共查询到20条相似文献,搜索用时 31 毫秒
1.
Tsukasa Sato Yasuhiko Midorikawa Takao Yamashita Akemi Araki F. Sendo 《Cancer immunology, immunotherapy : CII》1996,43(2):77-86
Effective treatment of a rat transplanted ascites tumor by i. p. injection of a streptococcal biological response modifier,
OK-432, was abrogated by selective in vivo depletion of neutrophils by a monoclonal antibody, RP-3. The mechanisms by which
neutrophils participate in the therapeutic action of OK-432 were studied with Winn’s assay using peritoneal exudate cells
periodically obtained from rats i. p. injected with this biological response modifier. Intraperitoneal resident macrophages
were first activated with OK-432, and within 3 h, tumor-inhibitory activity had moved to the early exuded neutrophils. However,
6 h after injection, exuded macrophages were the only cells involved in tumor inhibition. Considered together with other findings,
it is likely that, in this system, neutrophils may transmit information from resident macrophages to exuded inflammatory macrophages
in a series of responses induced by i. p. injection of OK-432.
Received: 29 April 1996 / Accepted: 27 July 1996 相似文献
2.
Effects of interleukin-12 on in vitro culture with interleukin-2 of regional lymph node lymphocytes from lung cancer patients 总被引:2,自引:0,他引:2
T. Hanagiri Mitsuhiro Takenoyama Takashi Yoshimatsu Chikashi Hirashima Ichiro Yoshino Kozo Nakanishi Akira Nagashima Kikuo Nomoto Kosei Yasumoto 《Cancer immunology, immunotherapy : CII》1996,43(2):87-93
In the present study, we carried out a functional analysis of regional lymph node lymphocytes (RLNL) from patients with lung
cancer after in vitro activation by interleukin-2 (IL-2) and interleukin-12 (IL-12). IL-12 (100 U/ml) enhanced both the proliferation
and cytotoxic activity of RLNL in a culture with low doses of IL-2 (5 – 10 JRU/ml). After comparing an RLNL culture with a
low dose of IL-2 alone, a higher proportion of CD8+ cells and CD56+ cells and a lower proportion of CD4+ cells were found in the culture with both IL-12 and a low dose of IL-2. Such a combination of the cytokines effectively activated
RLNL in terms of the expression of IL-2 receptors. In the culture condition of IL-12 and a low dose of IL-2, a synergistic
effect was observed in the production of such cytokines as interferon γ, tumor necrosis factor α (TNFα), and TNFβ, as well
as in tumor cytotoxicity. However, the addition of IL-12 inhibited the cytotoxicity of RLNL in the culture with a high dose
of IL-2 (100 JRU/ml). This inhibition is considered to be partially due to the endogenous production of TNFα by lymphocytes,
because the neutralization of TNFα bioactivity partially restored the cytotoxic activities of RLNL. Furthermore, in the presence
of hydrocortisone, IL-12 synergistically enhanced the cytotoxic activity of RLNL cultured with a high dose of IL-2. These
results provide useful information about the improvement of adoptive immunotherapy against cancer using RLNL.
Received: 2 February 1996 / Accepted: 30 July 1996 相似文献
3.
Peter J. K. Kuppen Alexander M. M. Eggermont Katinka M. Smits Jaap D. H. van Eendenburg Sylvia P. G. Lazeroms Cornelis J. H. van de Velde Gert Jan Fleuren 《Cancer immunology, immunotherapy : CII》1993,36(6):403-408
In vivo targeting of lymphokine-activated killer (LAK) cells to tumour deposits by bispecific monoclonal antibodies (bimAb) may be a way to improve adoptive immunotherapy. We developed a bimAb against adherent LAK (ALAK) cells and colon tumour CC531 in Wag rats. The bimAb was produced by somatic hybridization of two mouse hybridomas, one producing monoclonal antibodies (mAb) against CD8 (IgG2b, OX8), and the other producing mAb against a CC531-associated antigen (IgG1, CC52). A bimAb-producing clone was selected by an enzyme-linked immunosorbent assay with CC531 tumour cells. BimAb were purified from ascitic fluid by protein A affinity chromatography. Each of five pooled peak fractions was analysed by flow cytometry for the presence of bimAb. Most bimAb were found in a fraction that was eluted at pH 4.5 from protein A. FPLC analysis of this fraction revealed that no parental antibodies were present. The OX8 × CC52 bimAb greatly increased conjugate formation in vitro between ALAK cells and CC531. Results of51Cr-release assays with CC531 as target cells and ALAK cells as effector cells were not significantly different in the presence or in the absence of the bimAb. The methods we used here, a cell enzyme-linked immunosorbent assay and flow cytometry, are simple methods for development and purification of a bimAb when a functional selection method is not a priori available. The OX8 × CC52 bimAb we developed this way may increase in vivo tumour targeting of ALAK cells and thus augment antitumour effect in vivo. 相似文献
4.
