Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of new therapeutic strategies for the treatment of bone metastases strongly depends on the availability of valid animal models. In this paper, we evaluate a preclinical model of bone metastases using a technique of tumor cell injection into the left heart ventricle of mice to study the efficacy of adoptive immunotherapy. Using flow cytometric analysis and histopathological and radiological examination, we investigated whether this experimental model of bony metastases using two murine cell lines of melanoma and breast cancer would be suitable for the study of adoptive immunotherapy for these diseases. We further report that anti-CD3-activated and IL-2-expanded tumor vaccine draining lymph node cells cause regression of tumor metastases, including bone metastases, following adoptive transfer to mice bearing 3-day metastases from the D5 melanoma cell line. These promising early results lead us to conclude the following: (1). this model of experimental bone metastases is suitable for the study of immunotherapy, and (2). further studies are warranted to extend these promising early findings of the therapeutic effects of adoptive immunotherapy in this animal model.
 ...
PMID:Evaluation of a preclinical model of bone metastasis for the study of adoptive immunotherapy. 1280 95

Adoptive T-cell therapy using CD3/CD28 co-stimulation likely requires in vivo generation of antigen specificity. Because CD28 promotes TH1/TC1 (T1) or TH2/TC2 (T2) differentiation, costimulation may generate donor T1 or T2 cells capable of differentially mediating allogeneic graft-versus-tumor (GVT) effects and graft-versus-host disease (GVHD). Costimulation under T1 or T2 conditions indeed generated murine TH1/TC1 cells secreting interleukin-2/interferon-gamma (IL-2/IFN-gamma) or TH2/TC2 cells secreting IL-4/IL-5/IL-10. In vivo, allogeneic T1 cells expanded, maintained T1 secretion, and acquired allospecificity involving IFN-gamma and IL-5. In contrast, allogeneic T2 cells expanded less and maintained T2 secretion but did not develop significant allospecificity.Allogeneic, but not syngeneic, T1 cells mediated a GVT effect against host-type breast cancer cells, as median survival time (MST) increased from 25.6 +/- 2.6 (tumor controls) to 69.2 +/- 5.9 days (P < 1.2 x 10(-9)). This T1-associated GVT effect operated independently of fasL because T1 cells from gld mice mediated tumor-free survival. In contrast, allogeneic T2 cells mediated a modest, noncurative GVT effect (MST, 29 +/- 1.3 days; P <.0019). T1 recipients had moderate GVHD (histologic score, 4 of 12) that contributed to lethality after bone marrow transplantation; in contrast, T2 recipients had minimal GVHD (histologic score, 1 of 12). CD3/CD28 co-stimulation, therefore, generates T1 or T2 populations with differential in vivo capacity for expansion to alloantigen, resulting in differential GVT effects and GVHD.
 ...
PMID:CD3/CD28-costimulated T1 and T2 subsets: differential in vivo allosensitization generates distinct GVT and GVHD effects. 1285 80

Protection against breast cancer was achieved with a DNA vaccine against murine transcription factor Fos-related antigen 1, which is overexpressed in aggressively proliferating D2F2 murine breast carcinoma. Growth of primary s.c. tumor and dissemination of pulmonary metastases was markedly suppressed by this oral DNA vaccine, carried by attenuated Salmonella typhimurium, encoding murine Fos-related antigen 1, fused with mutant polyubiquitin, and cotransformed with secretory murine IL-18. The life span of 60% of vaccinated mice was tripled in the absence of detectable tumor growth after lethal tumor cell challenge. Immunological mechanisms involved activation of T, natural killer, and dendritic cells, as indicated by up-regulation of their activation markers and costimulatory molecules. Markedly increased specific target cell lysis was mediated by both MHC class I-restricted CD8+ T cells and natural killer cells isolated from splenocytes of vaccinated mice, including a significant release of proinflammatory cytokines IFN-gamma and IL-2. Importantly, fluorescence analysis of fibroblast growth factor 2 and tumor cell-induced vessel growth in Matrigel plugs demonstrated marked suppression of angiogenesis only in vaccinated animals. Taken together, this multifunctional DNA vaccine proved effective in protecting against growth and metastases of breast cancer by combining the action of immune effector cells with suppression of tumor angiogenesis.
 ...
PMID:Transcription factor Fos-related antigen 1 is an effective target for a breast cancer vaccine. 1285 59

