Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice.

Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely prevented the appearance of bone metastasis of the high metastatic variant in nude mice (P < 0.001). After injection of the highly bone-metastatic breast cancer variant to the tibia of nude mice, S. typhimurium A1-R treatment significantly reduced tumor growth in the bone (P < 0.001). These data indicated that S. typhimurium A1-R is useful to prevent and inhibit breast cancer bone metastasis and should be of future clinical use for breast cancer in the adjuvant setting

Establishment of a patient-derived orthotopic Xenograft (PDOX) model of HER-2-positive cervical cancer expressing the clinical metastatic pattern.

Squamous cell carcinoma of the cervix, highly prevalent in the developing world, is often metastatic and treatment resistant with no standard treatment protocol. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). Unlike subcutaneous transplant patient-derived xenograft (PDX) models, PDOX models metastasize. Most importantly, the metastasis pattern correlates to the patient. In the present report, we describe the development of a PDOX model of HER-2-positive cervical cancer. Metastasis after SOI in nude mice included peritoneal dissemination, liver metastasis, lung metastasis as well as lymph node metastasis reflecting the metastatic pattern in the donor patient. Metastasis was detected in 4 of 6 nude mice with primary tumors. Primary tumors and metastases in the nude mice had histological structures similar to the original tumor and were stained by an anti-HER-2 antibody in the same pattern as the patient's cancer. The metastatic pattern, histology and HER-2 tumor expression of the patient were thus preserved in the PDOX model. In contrast, subcutaneous transplantation of the patient's cervical tumors resulted in primary growth but not metastasis

The disintegrin echistatin in combination with doxorubicin targets high-metastatic human osteosarcoma overexpressing ανβ3 integrin in chick embryo and nude mouse models.

Echistatin, a cyclic RGD peptide, which is an antagonist of αvβ3 integrin (disintegrin), inhibited human osteosarcoma in the chick chorioallontoic membrane (CAM) model and tumor growth and pulmonary metastases in a nude mouse orthotopic model. A high-metastatic variant of human osteosarcoma, 143B-LM4, overexpressing αvβ3 integrin was used. Tumor angiogenesis by high-metastatic variant 143B-LM4 cells in the CAM was significantly inhibited by echistatin (P<0.05) as was overall growth. A doxorubicin (DOX)-echistatin combination inhibited orthotopic tumor growth compared to untreated control (P<0.01) or DOX alone (P<0.05) in nude mice. Tumor-bearing mice treated with the DOX-echistatin combination survived longer than those treated with DOX alone or control PBS (P<0.01 and P<0.01, respectively). Echistatin also inhibited experimental lung metastasis of 143B-LM4 cells in nude mice. These results suggest that DOX in combination with a disintegrin has potential to treat osteosarcoma and that αvβ3 integrin may be a target for osteosarcoma

Comparative Study between Nude Mice and Immunosuppressed Hamsters as Recipients of Human Tumor Xenografts

We comparatively examined nude mice and hamsters as to their suitability as recipients of human cancers. CD-1 nude mice and golden hamsters immunosuppressed with anti-hamster thymocyte serum were used. Nude mice were superior in the areas of primary transplantation and subsequent transfer and maintenance. However, growth of tumors transplantable to both animals (a lung cancer line LC-1, a colon cancer line RPMI4788) tends to be better in hamsters than in nude mice. The better development of LC-1 and RPMI4 788 cells in hamsters than in nude mice appears to be related to the superior gain in body weight shown by hamsters

Temozolomide and Pazopanib Combined with FOLFOX Regressed a Primary Colorectal Cancer in a Patient-derived Orthotopic Xenograft Mouse Model.

PurposeThe goal of the present study was to determine the efficacy of temozolomide (TEM) and pazopanib (PAZ) combined with FOLFOX (oxaliplatin, leucovorin and 5-fluorouracil) on a colorectal cancer patient-derived orthotopic xenograft (PDOX) mouse model.Materials and methodsA colorectal cancer tumor from a patient previously established in non-transgenic nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Then labeled tumors were orthotopically implanted into the cecum of nude mice. Mice were randomized into four groups: Group 1, untreated control; group 2, TEM + PAZ; group 3, FOLFOX; group 4, TEM + PAZ plus FOLFOX. Tumor width, length, and mouse body weight were measured weekly. The Fluor Vivo imaging System was used to image the GFP-lableled tumor stromal cells in vivo. H&E staining and immunohistochemical staining were used for histological analysis.ResultsAll three treatments inhibited tumor growth as compared to the untreated control group. The combination of TEM + PAZ + FOLFOX regressed tumor growth significantly more effectively than TEM + PAZ or FOLFOX. Only the combination of TEM + PAZ + FOLFOX group caused a decrease in body weight. PAZ suppressed lymph vessels density in the colorectal cancer PDOX mouse model suggesting inhibition of lymphangiogenesis.ConclusionOur results suggest that the combination of TEM + PAZ + FOLFOX has clinical potential for colorectal cancer patient