Rosalind A. Graham J. M. Burchell J. Taylor-Papadimitriou 《Cancer immunology, immunotherapy : CII》1996,42(2):71-80
The identification and cloning of several tumour antigens together with an improvement in the understanding of the mechanisms
involved in antigen presentation and immune recognition has opened up the possibility of using active specific immunotherapy
as a treatment for certain cancers. This review discusses the tumour-associated MUC1 gene product of the polymorphic epithelial mucin (PEM), as a potential target molecule for cancer treatment. PEM is both
over-expressed and aberrantly glycosylated in many carcinomas resulting in an antigenically distinct molecule. Furthermore,
immune responses specific for PEM have been detected in cancer patients. Both syngeneic and transgenic murine model systems
have been developed in order to compare the efficacy and toxicity of various PEM-based immunogens in tumour rejection studies,
and to further improve the understanding of antigen presentation and the mechanisms underlying tumour rejection. Such models
also allow the examination of MUC1-based immunogens as a treatment for existing tumours. Clinical trials in progress using
immunogens based on the MUC1 gene product are briefly discussed.
Received: 23 November 1995 / Accepted: 4 January 1996 相似文献
5.
Lola Weiss Samir Nusair Shoshana Reich Haim Sidi S. Slavin 《Cancer immunology, immunotherapy : CII》1996,43(2):103-108
The feasibility of inducing graft versus leukemia (GVL) effects with allogeneic T cells in recipients of autologous bone
marrow transplantation (BMT) was studied in a murine model (BCL 1) of human B cell leukemia/lymphoma. Allogeneic cell therapy,
induced by infusion with peripheral blood lymphocytes, a mixture of allogeneic spleen and lymph node cells and allogeneic
activated cell therapy, induced by in vitro recombinant-interleukin-2(rIL-2)-activated allogeneic bone marrow cells in tumor-bearing
mice, prevented disease development in adoptive BALB/c recipients. Concomitant in vivo activation of allogeneic lymphocytes
with rIL-2 suppressed even more effectively the development of leukemia in secondary adoptive recipients of spleen cells obtained
from treated mice. In contrast, in vivo administration of rIL-2 after syngeneic BMT, with or without equal numbers of syngeneic
lymphocytes, led to disease development in secondary recipients. Our data suggest that effective cell therapy can be achieved
after SBMT by allogeneic but not syngeneic lymphocytes and that anti-leukemic effects induced by allogeneic lymphocytes can
be further enhanced by in vitro or in vivo activation of allogeneic effector cells with rIL-2. Therefore, cell therapy by
allogeneic lymphocytes following autologous BMT could become an effective method for inducing GVL-like effects on minimal
residual disease provided that graft versus host disease can be prevented or adequately controlled.
Received: 14 May 1996 / Accepted: 6 August 1996 相似文献
6.