The majority of breast cancers are oestrogen dependent and although current treatment strategies have improved, approximately 50% of the patients will develop metastasis. New treatments that result in long-term systemic immunity are therefore being developed. We have previously shown that adenoviral gene transfer of B7-1/IL-2 to murine breast cancer induces a high rate of complete tumour regression and systemic immunity. Since oestrogens not only affect breast cancer but also have been shown to modulate immune function and secretion of immune-regulatory cytokines, we explored whether administration of oestradiol altered the immune response induced by an adenoviral vector expressing B7-1/IL-2. An oestrogen-dependent murine breast cancer tumour was used in ovariectomised mice, supplemented either oestradiol or placebo. We report the somewhat unexpected finding that intratumoral injection of adenovirus expressing B7-1/IL-2 induces complete tumour regression in 76% of oestradiol-supplemented mice, while only 18% of the tumours regressed in the oestrogen-depleted group. Cured mice in both groups exhibited a similar CTL response against the tumour antigen. However, intratumoral IFN-gamma levels, 2 days after B7-1/IL-2 injection, were significantly higher in mice treated with oestradiol compared to placebo. This may be one mechanism explaining the higher response rate of tumours in oestradiol-replenished mice.
 ...
PMID:Oestradiol enhances tumour regression induced by B7-1/IL-2 adenoviral gene transfer in a murine model of breast cancer. 1286 33

Immunotherapy (biological therapy) comprises such things as active specific immunotherapy ("cancer vaccines"), nonspecific immunostimulation with cytokines, and the inhibition of suppressor influences exerted or elicited by the tumor. Just as cancer chemotherapy began with the use of single agents and evolved into combination therapy, so immunotherapeutic agents have been combined with each other and with chemotherapy. The alkylating agent cyclophosphamide (Cytoxan; CYC) has been used for many years to inhibit tumor-derived suppressor influences in rodents, and has been exploited for the same use in humans. Combinations of CYC and cancer vaccines such as autologous tumor cells, Melacine, large multivalent immunogen (LMI), and Theratope have been tested with some success in humans for more than a decade. In this use, the CYC is a biological response modifier rather than an antitumor agent, intended to inhibit suppressor influences. CYC and low- to moderate-dose IL-2 has also been a useful regimen in treating human melanomas. IL-2 is itself a useful component of combination immunotherapy, such as with melanoma peptide vaccines, or with interferon alpha-2b, (IFN-alpha), as a dual combination or part of a biochemotherapy regimen. Several different combinations of drugs and biological agents have been used as biochemotherapy for melanoma, but although there are higher response (regression) rates the long-range survival benefits have been marginal, not justifying the severe toxicity. Combinations of 5-fluorouracil (5-FU) and IFN-alpha or levamisole have had efficacy in colon and head and neck cancers, but here the biological agents have been biochemical modulators, not immunotherapy. Although experience with combinations of monoclonal antibodies and chemotherapy has been limited, it appears that trastuzumab (Herceptin) potentiates antitumor therapy in breast cancer but also increases the cardiotoxicity of those regimens.
 ...
PMID:Combinations of anticancer drugs and immunotherapy. 1294

MUC1 is expressed by glandular epithelial cells. It is overexpressed in the majority of breast tumours, making it a potential target for immune therapy. The objectives of the present study were to evaluate the anti-tumour activity and tolerance of repeated administration of TG1031 (an attenuated recombinant vaccinia virus containing sequences coding for human MUC1 and the immune stimulatory cytokine IL-2) in patients with MUC1-positive metastatic breast cancer. This was an open-label, randomised study comparing two dose levels, 5 x 10E6 and 5 x 10E7, with 14 patients in each arm. The treatment was administered intramuscularly every 3 weeks for the first 4 doses and every 6 weeks thereafter, until progression. Two patients had a partial tumour regression ( > 50%), and 15 patients had stable disease as their best overall response until at least the 5th injection. Partial regression lasted for 11 months in one patient and for 12 months in the second patient who then underwent surgical resection of her hepatic metastases. The most frequent adverse events included inflammation at injection site: 7 patients, itching or pain at injection site: 5 patients, and moderate fever: 6 patients. One responding patient developed antinuclear, anti-DNA, and increased anti-TPO antibodies after the fifth injection, and which resolved at the end of treatment. The treatment regimes were well tolerated with a low toxicity profile. Although clinical efficacy remains limited, this study demonstrates the potential use of MUC1-based immune therapy in breast cancer.
 ...
PMID:Metastatic Breast Tumour Regression Following Treatment by a Gene-Modified Vaccinia Virus Expressing MUC1 and IL-2. 1297 34

