title: Cytoreductive chemotherapy improves the biodistribution of antibodies directed against tumor necrosis in murine solid tumor models.
abstract: Current strategies in cancer treatment employ combinations of different treatment modalities, which include chemotherapy, radiotherapy, immunotherapy, and surgery. Consistent with that approach, the present study demonstrates how chemotherapeutic agents can potentiate the delivery of radiolabeled, necrosis-targeting antibodies (chTNT-3, NHS76) to tumor. All chemotherapeutics in this study (5-fluorouracil, etoposide, vinblastine, paclitaxel, and doxorubicin) resulted in statistically significant increases in tumor uptake of radiolabeled antibodies and their F(ab')2 fragments compared to no pretreatment with chemotherapy. Labeled antibodies were administered at various time points following a single dose of chemotherapy in multiple tumor models, and the biodistribution of the antibodies was determined by measuring radioactivity in harvested tissues. MicroPET/CT was also done to demonstrate clinical relevancy of using chemotherapy pretreatment to increase antibody uptake. Results of biodistribution and imaging data reveal specific time frames following chemotherapy when necrosis-targeting antibodies are best delivered, either for imaging or radiotherapy. Thus, the present work offers the prospect of using cytoreductive chemotherapy to increase tumor accumulation of select therapeutic antibodies, especially when combined with other forms of immunotherapy, for the successful treatment of solid tumors.
authors.affiliation: Corresponding Author: Alan L. Epstein, Department of Pathology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR 205, Los Angeles, CA 90033. aepstein@usc.edu.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Jang
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Khawli
authors.forename: Ryan
authors.initials: R
authors.lastname: Park
authors.forename: Brian W
authors.initials: BW
authors.lastname: Wu
authors.forename: Zibo
authors.initials: Z
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Canter
authors.forename: Peter S
authors.initials: PS
authors.lastname: Conti
authors.forename: Alan L
authors.initials: AL
authors.lastname: Epstein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D009336:Necrosis / Q000188:drug therapy*; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D049268:Positron-Emission Tomography; D014018:Tissue Distribution; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates