < 0.05). Specific binding of [I-125]MRK-16 was confir med by comparison to [I-131]A33 in biodistribution studies, and locali zed to cellular components of tissue stroma by comparison of histologi c and autoradiographic sections of sensitive and resistant tumors. Imm unoblot analysis demonstrated a 4.5-fold difference in P-glycoprotein expression between sensitive and resistant cell lines without colchici ne selective pressure. We conclude that in vivo quantitation of P-glyc oprotein in MDR tumors can be performed with [I-125]MRK-16. These find ings suggest a potential clinical application for radiolabeled MRK-16 in the in vivo evaluation of multidrug resistance in tumors.