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1.
Jeffrey S. Barrett Susan J. Fisher R. L. Wahl 《Cancer immunology, immunotherapy : CII》1997,44(3):173-178
To optimize the regional delivery advantage with i. p. administration of monoclonal antibody (mAb) for radioimmunotherapy,
it may be possible to delay the rate and extent of mAb absorption from the peritoneal cavity by simply altering the position
of a patient after radioantibody administration. It has been shown that the hydrostatic pressure against the diaphragm plays
a major role in the rate of egress of radioantibodies from the peritoneal cavity and that fluid removal from the peritoneal
cavity can be altered by posture. The current study examined postural effects in normal rats following the i. p. injection
of 125I-5G6.4 murine IgG2a anticarcinoma antibody (45 μCi). A 10-ml injection volume of the radioantibody solution was administered
to rats restrained in either a supine or inclined (reverse Trendelenburg; feet down at a 45° angle) position. Pharmacokinetic
analysis confirmed that the appearance of the radioantibody into the systemic circulation was delayed in the inclined group.
The time to peak blood concentration was prolonged from 14.7 (supine) to 19.2 (inclined) hours (P = 0.005). All other pharmacokinetic parameters were equivalent across the treatment groups. The mean half-life of 166 h,
mean blood clearance of 9 ml/min, and mean steady-state volume of distribution of 36 ml were consistent with previous experience
with this radioantibody in the rat. The intrinsic absorption profile indicated that the mean percentage absorption from the
peritoneal cavity to the blood stream was greater in the supine animals from 4 h after i. p. injection until absorption was
complete. By 10 h after injection, absorption from the peritoneal cavity was essentially complete in the supine-dosed animals,
while those restrained in an inclined position had cleared only 50% of the total absorbed dose. Hence, the regional delivery
advantage afforded by intraperitoneal administration of the radioantibody may be further exploited by maintaining an inclined
position throughout the absorption phase, a strategy that may be applicable to radioimmunotherapy of patients.
Received: 26 July 1996 / Accepted: 27 January 1997 相似文献
2.
Navin Reddy Gaik Lin Ong T. M. Behr Robert M. Sharkey David M. Goldenberg M. J. Mattes 《Cancer immunology, immunotherapy : CII》1998,46(1):25-33
We reported previously that the blood clearance of injected mouse IgG2a was extremely rapid in many strains of nude and nu/+ mice. In an attempt to determine the cause of this phenomenon, the levels of endogenous IgG2a in the blood of these mice
was assayed. It was found that the serum level of IgG2a was extremely low in many of these mice, below 50 μg/ml, which is
20–100 times lower than the expected normal value. Great heterogeneity between individual mice was observed in their blood
level of IgG2a, and there was an excellent correlation between low blood IgG2a levels and rapid clearance of injected IgG2a.
Thus, the blood IgG2a levels are so low that a novel, previously undescribed effect occurs, namely the rapid clearance of
small amounts of injected IgG2a. The clearance is due primarily to binding sites in the spleen and liver. The low level of
endogenous IgG2a is not due to the lack of a thymus, since it occurs in nu/+ as well as nude mice, but can probably be attributed to the very clean environment in which these mice are raised. In assays
of sera from approximately 50 mouse strains, low IgG2a levels were found in all nude colonies and also in some normal mouse
strains. Some nude mice displayed relatively normal IgG2a clearance rates despite having low levels of endogenous IgG2a. In
repeated bleedings of individual mice, IgG2a levels were found to fluctuate greatly. A similar clearance effect was observed
with a human IgG1 Ab injected into mice. This rapid clearance of injected IgG, of certain subclasses, represents a practical
problem for many experiments in which antibodies are used for diagnosis or therapy, and several methods of circumventing the
problem are discussed.
Received: 15 August 1977 / Accepted: 14 October 1997 相似文献
3.
Characterization of a high-affinity monoclonal antibody specific for CD44v6 as candidate for immunotherapy of squamous cell carcinomas 总被引:5,自引:0,他引:5
K.-H. Heider Marlies Sproll Susanne Susani Erik Patzelt Paul Beaumier Elinborg Ostermann Horst Ahorn Günther R. Adolf 《Cancer immunology, immunotherapy : CII》1996,43(4):245-253
Variant isoforms of CD44, a family of cell-surface glycoproteins generated by alternative splicing and post-translational
modifications, are expressed in a variety of human tumors and play important roles in tumor progression and metastasis formation.
