ALBERT

Beschreibung: Introduction: Burkitt's lymphoma (BL) is is composed of highly proliferating mature B cells expressing a germinal center phenotype (Cai, Oncotarget 2015). It is one of the fastest growing human tumors and presents in extranodal as well as nodal sites. The genetic hallmark of BL is the MYC translocation with MYC and TP53 mutations in ∼60% and 40% of the cases, respectively (Ott, Blood 2014). While prompt administration of multiagent immunochemotherapy regimens is associated with favorable outcomes for the majority of patients, prognosis of refractory or relapsed disease is poor (Jacobson, Blood 2014). We previously identified a novel near-infrared heptamethine carbocyanine fluorescent dye (NIR-dye) that has tumor homing property through cell surface transporters, organic anion transporting peptides (OATPs), and shows preferential uptake in tumor but not normal cells as demonstrated in cell culture, mouse and dog tumor models, patient-derived xenografts (PDXs), and perfused kidney cancers in patients (Wu, Biomaterials 2014). Here, we describe the effects of a newly synthesized NIR-dye-cisplatin conjugate (NIR-dye-Cis) on MYC-driven TP53 mutated aggressive B-cell BL cell lines in culture and tumors in mice. Methods:The growth and viability of immortalized B-cell lymphoma cell lines, Namalwa, Raji, CA46, Ramos, Daudi, were evaluated by MTT upon 72 h exposure to conventional cisplatin (Cis) and NIR-dye-Cis. Induction of apoptosis was assesed using a caspase 3/7 luminescent assay. Cleavage of apoptosis substrates and inhibition of c-myc was determined by western blotting, with images quantified by ImageJ after normalization with GAPDH. NIR-dye-Cis uptake in cells and tumors were imaged by NIRF microscopy and IVIS Lumina XR Imaging System, respectively. Male NCr nude and NOD/SCID mice bearing s.c. Namalwa tumors were injected i.p. with equimolar doses of NIR-dye-Cis and conventional Cis 3 times a week for 4 weeks. Formalin-fixed tumor and kidney sections were stained with hematoxylin and esosin and kidney sections scored using a semiquantitative scale designed to assess AKI-associated tubular injury (tubular epithelial cell loss, necrosis, tubular epithelial simplification, intratubular debris, and casts). Results: 1) All BL cell lines tested are sensitive to growth inhibition by NIR-dye-Cis but not Cis with IC50 ranging between 720 nM - 2.53 µM and 〉64 µM (p