S. Lausson B. Fournes C. Borrel G. Milhaud F. Treilhou-Lahille 《Cancer immunology, immunotherapy : CII》1996,43(2):116-123
The existence of inherited aggressive forms of medullary thyroid carcinoma (MTC), and their resistance to all classical therapies,
make it a prime candidate for adoptive immunotherapy. As a prelude to a vaccine for the protection of family members at risk
of developing the disease, we investigated the immunological antitumour response provoked by the 6/23 rMTC cell line, compared
to that of the same cells engineered to secrete interleukin-2 (rMTC-IL2), in an animal model of familial human MTC, the inbred
strain of Wag/Rij rats. The rMTC cells developed a tumour that invaded the whole neck 15 days after orthotopic injection (into
the thyroid), while the rMTC-IL2 cells were progressively rejected. Co-injection of rMTC-IL2 with the parental cells induced
the rejection of the rMTC transplants. When injected, both tumoral cell types showed a similar positive immunoreaction with
anti-MHC class I (major histocompatibility complex class I) antibodies. They both recruited natural killer cells and eosinophils
at the site of injection. In addition, CD8+ T lymphocytes infiltrated the rMTC-IL2 cells, and eosinophil recruitment was amplified. Neutrophils, macrophages and CD4+ T lymphocytes were scarce. Our results suggest that the CD8+ T lymphocytes are implicated in the antitumour reaction elicited by the Il-2-transfected cells. As these effectors are known
to induce a specific immunological response, including memory, such a protocol should be tested as a vaccine on the young
population genetically at risk of developing a MTC.
Received: 18 December 1995 / Accepted: 21 August 1996 相似文献
7.
Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes 总被引:4,自引:0,他引:4
Marjorie J. Arca John C. Krauss Scott E. Strome Mark J. Cameron A. E. Chang 《Cancer immunology, immunotherapy : CII》1996,42(4):237-245
We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine melanoma genetically altered to secrete
interleukin-2 (IL-2), IL-4, interferon γ (IFNγ) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). Three parameters
were evaluated: (1) tumorigenicity, (2) vaccination of naive animals, and (3) assessment of antitumor reactivity of T cells
derived from tumor-draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of BL6, while IFNγ and IL-4
partially reduced tumorigenicity, and GM-CSF had no effect. Protective immunity to wild-type tumor challenge could not be
achieved by vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4 secretion appeared to retard the
growth of the challenge inoculum significantly. An alternative method to evaluate the immunogenicity of the cytokine-secreting
tumors was to measure the ability of T cells obtained from TDLN to mediate regression of wild-type tumor in adoptive immunotherapy.
Neither IL-2 nor IFNγ secretion resulted in the induction of immune T cells. By contrast, GM-CSF and IL-4 secretion were found
to induce immune T cells in the TDLN with GM-CSF being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not
lead to enhanced induction of immune T cells. GM-CSF secretion was found to up-regulate B7-1 expression in TDLN, consistent
with an increase in the population of antigen-presenting cells. These studies demonstrated that reduced tumorigenicity by
cytokine secretion did not correlate with increased immunogenicity. With the cytokines examined, there was limited capability
of developing protective immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion significantly enhanced T
cell immune reactivity to the poorly immunogenic BL6 tumor.
Received: 30 January 1996 / Accepted: 22 March 1996 相似文献
8.
C. A. McIntyre Robert C. Rees Kathryn E. Platts Catherine J. Cooke M. Olivia Smith Kevin A. Mulcahy Anna K. Murray 《Cancer immunology, immunotherapy : CII》1996,42(4):246-250
The MAGE gene family of tumour antigens are expressed in a wide variety of human cancers. We have identified 43 nonamer peptide sequences,
from MAGE-1, -2 and -3 proteins that contain binding motifs for HLA-A3 MHC class I molecules. The T2 cell line, transfected
with the cDNA for the HLA-A3 gene, was used in a MHC class I stabilisation assay performed at 37°C and 26°C. At 37°C, 2 peptides
were identified that stabilised HLA-A3 with high affinity (fluorescence ratio, FR >1.5), 4 peptides with low affinity (FR
1.11 – 1.49) and 31 peptides that did not stabilise this HLA haplotype (FR <1.1). At 26°C, 12 peptides were identified that
stabilised HLA-A3 with high affinity, 8 peptides with low affinity and 17 peptides that did not stabilise this HLA haplotype.
Two peptides stabilised HLA-A3 at both temperatures. Small changes in one to three amino acids at positions distinct from
the anchor residues altered peptide affinity. Data were compared to a similar study in which a peptide competition assay was
used to investigate MAGE-1 peptide binding to several HLA haplotypes. This study demonstrates that anchor residues do not
accurately predict peptide binding to specific HLA haplotypes, changes in one to three amino acids at positions distinct from
anchor residues influence peptide binding and alternative methods of determining peptide binding yield different results.