The murine monoclonal IgG1 antibody VFF18, specific for an epitope encoded by human CD44 variant exon 6, binds with high affinity
to the recombinant protein (K
d = 1.7×10–10 M) as well as to tumor cell lines in vitro, and is suitable for immunohistochemical analysis of human tumors. Screening of
more than 500 tumor samples of different histogenesis showed that VFF18 most strongly and uniformly reacts with squamous cell
carcinomas (SCC). Detailed analysis of 185 SCC (head and neck, lung, skin) confirmed reactivity of the antibody with 99% of
the samples, with intense and homogeneous staining of the tumor cells in the majority of cases, whereas reactivity of VFF18
with normal tissues is limited to certain epithelia and activated lymphocytes. When radiolabelled VFF18 was administered to
nude mice bearing human epidermoid carcinoma (A-431) xenograft, fast and selective tumor uptake of the radioimmunoconjugate
with a maximum of 18% of the injected dose per gram of tissue was observed. Taken together, these data suggest that mAb VFF18
is a promising targeting vehicle for radioimmunotherapy of squamous cell carcinomas in humans.
Received: 9 September 1996 / Accepted: 25 September 1996 相似文献
4.
Construction and characterization of the chimeric monoclonal antibody E48 for therapy of head and neck cancer 总被引:1,自引:0,他引:1
Ruud H. Brakenhoff Frank B. van Gog James E. Looney Marijke van Walsum Gordon B. Snow Guus A. M. S. van Dongen 《Cancer immunology, immunotherapy : CII》1995,40(3):191-200
Data from an ongoing clinical radioimmunoscintigraphy trial indicate that99mTc-labeled monoclonal antibody (mAb) E48 is highly capable of selectively targeting squamous cell carcinoma of the head and neck (HNSCC). The percentage of the injected dose per gram of tumor tissue was found to be high, rendering mAbE48 a promising candidate mAb for therapeutic purposes. We now describe the construction of a chimeric (moouse/human) mAb E48 by recombinant DNA technology. The genes encoding the variable domains of the heavy and light chain were cloned and ligated into experession vectors containing the human 1 heavy-chain gene and the human k lightchain gene respectively. Biological properties of the resulting chimeric mAb E48 were compared to the murine form in vitro and in vivo. The reactivities of chimeric (c)mAb and murine (m)mAb E48 with HNSCC, as assessed by immunohistochemical staining as well as immuno-blotting were shown to be similar. The affinity constant appeared to be 0.9×1010 M–1 and 1.6×1010 M–1 for the mmAb and cmAb respectively. The biodistribution of both antibodies was tested by simultaneous injection into nude mice bearing human HNSCC xenografts. cmAb E48 was found to be cleared more rapidly from the blood than mmAb E48, resulting in a 30% lower tumor uptake but similar tumor to non-tumor ratios, 3 days after injection. Moreover, it was shown that cmAb E48 is highly capable of lysing HNSCC targets in ADCC assays in vitro, whereas the mmAb appeared to be almost incative. These data indicate that cmAb E48 has potential as a targeting agent for the eradication of HNSCC in man. 相似文献
5.
Fataki Bombil Jean Pierre Kints Xavier Havaux Jean Marie Scheiff Hervé Bazin Dominique Latinne 《Cancer immunology, immunotherapy : CII》1995,40(6):383-389
The transfer of human peripheral blood mononuclear cells (hu-PBMC) from adult Epstein-Barr- virus(EBV)-seropositive donors
in SCID (severe combined immunodeficiency) mice frequently leads to the development of a human B lymphoproliferative syndrome
(hu-BLPS). Therefore, as 90% of adult potential donors are EBV-seropositive, efforts have to be made to avoid the occurrence
of this B lymphoproliferative disorder. McCune et al. [Science 241:1632 (1988)] used human fetal organs for a human SCID graft.
This system does not give rise to hu-BLPS but human fetal organs are much less available than peripheral blood leucocytes.
The experiments reported in this paper show how crucial is the presence of functional T lymphocytes for a graft to take and for development of hu-BLPS in hu-PBMC-reconstituted SCID mice, since inhibition of
T lymphocyte by a rat anti-(human CD2) monoclonal antibody (LO-CD2a) during the first 10 days of the graft prevents successful
engraftment of human normal lymphocytes as well as hu-BLPS in SCID mice. The transfer of B cells alone or B cells plus monocytes
in SCID mice does not permit either long-term engraftment or development of hu-BLPS. We also demonstrate that hu-PBMC treated
with L-leucine methyl ester are less susceptible to the development of hu-BLPS after engraftment in SCID mice than are untreated
hu-PBMC. The mechanism of action of L-leucine methyl ester on these cells is discussed.
Received: 12 December 1994 / Accepted: 20 March 1995 相似文献
6.
Human neutrophil interactions of a bispecific monoclonal antibody targeting tumor and human Fcγ RIII
L. M. Weiner R. Katherine Alpaugh Anne R. Amoroso Gregory P. Adams David B. Ring Malcolm W. Barth 《Cancer immunology, immunotherapy : CII》1996,42(3):141-150
2B1 is a bispecific murine monoclonal antibody (bsmAb) targeting the c-erbB-2 and CD16 (FcγRIII) antigens. c-erbB-2 is over-expressed
by a variety of adenocarcinomas, and CD16, the low-affinity Fcγ receptor for aggregated immunoglobulins, is expressed by polymorphonuclear
leukocytes (PMN), natural killer (NK) cells and differentiated mononuclear phagocytes. 2B1 potentiates the in vitro lysis
of c-erbB-2 over-expressing tumors by NK cells and macrophages. In this report, the interactions between 2B1 and PMN were
investigated to assess the impact of these associations on in vitro 2B1-promoted tumor cytotoxicity by human NK cells. The
peak binding of 2B1 to PMN was observed at a concentration of 10 μg/ml 2B1. However, 2B1 rapidly dissociated from PMN in vitro
at 37°C in non-equilibrium conditions. This dissociation was not caused by CD16 shedding. When PMN were labeled with 125I-2B1 and incubated at 37°C and the supernatants examined by HPLC analysis, the Fab regions of dissociated 2B1 were not complexed
with shed CD16 extracellular domain. While most of the binding of 2B1 to PMN was solely attributable to Fab-directed binding
to FcγRIII, PMN-associated 2B1 also bound through Fcγ-domain/FcγRII interactions. 2B1 did not promote in vitro PMN cytotoxicity
against c-erbB-2-expressing SK-OV-3 tumor cells. When PMN were coincubated with peripheral blood lymphocytes, SK-OV-3 tumor
and 2B1, the concentration of 2B1 required for maximal tumor lysis was lowered. Although PMN may serve as a significant competitive
binding pool of systemically administered 2B1 in vivo, the therapeutic potential of the targeted cytotoxicity properties of
this bsmAb should not be compromised.
Received: 3 May 1995 / Accepted: 6 February 1996 相似文献
7.
siRNA blocking the RAS signalling pathway and inhibits the growth of oesophageal squamous cell carcinoma in nude mice 下载免费PDF全文
Xinjie Wang Yuling Zheng Qingxia Fan Xudong Zhang Yonggang Shi 《Cell biochemistry and function》2014,32(8):625-629
The aim of this study was to study RAS‐siRNA blocking RAS pathway and suppressing cell growth in human oesophageal squamous cell carcinoma in nude mice. The methods in this study was to construct RAS‐siRNA expression vector, establish 40 oesophageal squamous cell carcinoma xenograft animal models and divided them into five groups: control group, siRNA control group, RAS‐siRNA group, paclitaxel group and RAS‐siRNA and paclitaxel group. We observed tumour growth in nude mice, studied histology by HE staining, tumour growth inhibition by TUNEL assay and detected the RAS, MAPK and cyclin D1 protein expression by immunohistochemistry and western blot. We have obtained the following results: (i) successfully established animal models; (ii) nude mice in each group after treatment inhibited tumour volume was significantly reduced compared with the control group (p < 0.05); (iii) compared with the control group, the number of apoptotic cells were significantly increased in the siRNA control group and the RAS‐siRNA group, and the number of apoptosis cells in the paclitaxel and RAS‐siRNA group is significantly most than the paclitaxel group and RAS‐siRNA group (p < 0.05); and (iv) after treatment, RAS, MAPK and cyclin D1 expression in five groups was decreasing gradually. After adding paclitaxel, the protein expression in the paclitaxel and RAS‐siRNA group was significantly lower than that of paclitaxel group, negative control and paclitaxel group (p < 0.05). We therefore conclude that RAS‐siRNA can block the RAS signal transduction pathway, reduce the activity of tumour cells, arrest tumour cell cycle, promote apoptosis, inhibit cell proliferation and increase tumour cell sensitivity to chemotherapeutic drugs. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
8.
