Pgp inhibition by UIC2 antibody can be followed in vitro by using tumor-diagnostic radiotracers, 99mTc-MIBI and 18FDG

The Strong In Vivo Anti-Tumor Effect of the UIC2 Monoclonal Antibody Is the Combined Result of Pgp Inhibition and Antibody Dependent Cell-Mediated Cytotoxicity

“…The above phenomenon was also confirmed in vitro , by measuring the cellular accumulation of various fluorescent Pgp substrates including DNR, R123, calcein and a radioactive tracer 99m Tc-Mibi [22]. In line with the above, combined treatment with either CSA + UIC2 or paclitaxel + UIC2 specifically decreased the rate of glucose metabolism in Pgp + cells, as measured in 2-[ 18 F]fluoro-2-deoxy-D-glucose ( 18 FDG) accumulation experiments, also suggesting that Pgp inhibition with concomitant decrease of energy consumption has occurred [23]. On the other hand, we also demonstrated in xenotransplanted severe combined immunodeficient (SCID) mice that UIC2 could readily penetrate into the compact solid tumors, intensively staining cell surface Pgps and increasing daunorubicin accumulation in the Pgp + tumors to the level of the Pgp - ones [22].…”

“…However, the observed effects have been proven to be Pgp specific, since decreased tumor size was detected exclusively in those animal groups that received UIC2 mAb treatment. In addition, in our previous studies we compared the KB-V1 cell line with mdr1 transfected NIH 3T3 murine fibroblast cells [22], and Pgp + A2780 AD ovarian carcinoma cells [23] and found them equivalent in every aspect of their multidrug resistant phenotype including the inhibition of Pgp-mediated drug transport by UIC2 mAb. On the other hand, ADCC effect is not dependent on the tissue origin of the target cells; rather it is determined by the interaction between the Fc part of the antibody and the Fc receptor of the effector cells.…”

“…It recognizes a complex epitope involving at least the first [19] and the third extracellular loops of the protein [20]. In the absence of Pgp substrates and modulators UIC2 can bind only to 10–40% of cell surface Pgps, while the rest adopts the UIC2 binding conformation only in the presence of a distinct group of substrates or modulators (e.g., cyclosporine A (CsA), SDZ PSC 833, vinblastine and paclitaxel [21]–[23]. In previous studies we have demonstrated that the UIC2 antibody itself completely inhibits Pgp function when it is applied together with any of the above Pgp modulators added at low, sub-inhibitory concentrations [22].…”

18FDG a PET tumor diagnostic tracer is not a substrate of the ABC transporter P-glycoprotein

“…Several authors reported that the accumulation of 18 FDG differs between Pgp expressing and non-expressing cancer cells and tumors (Lorke et al, 2001;Márián et al, 2003;Higashi et al, 2004;Yamada et al, 2005;Krasznai et al, 2006;Seo et al, 2009;Krasznai et al, 2010;Smith, 2010). A number of them accounted decreased accumulation of 18 FDG in cancer cells and tumors expressing Pgp at high level (Lorke et al, 2001;Higashi et al, 2004;Yamada et al, 2005;Seo et al, 2009;Smith, 2010, Yu et al, 2012.…”

Targeting of Multidrug‐Resistant Human Ovarian Carcinoma Cells With Anti‐P‐Glycoprotein Antibody Conjugates

“…[5,25,27] Expression of Pgp explains the MDR prevalence in tissues prior to treatment and induction of MDR in ovarian cancer following anti-cancer drug exposure. Alternative strategies in development to target Pgp include inhibitors, [3,25,26,55] mAb that target and partially reverse Pgp efflux, [32,33,56,57] and utilization of anti-Pgp mAb effector function to trigger antibody dependent cellular toxicity or complement dependent cytotoxicity. [58,59] To date, no clear strategy has demonstrated sufficient effect to overcome MDR.…”