We are currently investigating the ability of these peptides to induce antitumour cytotoxic T lymphocyte activity as they
may be of potential therapeutic value.
Received: 4 January 1996 / Accepted: 20 March 1996 相似文献
9.
Rutger L. van Bezooijen H. Goey Gerrit Stoter J. Hermans G. J. Fleuren 《Cancer immunology, immunotherapy : CII》1997,43(5):293-298
Interleukin-2 (IL-2)-based immunotherapy can induce antitumor responses in about 25% of patients with metastatic renal cell
carcinoma (RCC). The limited effect and the severe side-effects of IL-2 have led us to perform a prognostic factor analysis.
Twenty-four patients with metastatic RCC were treated with IL-2. Flow cytometry and immunohistology were used to determine
DNA ploidy, HLA-II expression on tumor cells, and the presence of macrophages in the primary tumor. These variables were examined
in relation to survival. The 4-year overall survival rate was 38%. Forty-six percent of the primary tumors were aneuploid.
All tumors, except one, showed HLA-II expression and macrophage presence. A statistically significant correlation (r = 0.66, P = 0.002) was found between HLA-II expression and macrophage presence. Patients with high HLA-II expression had a lower 4-year
survival (22% compared to 50%), as had patients with high macrophage presence (20% compared to 42%). Of note, patients characterized
by both high HLA-II and high macrophage expression had the worst survival (13% compared to 50%). We concluded that DNA ploidy
was not predictive for survival, whereas HLA-II expression and macrophage presence may represent valuable prognostic factors
related to survival. The present data suggest that more of the patients with no or moderate HLA-II expression and/or no or
moderate macrophage presence in the primary tumor could survive with persistance of their malignant disease after having received
IL-2 immunotherapy, as compared to patients with both high HLA-II and high macrophage expression.
Received: 2 April 1996 / Accepted: 15 October 1996 相似文献
10.
S. T. Dougherty Connie J. Eaves William H. McBride Graeme J. Dougherty 《Cancer immunology, immunotherapy : CII》1997,44(3):165-172
In order to better define the role played by tumor-cell-derived macrophage-colony-stimulating factor (M-CSF) in regulating
the recruitment and phenotype of tumor-associated macrophages, Polyoma large T-transformed fibroblastoid cell lines, derived
from M-CSF-deficient osteopetrotic op/op mice and their phenotypically normal op/+ littermate controls, were inoculated into
SCID (severe combined immunodeficiency) recipients and both the proportion and phenotype of the macrophages present within
the tumors generated were determined. The results obtained indicate that, although tumors derived from M-CSF-deficient and
M-CSF-producing tumor cell inoculate contain a similar proportion of macrophages, the macrophages isolated from tumors lacking
M-CSF appear morphologically less mature and express lower levels of interleukin 1β, tumor necrosis factor α and FcRγII mRNA.
Taken together, these data suggest that, although M-CSF does not appear to play a critical role in determining the macrophage
content of these tumors, it does play a role in modulating the phenotype, and potentially the functional activity of the macrophages
present within the tumor microenvironment.
Received: 30 August 1996 / Accepted: 7 February 1997 相似文献
11.
Milky spots in the greater omentum are predominant sites of local tumour cell proliferation and accumulation in the peritoneal cavity 总被引:5,自引:0,他引:5
Lambert F. G. Krist Miranda Kerremans Donna M. Broekhuis-Fluitsma Inge L. Eestermans Sybren Meyer Robert H. J. Beelen 《Cancer immunology, immunotherapy : CII》1998,47(4):205-212
The role that milky spots in the greater omentum play in tumour cell spread in the peritoneal cavity is presently not fully
understood. To study whether intraperitoneally injected tumour cells appear preferentially in milky spots of the greater omentum
and to study the changes in the greater omentum, and especially in the cell population of milky spots after tumour cell infiltration,
the following study was performed. A detailed temporal sequences of changes in morphology and cellular composition in milky
spots of the greater omentum of Wag/Rij rats 5, 15, 30, 60 min, 2, 4, 8, 16, 24 h, 2, 4, 8 days and 2 and 4 weeks after intraperitoneal
administration of 2.0 × 106 CC 531 tumour cells was investigated by light microscopy and electron microscopy (pre-embedding labelling). Our data showed
that the milky spots in the greater omentum were the sites to which tumour cells migrated preferentially from the peritoneal
cavity. The tumour cells infiltrated the milky spots and formed clusters within. The cellular population in milky spots reacted
by a very rapid influx of young macrophages during the first hour and an increase of the total number of cells (P < 0.01). After 4 h tumour cells were also located on the greater omentum outside the area of the milky spots. Around these
tumour cell deposits, new milky spots are formed, which increased the total number of milky spots. The cells present in milky
spots are not capable of reversing the growth of tumours and finally a solid omental cake of tumour cells is formed.