Nicole L. W. Van Hal G. A. M. S. Van Dongen C. B. M. Ten Brink Jim N. Herron Gordon B. Snow R. H. Brakenhoff 《Cancer immunology, immunotherapy : CII》1997,45(2):88-92
Monoclonal antibody (mAb) U36 was developed for the treatment of minimal residual disease of head and neck squamous cell
carcinoma (HNSCC). The mAb-U36-defined antigen was characterized by cDNA cloning, and was shown to be identical to the keratinocyte-specific
CD44 splice variant epican. The epitope recognized by mAb U36 was shown to be located in the v6 domain. Two amino acids within
the epitope appeared to differ from the sequences that have been described in literature. The sequence of the epitope appeared
to contain glutamic acid at position 367 and lysine at position 374, while valine and arginine respectively have been described
before. Interestingly, another anti-CD44v6 antibody with possible clinical application, VFF18, recognizes an epitope in the
same area. With respect to the applicability of these antibodies for tumor targeting, this variation might have an influence
on antibody-antigen interaction and mAb accumulation in the tumor. Furthermore, this observation raised the question whether
the different epitopes are related to the malignant behavior of tumor cells. In this paper we determine the relative affinity
of mAb U36 for the variant epitope sequences by tumor cell binding assays using synthetic peptides for competition. The presence
of glutamic acid instead of valine at position 367 caused strong competition. Further evaluation showed that the published
valine variant does not exist in vivo, and is the result of a sequencing artefact. The effect of substitution of lysine for
arginine at position 374 had no effect on the binding of mAb U36 to the cells. This amino acid variation was shown to be due
to allelic polymorphism. There was no trend towards allelic imbalance in tumor cells as compared to normal cells.
Received: 5 June 1997 / Accepted: 14 August 1997 相似文献
9.
Humoral anti-idiotypic and anti-anti-idiotypic immune response in cancer patients treated with monoclonal antibody 17-1A 总被引:4,自引:0,他引:4
Peter Ragnhammar Maria Liljefors Anna-Lena Hjelm Håkan Mellstedt Jan-Erik Frödin J. Fagersberg 《Cancer immunology, immunotherapy : CII》1996,42(2):81-87
A group of 96 patients with advanced colorectal carcinoma were treated with the mouse (m) or chimeric (c) (mouse variable
regions × human IgG1 constant regions) monoclonal antibody (mAb) 17-1A recognizing the tumour-associated antigen GA733-2.
Eighty-two of the 83 patients treated with mmAb17-1A and 69% of the patients given cmAb17-1A (n = 13) developed anti-idiotypic antibodies (ab2). Auto-antibodies binding to tumour cells expressing GA733-2 were found in 7% of the patients. In a further 38 patients (40%)
antitumour-cell antibodies, i.e. anti-anti-idiotypic antibodies (ab3), were induced by the mAb17-1A therapy. Patients with detectable ab3 after treatment had significantly higher ab2 levels than those not developing ab3. Addition of granulocyte/macrophage-colony-stimulating factor (GM-CSF) to mmAb17-1A significantly enhanced the induction
of ab2 as well as induction of anti-anti-idiotypic antibodies (ab3), compared to mmAb17-1A alone. Patients with a high increase in antitumour-cell antibodies (ab3) induced by the therapy lived significantly longer than patients with no or a low level of induction of ab3 (P = 0.016). The results indicate that induction of an idiotypic network response might be an important effector mechanism in
mAb therapy.
Received: 20 October 1995 / Accepted: 18 December 1995 相似文献
10.
Tove Olafsen Charlotte K. Munthe Lund Øyvind S. Bruland Inger Sandlie Terje E. Michaelsen 《Cancer immunology, immunotherapy : CII》1999,48(7):411-418
Osteosarcoma is the commonest malignant tumour of the bones. The presence of micrometastases at the time of primary diagnosis
is associated with poor prognosis. Despite developments in surgery and aggressive chemotherapy, about 50% of the patients
still succumb to the disease. Thus, there is a need to develop alternative treatment modalities. One such strategy is to use
antibodies with improved effector functions. The two monoclonal antibodies, TP-1 and TP-3, recognize a tumour-associated antigen
on human osteosarcoma cells. In the present study, we describe the cloning of the TP-1 variable genes, and the production
of complete chimeric mouse/human monoclonal antibodies. Constructs containing the constant genes from human IgG1, IgG3 or
a mutant IgG3 with a shortened hinge region, called m15, were expressed in the mouse myeloma cell line, NS0. The m15 mutant
has been shown to be very potent in triggering complement-mediated lysis. Our goal was to investigate whether this mutant
could overcome the complement protection on human osteosarcoma cells, which is generally present on all human cells. We found
that the target cells expressed several membrane-bound complement inhibitors, and that masking of these inhibitors rendered
the cells sensitive to lysis. The m15 mutant exhibited greater lytic activity than both IgG3 and IgG1, although it could not
cause extensive killing of the target cells alone.
Received: 21 January 1999 / Accepted: 3 June 1999 相似文献
11.