ヒト白血病細胞を用いたマウス subrenal capsule grafting の検討

In this study we improved the prescription of fibrin clot embedded human leukemia cells for murine subrenal capsule grafting. By pretreatment of thrombin, fibrin gel was generated tightly and better suited for grafting and evaluation. Comparison of cell-growth among immunocompetent normal mice, immunosuppressed mice and immunodeficient mice (nude mice) using this assay procedure showed normal mice was out of order for the antitumor evaluation because severe invasion of host immune cells were observed at cell-gtafting site. Otherwise, leukemia cells were well proliferated without host immune response at the subrenal capsule ground in immunosuppressed mice and nude mice. In conclusion nude mice and immunosuppressed mice were right animals for antitumor activity assay by subrenal capsule grafting using fibrin-cancer cell clot.In this study we improved the prescription of fibrin clot embedded human leukemia cells for murine subrenal capsule grafting. By pretreatment of thrombin, fibrin gel was generated tightly and better suited for grafting and evaluation. Comparison of cell-growth among immunocompetent normal mice, immunosuppressed mice and immunodeficient mice (nude mice) using this assay procedure showed normal mice was out of order for the antitumor evaluation because severe invasion of host immune cells were observed at cell-gtafting site. Otherwise, leukemia cells were well proliferated without host immune response at the subrenal capsule ground in immunosuppressed mice and nude mice. In conclusion nude mice and immunosuppressed mice were right animals for antitumor activity assay by subrenal capsule grafting using fibrin-cancer cell clot

Effect of all-trans retinoic acid on growth of xenograft tumor and its metastasis in nude mice

Objective To study the effect of all-trans retinoic acid on growth of xenograft tumor and its metastasis in nude mice. Methods Human gastric cancer BGC-823 and MKN-45 cells were inoculated into spleen subcapsule of nude mice, respectively. The nude mice were subsequently administered with all-trans retinoic acid every other day. Food consuming and body weight of nude mice were measured weekly. Six weeks later, the nude mice were killed. Xenograft tumors in spleen and metastatic tumors in liver were pathologically examined. Microvessel density in the tumors was detected immunohistochemically, and serum carcinoembryonic antigen was measured by radioimmunoassay. Results After the nude mice were fed with all-trans retinoic acid, the growth of splenic tumor and its liver metastasis were inhibited and the metastatic rates decreased by 50% ( BGC-823) and 33.3% (MKN-45), respectively. The microvessel density in splenic and hepatic tumors reduced by 28.58% and 35.47% (BGC-823), 19.45% and 14.52% (MKN-45), respectively. The concentration of carcinoembryonic antigen decreased by 50.24% (BGC-823) and 48.10% (MKN-45). Conclusion All-trans retinoic acid may effectively inhibit the growth of xenograft tumor in spleen and its metastasis to liver in nude mice, which can be corroborated by the decrease of carcinoembryonic antigen and microvessel density

Bone Marrow Colony-Formation In Vitro After Infection of Genetically Defined Inbred Mice with Candida Albicans

The effect of C. albicans infection on the production of haematopoietic precursor cells in the bone marrow of CBA/CaH and BALB/c mice was evaluated by assay of colony formation in vitro. In immunocompetent mice, neither systemic nor oral infection induced significant alterations in colony formation by bone marrow from the two mouse strains, and Candida infection did not alter the proportion of morphological cell types in the colonies. However, the number of neutrophil-like was relatively greater in colonies derived from acutely infected CBA/CaH nude mice than in those from BALB/c nude mice, whereas small mononuclear cells were present in higher proportions in the latter strain. In both strains of nude mice, there was an increase in colony formation at 6 days after oral infection, but at 8 weeks, when the infection had become chronic, the production of bone marrow cells by CBA/CaH nude mice was significantly less than that by BALB/c nude mice. Reconstitution of nude mice with syngeneic lymphocytes enhanced the production of bone marrow precursor cells by BALB/c, but not by CBA/CaH mice, suggesting that T cells can enhance host resistance by promoting the colony-forming response of the bone marrow in BALB/c mice that are genetically resistant to tissue damage, but not in CBA/CaH that are prone to severe lesions. Finally, culture with Candida antigen in vitro decreased the number of colony-forming cells in cultures from CBA/CaH, but not from BALB/c mice

Proteção de camundongos atímicos BALB/c (Nu/Nu) contra Plasmodium berghei por esplenócitos oriundos de camundongos normais BALB/c (Nu/+)

Camundongos atímicos BALB/c (Nu/Nu) sucumbem entre 7-13 dias após a inoculação (DAI) da cepa NK65 de Plasmodium berghei. Todavia, seus singenêicos heterozigotos (Nu/+) morrem em 7-8 DAI. Camundongos nude (Nu/Nu) reconstituídos com 2xl0(7) esplenócitos de camundongos heterozigotos singenêicos normais não infectados (Nu/+) 20 dias antes da inoculação a (DBI) do parasita, sucumbem 2 dias antes que os animais controles. Camundongos nude reconstituídos 10 ou 2 DBI, vivem 2-4 dias a mais que os animais controles e alguns deles sobrevivem. Esses achados indicam que a cepa NK65 de P. berghei induz, no mínimo, dois imunofenômenos dependentes de linfócitos T; um supressivo e outro estimulatório. A reconstituição de camundongos nude com células T de camundongos BALB/c (Nu/+) parece reduzir ou "By-pass" a atividade supressora das células T, o qual leva à formação de uma resposta imune protetora por alguns dos camundongos nude.Athymic BALB/c (Nu/Nu) mice died at 7-13 days after inoculation (DAI) of Plasmodium berghei NK65, whereas their heterozygous (Nu/+) littermates died at 7-8 DAI. Nude (Nu/Nu) mice, reconstituted with 2 x 10(7) splenocytes from uninfected heterozygous (Nu/+) littermates at 20 days before parasite inoculation (DBI), died about 2 days earlier than control nude mice; nude mice reconstituted at 10 or 2 DBI lived 2 to 4 days longer than control nudes; and nude mice reconstituted 2 DAI lived even longer and some survived. These findings indicate that P. berghei NK65 induces at least two T-cell dependent immune phenomena, one suppressive and the other stimulatory. Reconstitution of nude mice with T-cells from BALB/c (Nu/+) mice appeared to reduce or bypass suppressive T-cell activities which allowed the formation of a protective immune response by some of the nude mice