While it is known that mice with genetic immune defects are useful for establishing durable engraftment of human tumor xenografts, the relative role of components of host innate and adoptive immunity in engraftment has not been determined. We directly compared the ability of four strains of genetically immunodeficient mice (NOD/SCID, SCID, Nude and Rag-1-deficient) to successfully engraft and support the human cell lines Daudi, Raji, Namalwa and Molt-4 as subcutaneous tumors. We additionally examined the effect of further immunosuppression of the mice by whole body irradiation at a dose of 600 cGy for Nude and Rag-1 and 300 cGy for SCID mice and by administration of anti-natural killer (asialo-GM1) antibody on tumor growth. Mice with each of the defects supported xenografts to varying degrees. We found differences in growth characteristics in the cell lines tested, with Namalwa consistently producing the largest tumors. With all cell lines studied, optimal growth was achieved using NOD/SCID mice. Overall, tumor growth was somewhat enhanced by pretreatment with radiation with little additional benefit from the addition of anti-asialo-GM1 antibody. The importance of multiple components of the innate and adoptive immune system in xenotransplantation were best demonstrated when results in untreated NOD/SCID mice were compared to SCID, nude and RAG-1-deficient mice. The NOD/SCID mouse with or without additional immunosuppression provides the optimal model for the study of the biology and treatment of human leukemias and lymphomas.
BACKGROUND: The type I insulin-like growth factor receptor (IGF1R) is a transmembrane tyrosine kinase involved in cancer proliferation, survival, and metastasis. METHODS: In this study, we used two different fluorescent technologies (small-molecule fluorophores and quantum dot (QD) nanoparticles) to detect receptor expression and its downregulation by antibodies in vivo. RESULTS: After conjugation with AVE-1642, a humanised anti-IGF1R monoclonal antibody, both QDs (705 nm) or Alexa 680 (smallmolecule fluorophore) detected expression and downregulation of IGF1R in vitro. To examine their utility in vivo, either AVE-1642 conjugates were intravenously delivered to mice bearing xenograft tumours of mouse embryo fibroblasts expressing human IGF1R or MCF-7 human breast cancer cells. Quantum dot fluorescence was mainly localised to the reticuloendothelial system in several organs and engulfed by macrophages, with only very small amount of QDs detected in the xenograft tumours. Depletion of macrophages by clodronate liposomes did not alter the nonspecific uptake of QDs. In contrast, AVE-1642-conjugated Alexa 680 solely targeted to xenograft tumour and was able to detect IGF1R downregulation, with little nonspecific targeting to other tissues or organs in mice. CONCLUSION: Taken together, our data suggest that small-molecule fluorophores, not QDs, are suitable to detect the expression and downregulation of IGF1R in vivo.
A series of cyclometalated Ir(III) complexes with morpholine and piperazine groups are designed as dual photosensitizers and photothermal agents for more efficient antitumor phototherapy via infrared low‐power laser. Their ground and excited state properties, as well as the structural effect on their photophysical and biological properties, are investigated by spectroscopic, electrochemical, and quantum chemical theoretical calculations. They target mitochondria in human melanoma tumor cells and trigger apoptosis related to mitochondrial dysfunction upon irradiation. The Ir(III) complexes, particularly Ir6, demonstrate high phototherapy indexes to melanoma tumor cells and a manifest photothermal effect. Ir6, with minimal hepato‐/nephrotoxicity in vitro, significantly inhibits the growth of melanoma tumors in vivo under 808 nm laser irradiation by dual photodynamic therapy and photothermal therapy and can be efficiently eliminated from the body. These results may contribute to the development of highly efficient phototherapeutic drugs for large, deeply buried solid tumors.
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