Establishment of internal-image anti-idiotype monoclonal antibodies to a human antibody to lung cancer 总被引:4,自引:0,他引:4
Hiroaki Saito Masaru Taniguchi Toshio Fukasawa Yutaka Yamaguchi T. Fujisawa 《Cancer immunology, immunotherapy : CII》1997,44(2):83-87
Internal-image anti-idiotype antibodies are expected to enhance anticancer effector mechanisms in vivo. The objective of
this study was to establish hybridomas producing anti-idiotype monoclonal antibodies against a human monoclonal antibody (hmAb)
4G12 that reacts strongly with lung squamous cell carcinomas. BALB/c female mice 6 weeks old were immunized with 4G12. Splenocytes
were hybridized with P3U1 cells and hybrid cells secreting anti-4G12 hmAb were cloned. Two clones reacted with 4G12 hmAb but
not with 3H12 IgM hmAb, human IgM, human serum or fetal calf serum. These two Ab2 antibodies (IgG1κ) 2B12 and 2H1 demonstrated
91.5% and 90.3% inhibition in their reactivity with radiolabelled 4G12 on PC10 cells, indicating that 2B12 and 2H1 antibodies
were of the Ab2β type. In criss-cross inhibition assays, the binding of 2B12 or 2H1 to 4G12 was not inhibited by 2H1 or 2B12.
Thus 2B12 and 2H1 were thought to recognize the different epitopes on the antigen-binding sites. Antisera against 2B12 and
2H1 demonstrated specific reactivity to PC10 cells. The two Ab2β antibodies, 2B12 and 2H1, express internal images of lung
squamous cell carcinoma recognized by the 4G12 antibody and may be useful for cancer immunotherapy.
Received: 20 September 1996 / Accepted: 2 January 1997 相似文献
12.
N. K. Egilmez Yong S. Jong Yoshimi Iwanuma Jules S. Jacob Camilla A. Santos Fang-An Chen Edith Mathiowitz Richard B. Bankert 《Cancer immunology, immunotherapy : CII》1998,46(1):21-24
A novel biodegradable poly(lactic acid) microsphere formulation was evaluated for in vivo cytokine immunotherapy of cancer
in a human tumor xenograft/severe combined immunodeficiency (SCID) mouse model. Co-injection of interleukin-2 (IL-2)-loaded
microspheres with tumor cells into a subcutaneous site resulted in the complete suppression of tumor engraftment in 80% of
animals. In contrast, bovine-serum-albumin(BSA)-loaded particles or bolus injections of poly(ethylene glycol)/IL-2 were ineffective
in preventing tumor growth. The antitumor effect of IL-2 released by the microspheres was shown to be mediated by the mouse
natural killer cells. This is the first evidence that the rejection of human tumor xenografts can be provoked by the sustained
in vivo delivery of IL-2 from biodegradable microspheres. The use of poly(lactic acid) microspheres to deliver cytokines to
the tumor environment could provide a safer and simpler alternative to gene therapy protocols in the treatment of cancer.
Received: 9 September 1997 / Accepted: 30 October 1997 相似文献
13.
Noboru Oriuchi Naoyuki Watanabe Hidetoshi Kanda Makoto Hashimoto Sumio Sugiyama Seiichi Takenoshita Kyouichi Imai Ryuzou Ueda K. Endo 《Cancer immunology, immunotherapy : CII》1998,46(6):311-317
The study was designed to clarify the difference in pharmacokinetics of monoclonal antibodies (mAb) in animal models and
humans, and to elucidate the applicability of animal models. 99mTc-labeled murine mAb – against carcinoembryonic antigen (designated BW431/26), and neural cell adhesion molecule (NE150)
– and one chimeric mouse/human mAb against nonspecific cross-reacting antigen (chNCA) were administered i.v. to normal mice
and athymic mice (370 kBq, 400 ng) xenografted with human cancer cells expressing antigens, and into patients with tumor (925
MBq, 1 mg). The biodistribution of two of the three mAb (not 99mTc-BW431/26) differed clearly in mice and patients. 99mTc-NE150 showed specific uptake in xenografted tumor and otherwise a normal biodistribution; however, clinical examination
showed increased uptake in the liver with rapid blood clearance (mean α half-life = 31.1 min) compared with 99mTc-BW431/26 (28.4 h). 99mTc-chNCA demonstrated increased blood clearance and renal excretion in both normal and athymic mice, with accumulation in
tumors. Clinical examination showed rapid blood clearance (mean α half-life = 6.4 min) and increased uptake in the liver.
High-performance liquid chromatographic analysis of 99mTc-chNCA revealed the immune complex in blood, suggesting uptake of the complex by the reticuloendothelial cells. The biodistribution
of radiolabeled mAb in animal and human models was variable and specific for each of the three mAb. The results of animal
studies with mAb should be evaluated carefully before being extrapolated to humans, on the basis of the nature of the mAb
and interacting substances.
Received: 9 April 1997 / Accepted 3 March 1998 相似文献
14.
Henning Bier Thomas Hoffmann Inge Haas Anke van Lierop 《Cancer immunology, immunotherapy : CII》1998,46(3):167-173
Squamous cell carcinomas of the head and neck (SCCHN) frequently display high levels of the epidermal growth factor receptor
(EGFR). Since EGFR is expressed on the cell surface it may form a suitable target for anticancer therapy with anti-receptor
monoclonal antibodies (mAb). Besides the interference with receptor/ligand interactions, binding of mAb to EGFR leads to immunoglobulin-coated
tumour cells that may induce or enhance non-specific immune effector mechanisms like antibody-dependent cell-mediated cytotoxicity
(ADCC). In established cell lines of SCCHN (UM-SCC 11B, 14C, 22B, and 8029 NA) we investigated the antitumour activity of
allogeneic peripheral blood mononuclear cells (PBMC) in combination with rat (ICR 62), mouse (EMD 55900), and humanized (EMD
72000) anti-EGFR mAb. In addition, autologous PBMC were available for tumour line UD-SCC 4. The EGFR protein content of the
tumour cell lines ranged between 170 fmol/mg protein and 8100 fmol/mg protein, and MCF-7 cells served as receptor-negative
controls. PBMC activity against SCCHN targets was determined in 96-well microtitre-plate monolayer cultures by the colorimetric
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after coincubation for 4 h, 24 h and 72 h at effector target
ratios of 1:1, 5:1, 10:1 and 20:1. PBMC subpopulations were obtained by macrophage depletion (plastic adherence) or natural
killer (NK) cell enrichment (magnetic bead negative selection). Prolonged time of exposure and increased effector:target ratios
revealed marked antitumour activity of PBMC alone. This non-specific immune destruction was enhanced considerably by humanized
and rat, but not mouse anti-EGFR mAb. Increased EGFR protein in tumour cells partly correlated with an intensification of
ADCC but was accompanied by decreased primary PBMC cytotoxicity. The utilization of PBMC subpopulations suggested a mainly
NK-cell-mediated ADCC, which appeared to benefit directly or indirectly, e.g. via the secretion of cytokines, from other PBMC
components. In conclusion, humanized (EMD 72000) and rat (ICR 62) anti-EGFR mAb were able to generate strong antitumour ADCC
in target monolayers of SCCHN.
Received: 5 December 1997 / Accepted: 15 January 1998 相似文献
15.
【目的】探讨斑蝥素酸镁对人肝癌细胞SMMC-7721及其裸鼠皮下移植瘤的影响。【方法】1、采用磺酰罗丹明染色法(SRB法)检测不同浓度斑蝥素酸镁在体外对人肝癌细胞SMMC-7721增殖的抑制作用;2、流式细胞术检测斑蝥素酸镁对人肝癌细胞SMMC-7721细胞周期和细胞凋亡的影响;3、Hoechst33342染色观察斑蝥素酸镁对人肝癌细胞SMMC-7721细胞形态的影响;4、透射电镜观察斑蝥素酸镁作用后人肝癌细胞SMMC-7721超微结构的变化;5、建立人肝癌细胞SMMC-7721裸鼠皮下移植瘤模型,实验组每只裸鼠瘤周注射斑蝥素酸镁6.26×10?5 mmol,对照组给予相同容积的无菌生理盐水瘤周注射,计算抑瘤率;6、原位末端标记染色(TUNEL)法检测人肝癌裸鼠皮下移植瘤组织细胞凋亡情况。【结果】1、斑蝥素酸镁对人肝癌细胞SMMC-7721有比较明显的抑制作用,抑制率随药物浓度的增加而升高,呈剂量效应关系,其半数抑制浓度(IC50)为1.79?mol/L;2、流式细胞检测结果显示:人肝癌细胞SMMC-7721在斑蝥素酸镁的作用下,G0/G1期细胞减少,G2/M期细胞增加,细胞出现G2/M期阻滞;细胞凋亡率随斑蝥素酸镁浓度加大而逐渐增加;3、Hoechst33342染色镜下显示:斑蝥素酸镁作用后人肝癌细胞SMMC-7721出现凋亡细胞形态特征;4、透射电镜观察:斑蝥素酸镁作用后人肝癌细胞SMMC-7721出现细胞核异形、染色质聚集成团、边集,见凋亡小体;5、斑蝥素酸镁组肿瘤体积、重量显著小于生理盐水组(P﹤0.05),抑瘤率为49%;6、TUNEL法提示斑蝥素酸镁组移植瘤组织细胞凋亡率显著高于生理盐水组(χ2=92.609,P﹦0.000)。【结论】斑蝥素酸镁对人肝癌细胞SMMC-7721在体内外均有抑制增殖作用,并可以诱导肿瘤细胞凋亡,其凋亡的发生与细胞分裂期阻滞有关。 相似文献
16.
Mitsuhiro Takenoyama Kosei Yasumoto Mamoru Harada Keizo Sugimachi Kikuo Nomoto 《Cancer immunology, immunotherapy : CII》1998,47(4):213-220
Monoclonal antibodies (mAb) are promising substances for the treatment of colorectal carcinoma, but the efficiency of this
therapy still needs further improvement. We used a flow-cytometric cytotoxicity test to determine the efficacy of the cytokines
interferon α (IFNα) and γ (IFNγ), interleukin-2 (IL-2), macrophage-colony-stimulating factor (M-CSF), granulocyte/macrophage-CSF
(GM-CSF) and tumor necrosis factor α (TNFα) in enhancing the antibody-dependent cellular cytoxicity (ADCC) of the mAb 17-1A
and the mAb BR55-2 against the colorectal carcinoma cell line HT29. In experiments performed at an effector to target ratio
of 9:1, with peripheral blood mononuclear cells from five healthy volunteers as effector cells, we found that IFNα, IFNγ and
IL-2 significantly augmented the ADCC of both mAb at concentrations between 3 ng/ml and 30 ng/ml. The other three cytokines
were not effective. In further experiments we examined combinations of the three effective cytokines in different concentrations.
The combination of IFNα and IL-2 proved to be optimal in enhancing ADCC of both mAb. Thus, the examination of ADCC by flow
cytometry may reveal potentially useful combinations of cytokines and mAb for the treatment of colorectal carcinoma.
Received: 11 September 1997 / Accepted: 19 February 1998 相似文献
17.
Efficacy and toxicity of plasma-cell-reactive monoclonal antibodies B-B2 and B-B4 and their immunotoxins 总被引:2,自引:0,他引:2
W. C. Vooijs J. Post J. Wijdenes H.-J. Schuurman A. Bolognesi L. Polito F. Stirpe E. J. E. G. Bast G. C. de Gast W. Vooijs 《Cancer immunology, immunotherapy : CII》1996,42(6):319-328
Immunotherapy based on the delivery of toxic agents to the tumor site using monoclonal antibodies (mAb) may be a promising
modality in the treatment of hematological malignancies. In the selection of mAb, both for ex vivo but even more for in vivo
therapy, not only their reactivity to the neoplastic cells should be considered, but also reactivity to other body constituents.
Here we describe the screening of two human plasma-cell-reactive mAb B-B2 and B-B4, which may be used for immunotherapy of
multiple myeloma. Cross-reactivity of B-B2 and B-B4 was determined by immunohistochemistry on a series of tissues. This revealed
for both B-B2 and B-B4 a strong staining of epithelial cells in various organs, e.g. lung, liver, skin, kidney and gut, while
only a weak and diffuse staining was seen with endothelial cells. In bone marrow reactivity was only found with plasma cells
and not with hemopoietic precursors (CD34+ cells). Immunotoxins from B-B2 and B-B4 were constructed by coupling them to the plant-derived ribosome-inactivating protein
saporin. Both B-B2 and B-B4 immunotoxins appeared to be efficient in specific inhibition of protein synthesis in plasma cell
lines (IC50 respectively 1 nM and 0.1 nm). The immunotoxins were also tested on epithelial cell line A431, on liver cell line HepG2 and
on human umbilical vein endothelial cells. The epithelial cell line A431 was reactive with both B-B2 and B-B4, but was only
inhibited by B-B4 immunotoxin. Cell line HepG2 was reactive with both mAb, but was not inhibited by either immunotoxin. The
endothelial cells showed no reactivity with B-B2 and B-B4 and were not inhibited by either immunotoxin. Bone marrow treated
with B-B2 and B-B4 immunotoxin did not show a decrease in colonies of hemopoietic precursor cells. Incubation of multiple-myeloma-derived
bone marrow with these immunotoxin resulted in a clear decrease of the number of plasma cells.
Received: 13 March 1996 / Accepted: 21 May 1996 相似文献
18.