Received: 30 June 1998 / Accepted: 3 September 1998 相似文献
12.
Toshihiro Fujimoto Michael A. O’Donnell Akos Szilvasi H. Yang R. B. Duda 《Cancer immunology, immunotherapy : CII》1996,42(5):280-284
Although immunotherapy with bacillus Calmette Guérin (BCG) is an established adjuvant treatment for malignant melanoma, the
mechanism of its role in this process is unclear. To investigate the possible contribution of tumor-inhibitory cytokines induced
by BCG, B16F10 melanoma cell growth in culture was assessed in response to purified cytokines and conditioned media of BCG-stimulated
splenocytes. Interferon-γ (IFNγ) was the most potent single agent (IC50≈50 pg/ml). Tumor necrosis factor α was substantially weaker (IC50>10 ng/ml) but provided synergy with IFNγ. None of the other
cytokines such as interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12, or granulocyte/macrophage-colony-stimulating factor had
direct antitumor activity against B16F10 melanoma cells. However, when IL-2 and/or GM-CSF were combined with BCG either by
exogenous addition or through endogenous production by novel cytokine-secreting recombinant BCG (rBCG), a substantial increase
in INFγ production by splenocytes was observed. Antitumor activity of this conditioned medium directly correlated with IFNγ
concentration and was completely blocked by neutralizing antibody to IFNγ. These results suggest that BCG may exert part of
its antitumor action on melanoma through the induction of IFNγ, which can be greatly enhanced through the concomitant addition
of IL-2 and/or GM-CSF. Furthermore, by utilizing rBCG that secrete these cytokines, it may be possible to potentiate the antitumor
effect of BCG directly at the site of BCG inoculation.
Received: 29 January 1996 / Accepted: 9 April 1996 相似文献
13.
Induction of accessory cell function of human alveolar macrophages by inhalation of human natural interleukin-2 总被引:1,自引:0,他引:1
Gernot Zissel Walter E. Aulitzky J. Lorenz Christoph Huber J. Müller-Quernheim 《Cancer immunology, immunotherapy : CII》1996,42(2):122-126
Accessory function allows antigen-presenting cells to produce sufficient secondary signals for optimum T cell proliferation
and interleukin-2 (IL-2) production. Alveolar macrophages are inferior accessory cells compared to monocytes (PBM). We report
here that the accessory index (AI) of alveolar macrophages and PBM of patients with lung metastases of solid tumors treated
with inhalations of human natural IL-2 (hnIL-2) increased following its administration (P<0.005). The accessory index was significantly elevated from baseline values after 2 weeks of inhalation of 300 000 IU hnIL-2/day
(8.2±10.2 compared to 1.1±1; P<0.001). The inhalation of 150 000 IU also induced increases in the index (AI = 2.3±1.9), however, without reaching statistical
significance. In addition at 300 000 IU IL-2/day a significant increase in the accessory index was observed for PBM (4±2.5;
P<0.05). The indices of PBM and alveolar macrophages prior to inhalation showed a significant negative correlation with the
age of the patients (r
s = – 0.5; r
s = – 0.8, respectively; P<0.03 for all comparisons). Our data demonstrate that the inhalational application of hnIL-2 enhances the accessory function
of alveolar macrophages and, to lesser extent, the accessory index of PBM, indicating the occurrence of pharmacological immunostimulation.
