Head and neck cancer is the seventh common cancer in the world, and various existing treatment strategies provide modest benefit for most patients with head and neck cancer. Meanwhile, therapeutic strategies lacking molecular typing significantly hinder the development of individualized treatment for head and neck cancer. In recent years, connected by preclinical models, the novel ideal has gradually reached a consensus in terms of facilitating inter-transformation of clinical problems and basic achievements. As a bridge between basic research and clinical transformation, patient-derived xenografts (PDX) models precisely replicate genetic characteristics and tumor evolution, which are displaying great vitality in elucidating the mechanism of tumorigenesis and progression. Moreover, cohorts composed of several PDX models highlight the unique advantages of mice for drug screening and biomarker analysis for patients. This ideal preclinical model explores potential treatment strategies suited the ethical standards as much as possible for patients.
Animals ; Disease Models, Animal ; Head and Neck Neoplasms ; Heterografts ; Humans ; Mice ; Xenograft Model Antitumor Assays

PURPOSE: The purpose of this study was to investigate the predictability of pretreatment values including Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) derived parameters (Ktrans, Kep and Ve), early changes in parameters (Ktrans, tumor volume), and heterogeneity (standard deviation of Ktrans) for radiation therapy responses via a human colorectal cancer xenograft model. MATERIALS AND METHODS: A human colorectal cancer xenograft model with DLD-1 cancer cells was produced in the right hind limbs of five mice. Tumors were irradiated with 3 fractions of 3 Gy each for 3 weeks. Baseline and follow up DCE-MRI were performed. Quantitative parameters (Ktrans, Kep and Ve) were calculated based on the Tofts model. Early changes in Ktrans, standard deviation (SD) of Ktrans, and tumor volume were also calculated. Tumor responses were evaluated based on histology. With a cut-off value of 0.4 for necrotic factor, a comparison between good and poor responses was conducted. RESULTS: The good response group (mice #1 and 2) exhibited higher pretreatment Ktrans than the poor response group (mice #3, 4, and 5). The good response group tended to show lower pretreatment Kep, higher pretreatment Ve, and larger baseline tumor volume than the poor response group. All the mice in the good response group demonstrated marked reductions in Ktrans and SD value after the first radiation. All tumors showed increased volume after the first radiation therapy. CONCLUSION: The good response after radiation therapy group in the DLD-1 colon cancer xenograft nude mouse model exhibited a higher pretreatment Ktrans and showed an early reduction in Ktrans, demonstrating a more homogenous distribution.
Animals ; Colonic Neoplasms/*pathology/*radiotherapy ; Female ; Humans ; Magnetic Resonance Imaging/*methods ; Mice ; Mice, Nude ; Xenograft Model Antitumor Assays

OBJECTIVETo assess the safety of hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis in patients with prostate cancer, and to investigate its effect on the growth of indolent prostate cancer in vivo.

METHODSThirty severe combined-immunodeficient mice received subcutaneous injection of human prostate cancer LNCaP cells. Then they were randomized to an experimental and a control group and exposed to 20 sessions of hyperbaric oxygen and normobaric air, respectively, followed by a 4-week observation on the growth of the transplanted tumors and analyses of their histopathological features at 28 days, including the volume, microvessel density (CD34), apoptosis markers (p53 and p27 proteins) and the proliferation index (Ki-67) of the LNCaP tumors.

RESULTSOn the 28th day after tumor vaccination, the tumor volume was (120 +/- 7.9) mm3 in the HBO and (122 +/- 8.2) mm3 in the control group; the microvessel density and the expressions of Ki-67, p53 and p27 were 39.3 +/- 5.2, (78.1 +/- 7.6)%, (40.4 +/- 6.2)% and (63.7 +/- 5.1)% in the former, and 36.2 +/- 4.9, (75.3 +/- 8.4)%, (44.2 +/- 5.7)% and (61.5 +/- 5.5)% in the latter. There were no significant differences in all the indexes above between the two groups (P > 0.05).

CONCLUSIONHyperbaric oxygen did not promote the growth of indolent prostate cancer in the murine model, nor did it have any significant effect on the new vessels.

