Visualizing the kinetics of tumor-cell clearance in living animals.

Evaluation of potential antineoplastic therapies would be enhanced by noninvasive detection of tumor cells in living animals. Because light is transmitted through mammalian tissues, it was possible to use bioluminescence to monitor (both externally and quantitatively) growth and regression of labeled human cervical carcinoma (HeLa) cells engrafted into immunodeficient mice. The efficacy of both chemotherapy and immunotherapeutic treatment with ex vivo expanded human T cell-derived effector cells was evaluated. In the absence of therapy, animals showed progressive increases in signal intensity over time. Animals treated with cisplatin had marked reductions in tumor signal; 5'-fluorouracil was less effective, and cyclophosphamide was ineffective. Immunotherapy dramatically reduced signals at high effector-to-target cell ratios, and significant decreases were observed with lower ratios. This model system allowed sensitive, quantitative, real-time spatiotemporal analyses of the dynamics of neoplastic cell growth and facilitated rapid optimization of effective treatment regimens.

[1]  L. Lanier,et al.  The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. , 1986, Journal of immunology.

[2]  Masafumi Oshiro,et al.  Visualizing Gene Expression in Living Mammals Using a Bioluminescent Reporter , 1997, Photochemistry and photobiology.

[3]  R. Negrin,et al.  The use of the polymerase chain reaction for the detection of minimal residual malignant disease [editorial] , 1991 .

[4]  I. Weissman,et al.  Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells. , 1995, Blood.

[5]  David K. Stevenson,et al.  Bioluminescent indicators in living mammals , 1998, Nature Medicine.

[6]  C. Contag,et al.  Noninvasive assessment of tumor cell proliferation in animal models. , 1999, Neoplasia.

[7]  J F Keij,et al.  Homing of fluorescently labeled murine hematopoietic stem cells. , 1996, Experimental hematology.

[8]  J. Dick,et al.  A model of human acute lymphoblastic leukemia in immune-deficient SCID mice. , 1989, Science.

[9]  H. Cavé,et al.  Clinical Significance of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia , 1998 .

[10]  F. Bach,et al.  Long-term growth of lymphokine-activated killer (LAK) cells: role of anti-CD3, beta-IL 1, interferon-gamma and -beta. , 1987, Journal of immunology.

[11]  R. Shoemaker,et al.  Two serologic markers to monitor the engraftment, growth, and treatment response of human leukemias in severe combined immunodeficient mice. , 1996, Blood.

[12]  A. Bleyer,et al.  Leukemic cell growth in SCID mice as a predictor of relapse in high-risk B-lineage acute lymphoblastic leukemia. , 1995, Blood.

[13]  F. Uckun.  Severe combined immunodeficient mouse models of human leukemia. , 1996, Blood.

[14]  R. Negrin,et al.  Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice. , 1998, Blood.

[15]  E. G. Shpaer,et al.  Genetic relationships determined by a DNA heteroduplex mobility assay: analysis of HIV-1 env genes. , 1993, Science.

[16]  N Kajiyama,et al.  Isolation and characterization of mutants of firefly luciferase which produce different colors of light. , 1991, Protein engineering.

[17]  R. Negrin,et al.  A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. , 1994, Journal of immunology.

[18]  J. Ritz,et al.  A subset of natural killer cells in peripheral blood displays a mature T cell phenotype , 1986, The Journal of experimental medicine.

[19]  J. Roder,et al.  High level functional engraftment of severe combined immunodeficient mice with human peripheral blood lymphocytes following pretreatment with radiation and anti-asialo GM1. , 1994, Journal of immunological methods.

[20]  I. Puisieux,et al.  Inhibition of human colon cancer growth by antibody-directed human LAK cells in SCID mice. , 1993, Science.

[21]  S. Glantz,et al.  Primer of Applied Regression & Analysis of Variance , 1990 .

[22]  C. Hirsch-Ginsberg.  Detection of minimal residual disease: relevance for diagnosis and treatment of human malignancies. , 1998, Annual review of medicine.

[23]  H. Young,et al.  Comparative studies of CD3- and CD3+ CD56+ cells: examination of morphology, functions, T cell receptor rearrangement, and pore-forming protein expression. , 1991, Cellular immunology.

[24]  D. Huhn,et al.  Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells. , 1996, Cellular immunology.

[25]  J. Mullins,et al.  Photonic detection of bacterial pathogens in living hosts , 1995, Molecular microbiology.

[26]  I. Weissman,et al.  Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity , 1991, The Journal of experimental medicine.

[27]  I. Weissman,et al.  Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. , 1993, Experimental hematology.