Received: 16 August 1995 / Accepted: 4 January 1996 相似文献
14.
David Vermijlen Christopher J. Froelich Dianzhong Luo Nathalie Suarez-Huerta Bernard Robaye Eddie Wisse 《Cancer immunology, immunotherapy : CII》2001,50(4):212-217
Cytotoxic lymphocytes may induce apoptosis in their target cells by the FasL (Fas ligand) pathway or the perforin/granzyme
B pathway. It has been shown that Fas-expressing colon carcinoma (CC) cells are resistant to FasL-mediated apoptosis. The
aims of this study were to determine whether CC cells are also resistant to perforin/granzyme B and whether the FasL resistance
lies upstream of caspase-3 activation. The resistance of the Fas-expressing rat CC531s cells to the FasL pathway was confirmed
by treating them with recombinant human soluble FasL, using rat hepatocytes as a positive control. The intracellular delivery
of granzyme B by sublytic concentrations of perforin, on the other hand, resulted in many features of apoptosis (chromatin
condensation, nucleus fragmentation, loss of microvilli and internucleosomal DNA fragmentation) within 3 h. Since both the
FasL and perforin/granzyme B pathways converge at caspase-3, we measured caspase-3 activity to learn whether the FasL resistance
was due to failure to activate this crucial executioner. Caspase-3 activation occurred in CC531s cells after perforin/granzyme
B treatment, but not after the addition of recombinant FasL. Furthermore, we showed that caspase-3 activity is involved in
the execution of perforin/granzyme-B-induced apoptosis in CC531s cells, since the cell-permeable caspase-3 inhibitor Z-DEVD-FMK
abrogated DNA fragmentation. Together, these results suggest that CC cells are sensitive to perforin/granzyme-B-induced apoptosis
by activating caspase-3 and FasL resistance lies upstream of this executioner caspase.
Received: 20 November 2000 / Accepted: 8 March 2001 相似文献
15.
Interleukin-2: hope in cases of cisplatin-resistant tumours 总被引:1,自引:1,他引:0
Monique R. Bernsen Alike W. Van Der Velden Linda A. Everse Hub F. J. Dullens Willem Den Otter A. Peter M. Heintz 《Cancer immunology, immunotherapy : CII》1998,46(1):41-47
To establish whether or not local low-dose recombinant interleukin-2 (rIL-2) therapy might result in therapeutic benefit
for ovarian cancer patients treated with cisplatin, the antitumour effects of rIL-2 and of combined treatment with cisplatin
and rIL-2 in a mouse ovarian tumour (MOT) model were studied. In addition, some possible mechanistic aspects underlying the
observed antitumour responses were analysed. MOT cells were injected i.p. into syngeneic, immunocompetent, female C3HeB mice.
Tumour-bearing mice received i.p. treatment with cisplatin, rIL-2 or both. The MOT tumour appeared to be hardly responsive
to treatment with cisplatin only or rIL-2 only. In contrast, combined local treatment with low doses of cisplatin (1 and 5
mg/kg body weight) and rIL-2 (60 000 U/day) resulted in an effective antitumour response in MOT-bearing mice. Complete rejection
of the i.p. (local) tumour occurred in up to 60% of the cases. In vitro studies showed that cisplatin and rIL-2 do not have
cumulative direct toxic effects on MOT cells. Mice cured after combined treatment with cisplatin and rIL-2 were not able to
reject a rechallenge with tumour cells, indicating that these mice had not developed immunity to the tumour. Analysis of tumour-associated
leucocytes, however, showed that combined treatment with cisplatin and rIL-2 did result in enhanced non-specific cytolytic
activity of peritoneal leucocytes. We have thus demonstrated that, in the MOT model, combined local treatment with low doses
of cisplatin and of rIL-2 is far more effective than therapy with cisplatin alone. Non-specific cytotoxicity of leucocytes
appears to be involved in antitumour responses induced by combined treatment with cisplatin and rIL-2. These results suggest
that, in human ovarian carcinoma, much better results may be obtained with the combined treatment of cisplatin and low (non-toxic)
doses of rIL-2 than with cisplatin only. This may also apply to cisplatin-resistant ovarian carcinoma.