Animals ; Cell Line, Tumor ; Humans ; Hyperbaric Oxygenation ; Male ; Mice ; Mice, SCID ; Prostatic Neoplasms ; Xenograft Model Antitumor Assays

Animals ; Cell Cycle ; Doxorubicin ; pharmacology ; Drug Resistance, Multiple ; Humans ; Hyperbaric Oxygenation ; K562 Cells ; Mice ; Mice, Nude ; Xenograft Model Antitumor Assays

OBJECTIVE: To investigate inhibitory activities of a homogenous anti-human epidermal growth factor receptor 2 (HER2)-antibody drug conjugate (ADC) on the proliferation of nine tumor cell lines with different levels of HER2 expressions, and its activities on the tumor growth of five xenograft mouse models. METHODS: The HER2 expression levels of BT-474, Calu-3, MCF-7, MDA-MB-231, MDA-MB-468, SK-BR-3, SK-OV-3, HCC1954, NCI-N87 tumor cell lines were measured using QIFI KIT. For the in vitro anti-proliferation assay, serial diluted anti-HER2-ADC, ado-trastuzumab emtansine, AS269, pAF-AS269 and paclitaxel were added to the seeded cells, and after 72 or 96 hours of incubation, the cell proliferation was analyzed. For the in vivo activity, 5-6 weeks old mice were inoculated with four HER2 positive tumor cell lines HCC1954, BT-474, SK-OV-3, NCI-N87 or one HER2 negative tumor cell line MDA-MB-468. Different amounts of anti-HER2-ADC, ado-trastuzumab emtansine, trastuzumab, paclitaxel and phosphate buffered saline control were injected after the tumor volume reached a certain size, then the tumor growth inhibition was analyzed. RESULTS: The expression levels of the six high HER2-expression cell lines SK-OV-3, NCI-N87, SK-BR-3, Calu-3, HCC1954, BT-474 were between 430 000 to 800 000 receptors per cell, which were 50 times higher than those of the other three low HER2 expression tumor cell lines MDA-MB-231, MCF-7, MDA-MB-468. Anti-HER2-ADC had inhibition effects on cell lines with high level of HER2 expression in the in vitro anti-proliferation assay. The half maximal inhibitory concentrations of anti-HER2-ADC on SK-OV-3, NCI-N87, SK-BR-3, Calu-3, HCC1954, BT-474 tumor cell lines were 46 pmol/L, 17 pmol/L, 17 pmol/L, 161 pmol/L, 125 pmol/L, 50 pmol/L, respectively. Anti-HER2-ADC had a dose dependent antitumor activity in vivo in all the HER2 positive xenograft mouse models. In NCI-N87 xenograft tumor model, the same dose of anti-HER2-ADC showed better anti-tumor activity compared with trastuzumab and ado-trastuzumab emtansine, and its relative tumor proliferation rates were about 1/30 to 1/20 of the two. In HCC1954 xenograft tumor model, the complete regression of the tumor was observed. As expected, anti-HER2-ADC had no tumor inhibitory effects on MDA-MB-468 xenograft models with low HER2 expression. The antitumor activities of anti-HER2-ADC in HER2 positive xenograft tumor models were the same as or better than the activities of ado-trastuzumab emtansine. CONCLUSION The homogenous site-specific anti-HER2-ADC obtained using unnatural amino acid technology can inhibit the growth of high HER2-expression tumor cells with high potency both in vivo and in vitro.
Amino Acids ; Animals ; Breast Neoplasms ; Cell Line, Tumor ; Humans ; Immunoconjugates ; Mice ; Receptor, ErbB-2 ; Trastuzumab ; Xenograft Model Antitumor Assays

Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) might be developed as a novel anti-tumor drug due to its selective cytotoxicity in tumor cells. The predicted Macaca mulatta TRAIL (mmTRAIL) is highly homologous to hTRAIL in nucleotide acid as well as amino acid sequence, suggesting that mmTRAIL might induce apoptosis of human cancer cells. However, the cytotoxicity of mmTRAIL in human cancer cells has not been investigated. In this paper, it is reported that the gene encoding mmTRAIL has been cloned by using reverse-transcriptase polymerase chain reaction (RT-PCR) from monkey peripheral blood mononuclear cells (PBMCs) in our laboratory. Subsequently, an expression plasmid was constructed by inserting mmTRAIL gene into pQE30 plasmid. After induction by addition of Isopropyl β-D-1-Thiogalactopyranoside (IPTG), mmTRAIL was expressed. MmTRAIL was recovered from supernatant of sonicated bacteria by Ni-NTA agarose affinity chromatography. SDS-PAGE and gel filtration chromatography demonstrated that mmTRAIL forms trimer in solution. In vitro assays indicated that mmTRAIL was cytotoxic to human COLO205 tumor cells but not to normal cells at low concentration of nanomole. In addition, antitumor effect of mmTRAIL was evaluated in mice bearing human COLO205 tumor xenografts. Intratumorally injected mmTRAIL significantly inhibited growth of tumor grafts. These results suggested that mmTRAIL was valuable as candidate drug for cancer-targeted therapy.
Animals ; Antineoplastic Agents ; Apoptosis ; Cell Line, Tumor ; Cloning, Molecular ; Humans ; Leukocytes, Mononuclear ; Macaca mulatta ; Mice ; Plasmids ; TNF-Related Apoptosis-Inducing Ligand ; genetics ; metabolism ; Xenograft Model Antitumor Assays

OBJECTIVETo investigate the biodistribution of 131I-GM-CSF in SCID mice bearing human AML in vivo.

METHODSThe xenograft model of human leukemia was established in SCID mice. In the leukemia mice, the biodistribution of 131I-GM-CSF produced by chlo amine-T method was studied.

RESULTS(1)The inoculated HL-60 cells could grow in SCID mice, which developed leukemia after 4 weeks. (2) 131 I-GM-CSF was concentrated in spleen, bone marrow and tumor tissue of the mice. In spleen and bone marrow, 131 I-GM-CSF was uptaken to peak in 30 minutes after injection, the up taking rate was (442. 9+/-86. 4) % ID/g and (4283. 8+/-252. 8)% ID/g, respectively, and maintained on higher level in 24 hours. The injection of 131I resulted in an even distribution in the whole body.

CONCLUSIONS131 I-GM-CSF is able to concentrate electively in spleen, bone marrow and organs infiltrated by leukemia cells. The biodistribution of 131I-GM-CSF in the leukemia mice is tissue specific.

Animals ; Female ; Flow Cytometry ; Granulocyte-Macrophage Colony-Stimulating Factor ; pharmacokinetics ; HL-60 Cells ; Humans ; Iodine Radioisotopes ; Leukemia, Myeloid, Acute ; metabolism ; Mice ; Mice, SCID ; Xenograft Model Antitumor Assays

BACKGROUNDZhongfei Mixture (ZM), a traditional Chinese medicine, exploited from the clinical experience, has mainly been used for the treatment of advanced lung cancer since it was produced in 1983. However, little research has been conducted on its anti-tumor mechanism. In this study, we aimed to investigate the anti-tumor and apoptotic effects of ZM in vitro and in vivo.

METHODSThe growth inhibition effect of ZM on A549 cells was evaluated by MTT assay. Morphological observation and clone forming tests were performed to determine the effect of ZM on cell viability. Cell cycle distribution and apoptosis were analyzed by flow cytometry. In addition, the in vivo anti-proliferation activity of ZM was evaluated using mice bearing Lewis lung carcinoma. Further, the apoptosis of cells in tumor tissue was determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and the expression of Ki-67 protein in tumor tissues was analyzed by En-Vision immuno-histochemistry staining.

RESULTSZM exerted an obvious inhibitory effect on proliferation of A549 cells. It arrested A549 cells in G(2)-M phase and induced apoptosis. Compared with 3.02% and 5.32% in control group, the percentages of cells arrested in G(2)-M phase were 19.20% and 19.58% in 7.94 mg/ml ZM treated A549 cells at 24 hours and 48 hours. Moreover, the apoptosis rate increased from 0.18% to 18.01% after ZM treatment for 48 hours. ZM also significantly inhibited tumor growth in the tumor-implanted mice. Compared with saline control group, the effects of ZM showed significant tumor growth inhibition (P < 0.05). Furthermore, ZM could down-regulate the expression of Ki-67 in tumor tissue in mice bearing Lewis lung carcinoma.