Y. Kikuchi Eiji Imaizumi Yoshitaka Kataoka Junko Hirata Tsunekazu Kita Takehiko Tode Ichiro Nagata 《Cancer immunology, immunotherapy : CII》1997,43(5):257-261
The aim of this study was to elucidate the effect of intraperitoneal (i.p.) instillations of granulocyte-colony-stimulating
factor (G-CSF) and/or interleukin-2 (IL-2) on ascites formation and the survival time of nude mice with malignant ascites,
produced by i.p. inoculation of human ovarian cancer cells. When the nude mice were treated with medium alone, ascites was
observed in all mice 28 days after tumor inoculation. When the mice were treated with cis-diamminedichloroplatinum(II) (cisplatin) alone, G-CSF alone or IL-2 alone, it took 35 days for the ascites to form in all
mice. When cisplatin was combined with G-CSF or IL-2, one of ten mice did not form ascites during the observation period.
Surprisingly, when G-CSF and IL-2 were simultaneously administered, ascites formation was not observed in any mice. Although
i.p. treatment with cisplatin alone significantly prolonged the survival time, compared to medium alone, the lytic activity
of spleen cells against HRA cells was significantly suppressed. When G-CSF or IL-2 was combined with cisplatin, the suppression
by cisplatin was eliminated and subsequently resulted in a prolongation of the survival time. When G-CSF was combined with
IL-2, both the peritoneal and splenic macrophages/monocytes were stimulated and the splenic lytic activity was about double
that following treatment with G-CSF alone on IL-2 alone, suggesting that complete inhibition of ascites formation results
not only from a significant increase of the peritoneal macrophages but also from enhancement of the lytic activity. Two mice,
died from dissemination of tumor in the abdominal cavity, but eight mice survived without tumor for more than 90 days. As
confirmed by monitoring body weight and hematocrit, G-CSF and IL-2 seemed to have no adverse effect. From these results, we
conclude that a combination therapy with G-CSF and IL-2 might be of clinical use for inhibiting large amounts of ascites,
which may inhibit therapeutic effects for ovarian cancer patients.
Received: 20 May 1996 / Accepted: 19 September 1996 相似文献
19.
Bryan J. Drucker Francesco M. Marincola Don Y. Siao Timothy A. Donlon Charles D. Bangs Walter D. Holder Jr. 《In vitro cellular & developmental biology. Plant》1988,24(12):1179-1187
Summary A human tumor cell line designated SU.86 has been established from a moderate-to-poorly differentiated pancreatic carcinoma
of ductal origin specifically for adoptive immunotherapy studies. This line was characterized as to its ability to be lysed
in vitro by autologous and allogeneic lymphokine-activated killer (LAK) and natural killer cells and to grow in nude mice.
SU.86 has been growing continuously in cell culture for more than 100 passages since 22 September 1986. Transplantation orthotopically
and heterotopically into athymic Swiss nude mice showed that tumor take was 100% in the orthotopic position when young (4
to 6 wk old) mice were used and 0% when adult (8 wk old) mice were used (P=0.004). In the heterotopic position (subcutaneous), tumor take was 100% in neonate (2 to 3 wk old) and young mice and 50%
in adults. The rate of tumor growth was inversely correlated with age (P<0.001). The histologic pattern is similar to that observed in most human pancreatic carcinomas with pseudoglandular structures
and frequent mitotic figures. SU.86 has a doubling time of 77 h in vitro and produces carcinoembryonic antigen, 594 ng/106 cells in 3 d. Chromosomal analysis shows heterogeneity with two notable cell subpopulations. The cell line is moderately
sensitive to lysis by LAK cells in a standard, 4-h chromium-51 release assay (35.4±4.0%). When grown together with LAK cells
in vitro, it is lysed completely in culture in 8 to 15 d, depending on the serum concentration. 相似文献
20.
Immunogenicity increase of autologous tumor cell vaccines by virus infection and attachment of bispecific antibodies 总被引:4,自引:0,他引:4
A new type of cancer vaccine for therapeutic application in cancer patients is described. It consists of three components.
(1) autologous tumor cells, (2) Newcastle Disease Virus (NDV), to be used for infection and (3) bispecific antibodies (bsAb)
which attach to the viral hemagglutinin neuraminidase (HN) molecule on the infected tumor cells. A standardized procedure
has been developed for generating virus infected human autologous tumor cell vaccines (ATV-NDV) which includes cell dissociation,
removal of leukocytes and cell debris, gamma-irradiation and cryopreservation. Infection with the non-virulent strain NDV
Ulster is performed within 30 min of co-incubation. While virus infection already increased immunogenicity of the tumor vaccine,
further augmentation of T cell stimulatory capacity is achieved by attachment of specially designed bi-specific antibodies
(bs HN × CD28 or bs HN × CD3).
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献