Received: 6 March 1997 / Accepted: 30 October 1997 相似文献
16.
Philip O. Livingston Shengle Zhang Kenneth O. Lloyd 《Cancer immunology, immunotherapy : CII》1997,44(1):1-9
Resistance to chemotherapy is a major cause for failure in the treatment of lung cancer. Compared to conventional cytotoxic
drugs, immunotoxins act by different mechanisms and thus might be promising for the treatment of chemoresistant cancer. The
monoclonal antibody MOC31 recognises the epithelial glycoprotein-2 (EGP-2), a cell-surface antigen associated with small-cell
lung cancer (SCLC) and a major fraction of lung adenocarcinomas. An immunotoxin composed of MOC31 and a recombinant form of
Pseudomonas exotoxin A lacking the cell-binding domain (ETA252 – 613) was prepared, and its effect on lung cancer cell lines examined. MOC31-ETA252 – 613 was selectively cytotoxic to EGP-2-positive SCLC and adenocarcinoma cell lines inhibiting proliferation by 50% at concentrations
ranging from 0.01 nM to 0.3 nM. Moreover, the immunotoxin reduced the numberof clonogenic tumour cells from cultures by factors
of 104 and 105 during a 24-h and a 3-week exposure respectively. In athymic mice, the immunotoxin, which revealed a serum half-life of approximately
4 h, caused substantial regression of small (40 mm3) chemoresistant tumour xenografts and significantly delayed the growth of larger tumours (120 mm3). This finding indicates that MOC31-ETA252 – 613 may be useful for the treatment of lung cancer in the setting of chemoresistant minimal residual disease.
Received: 31 October 1996 / Accepted: 5 December 1996 相似文献
17.
Wim Van de Vrie Sylke A. M. Van der Heyden Eric E. O. Gheuens Amelie M. Bijma Ernst A. De Bruijn Richard L. Marquet Allan T. Van Oosterom Alexander M. M. Eggermont 《Cancer immunology, immunotherapy : CII》1993,37(5):337-342
The development of resistance to anticancer drugs urges the search for different treatment modalities. Several investigators have reported the concomitant development of drug resistance and resistance to natural killer (NK), lymphokine-activated killer (LAK) or monocyte/macrophage cell lysis, while others described unchanged or even increased susceptibility. We investigated this subject in the rat colon carcinoma cell line, CC531-PAR, which is intrinsically multidrug-resistant (MDR), and in three sublines derived from this parental cell line: a cell line with an increased MDR phenotype (CC531-COL), a revertant line from CC531-COL (CC531-REV), which demonstrates enhanced sensitivity to anticancer drugs of the MDR phenotype, and an independently developed cisplatin-resistant line (CC531-CIS). In a 4-h51Cr-release assay we found no difference in susceptibility to NK cell lysis. No significant differences in lysability by adherent LAK (aLAK) cells were observed in a 4-h assay. In a prolonged 20-h51Cr-release assay an enhanced sensitivity to aLAK-cell-mediated lysis was observed in the revertant, P-glycoprotein-negative cell line and in the cisplatin-resistant cell line (CC531-CIS). None of the cell lines was completely resistant to lysis by aLAK cells. Therefore, a role for immunotherapy in the treatment of drug-resistant tumors remains a realistic option. 相似文献
18.