CONCLUSIONSOur results indicated that ZM has notable anti-tumor effect and the effects of ZM in moderate dose groups were superlative both in vitro and in vivo. The possible mechanism of ZM might be associated with arresting cell cycle in G(2)-M phase as well as down-regulating Ki-67 expression in tumor tissues.

Animals ; Antineoplastic Agents ; therapeutic use ; Apoptosis ; drug effects ; Cell Line, Tumor ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Medicine, Chinese Traditional ; methods ; Mice ; Xenograft Model Antitumor Assays

OBJECTIVETo establish a bone metastasis model of prostate cancer by intratibia injection of Du145 in nude mice, observe the local growth of tumor in tibia and then assess application value of this model.

METHODSFor 9 male nude mice, Du145 (5 x 10(6)) was injected in tibia by a TB syringe with a 29-gauge needle at a dose of 30 microl per mouse. Then the vital signs of the nude mice were observed. When the mice were dying, they were sacrificed, and the tissues of right hindlimbs, lymphatic nodes, lungs and livers were taken out, fixed in 10% formalin, embedded in paraffin, stained by HE and then observed microscopically.

RESULTSIncidence of bone tumor after intratibia injection was 67% (6 out of 9). About 48 days later, there were some small palpable nodes in right hind-limbs of the 6 mice and they couldn't walk normally. About 55 days later, cachexia occurred in them. After dissection, some carrion-like tissue grew from marrow cavity to muscular spatium, which was identified as tumor tissue by HE. The envelop of livers became crampy, and acute hepatitis could be diagnosed through microscopy, which represented a large scale of hepatocytic death, liver sinus dilatation and hyperemia, hepatic lobule infiltrated by lymphocyte, macrophage and inconspicuous hyperplasia. Since hypohepatia occurred too early, we couldn't detected distant metastases.

CONCLUSIONThe intratibia injection model is an optimal animal model to study metastasis of prostate cancer. It mimics the natural situation of human prostate cancer and will help to understand the mechanisms of androgen-independence and osseous metastasis, and tumor-host determinants of PSA expression.

Animals ; Bone Neoplasms ; secondary ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Prostatic Neoplasms ; pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; methods

BACKGROUNDNeuroblastoma (NB) is one of the most common malignant solid tumors of childhood. It is still not clear whether the apoptosis of tumor cells or the non-tumor cells contributes to the increase of concentration of cytochrome c (Cyt c) in the serum of the cancer patients. The aim of this research was to identify the source of the Cyt c in the serum when the tumor grows up by subcutaneous inoculation of human NB cells into nude mice.

METHODSWe subcutaneously inoculated human NB cells (KP-N-NS) into nude mice and collected the sera of tumor-bearing mice (n = 14) and control mice (n = 25) 4 weeks later in order to screen for and identify differentially expressed proteins in the serum. Differentially expressed proteins in the serum were screened by surface-enhanced laser desorption/ionization-time-of-flight (SELDI-TOF) mass spectrometry.

RESULTSThe relative intensity of a protein having a mass-to-charge ratio (m/z) of 11 609 was 3338.37 ± 3410.85 in the tumor group and 59.84 ± 40.74 in the control group, indicating that the expression level of this protein in the tumor group was 55.8 times higher than that in the control group. Serum proteins were separated and purified by high-performance liquid chromatography (HPLC). Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to produce peptide mass fingerprints (PMFs). Spectrum analysis and a database search revealed that the highly expressed protein (m/z = 11 605.4) from the serum of tumor-bearing mice was the mouse Cyt c.

CONCLUSIONSIncreased concentration of Cyt c in the serum of tumor-bearing nude mice might be partially attributed to the secretion of this protein by non-tumor cells.

Animals ; Apoptosis ; physiology ; Cell Line, Tumor ; Chromatography, High Pressure Liquid ; Cytochromes c ; blood ; Female ; Humans ; Mice ; Mice, Nude ; Neuroblastoma ; blood ; Tandem Mass Spectrometry ; Xenograft Model Antitumor Assays