Treatment of advanced renal cancer has made little progress in the past 30 yr. Most clinical efforts have incorporated cytokine-based therapy. The presumption has been that the cytokines may trigger a host immune response against the renal cancer. Only IFN-alpha and high-dose IL-2 seemed to have positive effects on patient outcomes. IFN has prolonged the lives of patients by a few months, and high-dose IL-2 is capable of inducing very prolonged remissions (>5 yr) for a small number of patients. Nephrectomy in the presence of metastatic disease has been established as an effective procedure for select patients, providing palliation and prolonging survival. Finally, enthusiasm has focused on the use of nonmyeloablative allogeneic stem cell transplantation and donor leukocyte infusion for the induction of graft versus tumor effects. Early results are both provocative and promising. A number of agents that target the critical gene products downstream from pVHL and hypoxia-inducible factor-1, such as vascular endothelial growth factor, PDGF, EGF receptor, and TGF-alpha, have recently become available. The new agents are capable of inhibiting specific cellular targets, and the biologic characteristics of clear cell carcinoma of the kidney support their application. If the correct targets are carefully selected for inhibition in tumors in which the targets are present (clear cell histologic features and loss of VHL expression), then results should resemble those others have observed with targeted therapy, such as the use of STI-571 (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors or anti-HER2/neu (Herceptin; Genentech, South San Francisco, CA) for treatment of breast cancer.
 ...
PMID:Targeting of the VHL-hypoxia-inducible factor-hypoxia-induced gene pathway for renal cell carcinoma therapy. 1456 78

Since 1984, we have had 151 breast cancer patients with cytologically-confirmed malignant pleural effusions by local transfer of autologous effusion lymphocytes cultured with a conditioned medium containing T-cell growth factor after intrapleural preadministration of a streptococcal preparation, OK-432. Among the 81 patients given this therapy more than 5 years ago, 12 patients have survived 5 or more years, and 4 of these 12 have survived 10 (<) years. Patients surviving 5 (<) years had longer (32-204 months) disease-free periods, except for one patient with stage IV disease. Estrogen receptor was positive in 5 patients, negative in 1 patient, and unknown in 6 patients. Moreover, preceding or concomitant metastases in these patients were not life-threatening (6 chest-wall, 2 lymph-node, 4 lung, 3 bone metastases). In conclusion, effective therapy (effusion disappeared in all patients) and good control of concomitant metastases resulted in long-term survival of patients who had intrinsically better prognostic factors.
 ...
PMID:[Analysis of 5-year survival among breast cancer patients with malignant pleural effusion receiving intrapleural OK-432 followed by adoptive transfer with cultured effusion lymphocytes]. 1461 63

We examined several culture methods to induce proliferation of natural killer (NK) cells from peripheral blood mononuclear cells (PBMC). In the presence of IL-2, a remarkable proliferation of NK cells was observed when PBMC were co-cultured with MMC-treated K562, which is known as a highly sensitive in vitro target cell for the NK assay. Addition of OK-432 or TNF-alpha and IL-1 beta also induced marked NK proliferation in a dose dependent manner. These NK-enriched lymphokine activated killer (LAK) cells showed highly cytotoxic activities against various MHC class I positive or negative tumor cells. They also showed potent ADCC activities against Herceptin-coated SK-BR-3, a HER2/neu positive breast cancer cell line. These results indicated that NK-enriched LAK cells are potent effector cells, and suggested novel therapeutic strategies for nonspecific immunotherapy as well as target immunotherapy in combination with anticancer antibodies, such as Herceptin.
 ...
PMID:[Preparation of NK-enriched LAK cells--their potential cytotoxic and ADCC activities]. 1461 17

Peptides derived from over-expressed p53 protein are presented by class I MHC molecules and may act as tumour-associated epitopes. Due to the diversity of p53 mutations, immunogenic peptides representing wild-type sequences are preferable as a basis for a broad-spectrum p53-targeting cancer vaccine. Our preclinical studies have shown that wild-type p53-derived HLA-A2-binding peptides are able to activate human T cells and that the generated effector T cells are cytotoxic to human HLA-A2+, p53+ tumour cells. In this phase I pilot study, the toxicity and efficacy of autologous dendritic cells (DCs) loaded with a cocktail of three wild-type and three modified p53 peptides are being analysed in six HLA-A2+ patients with progressive advanced breast cancer. Vaccinations were well tolerated and no toxicity was observed. Disease stabilisation was seen in two of six patients, one patient had a transient regression of a single lymph node and one had a mixed response. ELISpot analyses showed that the p53-peptide-loaded DCs were able to induce specific T-cell responses against modified and unmodified p53 peptides in three patients, including two of the patients with a possible clinical benefit from the treatment. In conclusion, the strategy for p53-DC vaccination seems safe and without toxicity. Furthermore, indications of both immunologic and clinical effect were found in heavily pretreated patients with advanced breast cancer. An independent clinical effect of repeated administration of DCs and IL-2 can not of course be excluded; further studies are necessary to answer these questions.
 ...
PMID:Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. 1498 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>