B. Desrues F. Brichory H. Léna P. Bourguet P. Delaval L. Toujas L. Dazord 《Cancer immunology, immunotherapy : CII》1997,43(5):269-274
Po66, a mouse monoclonal antibody, is directed against an intracytoplasmic antigen present in human lung squamous cell carcinoma
cells. In previous work it was found that the co-administration of 125I-radiolabelled Po66 and doxorubicin strongly enhanced the uptake of radioactivity by the tumour. The present-work was designed
to evaluate, in a tumour-bearing mouse model of lung carcinoma, the ability of 131I-labelled Po66 to retard tumour growth when injected alone, or in combination with doxorubicin (8 mg kg – 1 at 1-week intervals). A single dose of 550 μCi 131I-Po66 alone had no effect on tumour growth, whereas three fractionated doses of 250 μCi 131I-Po66 decreased it over two doubling times from 14.5±1.5 days for untreated control mice to 24.8±2.7 days. Mice treated with
doxorubicin alone had a double tumour doubling time of 22.6±4.9 days, compared to 35.2±2.9 days (1.55-fold increase) in mice
treated with doxorubicin and a single dose of 550 μ Ci 131I-Po66. Doxorubicin combined with three fractionated doses of 250 μCi 131I-Po66 provoked a twofold decrease in tumour growth compared to mice treated with doxorubicin alone. The administration of
fractionated doses of 131I-Po66 simultaneously with doxorubicin resulted in a highly delayed mortality, which was not observed when 131I-Po66 was administered after doxorubicin. Thus, in a non-small-cell lung tumour model, a 131I-radiolabelled monoclonal antibody, directed against an intracellular antigen, significantly potentiated the effect of chemotherapy.
Such a therapeutic approach could be used as an adjuvant therapy and improve the effect of chemotherapy on distant small metastases.
Received: 20 June 1996 / Accepted: 3 October 1996 相似文献
19.
Chezian Somasundaram Robert Arch Siegfried Matzku Margot Zöller 《Cancer immunology, immunotherapy : CII》1996,42(6):343-350
A bispecific F(ab′)2 antibody conjugate (BAC) was constructed against the complement receptor CR3 of macrophages and a variant CD44 (CD44v6) antigen
of rat pancreatic adenocarcinoma cells to redirect macrophage-mediated tumor cytotoxicity. The Fab′ fragments of monoclonal
antibodies (mAb) 1.1ASML and OX42, recognizing the CD44v6 and the CR3 antigens respectively, were chemically coupled at the
hinge region using 5,5′-dithiobis(2-nitrobenzoate). The BAC was characterized in vitro for its specific, dual binding capacity
to CD44v6 and CR3 antigens. Although the monovalence of the BAC resulted in lower avidities to both the antigens as expected,
it was still able to form stable cross-linkages between tumor cells and macrophages in culture leading to the formation of
“clump-like” cell aggregates. The in vitro and in vivo tumor-targeting capacity of the BAC was compared with that of the parental
antitumor mAb 1.1ASML, which mediates tumor killing by antibody-dependent cell cytotoxicity. These results showed that, even
though the bivalent mAb 1.1ASML did not mediate stable cross-linking of target and effector cells, its Fc-receptor-mediated
killing of tumor cells was more effective when compared to the BAC. Thus, this study strongly supports the hypothesis that
firm persistent binding between effector and target cells per se is not as important as the choice of trigger molecule used for macrophage activation to redirect their tumor cytotoxic potential
effectively.
Received: 2 May 1996 / Accepted: 21 May 1996 相似文献
20.
Kiyoshi Asai Haruki Kato Shigeru Kimura Shigehiko Mukai Yutaka Kawahito Hajime Sano Motoharu Kondo Keiko Akaogi K. Hirose 《Cancer immunology, immunotherapy : CII》1996,42(5):275-279
We have elucidated the direct effects of PSK (a protein-bound polysaccharide) and OK-432 (a streptococcal preparation), both
immunomodulating drugs, on the gene expression for an inducible nitric oxide synthase and on the production of nitric oxide
(NO) in the RAW264.7 murine macrophage cell line. As determined by northern blot analysis, both immunomodulating drugs were
potent inducers of gene expression for inducible NO synthase when cells were costimulated with interferon-γ (IFNγ). Expression
of mRNA for the enzyme occurred in a dose-dependent manner after 3 h, when 10 – 50 μg/ml PSK or 0.001 – 1 KE/ml OK-432 was
used. Furthermore, NO was also produced in response to these drugs, as detected by the Griess reagent reaction. The enhancement
of NO synthesis was thought to be mediated, in part, through tumor necrosis factor α (TNFα) induction by these agents, since
a neutralizing antibody to TNFα significantly suppressed NO production in RAW264.7 cells stimulated with PSK or OK432 in combination
with IFNγ. We speculate that NO production may play a role in tumoricidal and microbicidal activities of PSK or OK-432 in
vivo.
Received: 9 August 1995 / Accepted: 1 April 1996 相似文献