Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumour-infiltrating lymphocytes (TIL) of paediatric tumours obtained from 37 lesions of different histotype (12 osteosarcomas, 5 Wilms' tumours, 7 soft-tissue sarcomas, 5 neuroblastomas and 8 miscellaneous) were studied to establish their potential for therapy. Fresh isolated TIL were cultured for the first 2 weeks with low doses of interleukin-2 (IL-2) (20 Cetus U/ml) to select for "tumour-specific" lymphocytes potentially present in the neoplastic lesion, followed by culture with high doses of IL-2 (1000 Cetus U/ml) to achieve TIL expansion. TIL were grown with more than 10-fold expansion in only 9 cases (mean expansion: 58-fold, range 13.5-346). In 17 cases no viable cells were obtained. After 30 days of culture with IL-2 the proliferative ability of TIL declined sharply in the majority of cases and TIL became refractory to any further stimulus, including addition of IL-4, tumour necrosis factor alpha (TNF alpha) or interferon gamma, and activation with OKT3 in solid phase. In 20 out of 37 cases TIL were available for phenotypic and functional analysis. TIL after long-term culture were predominantly CD3+ but 2 cases of osteosarcoma showed a predominance of CD3+TcR gamma/delta cells. The CD4/CD8 ratio was more than 1 in 10 cases, without correlation with tumour histology, site of lesion or TIL growth. The number of CD16+ and CD25+ lymphocytes decreased progressively during culture, the latter concomitantly with a reduction of TIL growth rate. The lytic pattern of TIL against allogenic and autologous tumour (Auto-Tu) cells was variable, but specific lysis of Auto-Tu was seen in only one case (Wilms' tumour) after culture with TNF alpha and irradiated Auto-Tu cells. The immunohistochemical analysis of tumour lesions revealed a limited lymphocyte infiltrate, a low expression of histocompatibility leukocyte antigens (HLA) class I and of the adhesion molecules ICAM1, LFA3, and a significant production of transforming growth factor beta (TGF beta). These data indicate that TIL obtained from paediatric patients are difficult to expand at levels required for immunotherapy and lack a significant number of tumour-specific T lymphocytes. A low expression of immunomodulatory molecules on tumour cells or the production of suppressive factors may prevent activation and expansion of TIL in paediatric tumours.
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PMID:Phenotypic and functional analysis of lymphocytes infiltrating paediatric tumours, with a characterization of the tumour phenotype. 131 Dec 18

Twelve women and 7 men, median age 58 (range 17-74), with a diagnosis of non-small-cell lung cancer (11 patients), inflammatory breast cancer (5 patients), osteosarcoma (2 patients), and colon carcinoma (1 patient) were studied. Treatment consisted of four consecutive 6-day courses of infusional interleukin-2 (IL2); 9 patients were treated with 20 X 10(6) IU/m2/day and 10 patients received weekly dose increments of 50% until the maximally tolerated dose was reached. One day after each course was completed patients received doxorubicin, 30 mg/m2; infusional IL2 was resumed 24 h after receiving doxorubicin. Rebounds of lymphocytes with high spontaneous synthetic rates of DNA occurred one day after stopping the infusion, despite doxorubicin administration. The kinetics were not different from earlier trials using IL2 alone. Sequential lymphocyte analysis showed that helper (CD4) and suppressor (CD8) T-cell subsets increased after the first week of treatment and declined thereafter, whereas the proliferation of natural killer (NK) cells (CD16) progressed through the 4-week treatment unaffected by doxorubicin. Mean cytolytic ability induced by IL2 against NK-resistant tumors in vitro was higher in patients who had evidence of clinical tumor regression and therefore is prognostically valuable (p = .02). Three patients left the study prematurely. Five partial remissions and 2 minimal responses were seen in the remaining 16 patients, but they were short-lived. Of the responding patients, only one had failed prior doxorubicin-containing chemotherapy. Toxicities attributable to IL2 and doxorubicin were encountered, and were manageable at these doses. Our data suggest that doxorubicin did not have cytotoxic or suppressive effects on lymphokine-induced lymphocyte functions and that both treatment modalities in combination are worthy of further investigation since they exert distinct and compatible cytotoxic mechanisms and induced tumor regressions with acceptable toxicity in a group of patients with poorly responsive cancers.
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PMID:Immunotherapy with IL2 by constant infusion and weekly doxorubicin. 183 Jul 17

Before dogs with lung tumors were treated by adoptive immunotherapy, the ability of canine blood lymphocytes (PBL) from the peripheral circulation to differentiate in vitro in the presence of human recombinant interleukin-2 (rIL-2) and become tumoricidal was investigated. The PBL from healthy dogs (n = 6) and dogs with lung tumors (n = 5) were grown in culture medium alone, in the presence of rIL-2 to generate lymphokine-activated killer (LAK) cells, or with phytohemagglutinin (PHA) and rIL-2 to generate autologous-stimulated lymphocytes (ASL). After 4 days, cytotoxicity by the ASL, LAK, and PBL was determined in a 4-hour 51chromium-release assay. Target cells in the assay were short-term cultured enzyme digests of autologous (self), allogeneic (genetically different) primary tumors, and Raji, the xenogeneic human lymphoma cell line. The PBL cultured without rIL-2 were not cytotoxic against any tumor. However, when a dog's PBL were activated in vitro, they killed the dog's own tumor, ASL more effectively than LAK cells. Pulmonary adenocarcinomas and an osteosarcoma metastasis to lung were among the autologous tumors assayed. Against an allogeneic canine osteosarcoma, ASL generated from healthy dogs were significantly more cytolytic than LAK from healthy dogs, or than ASL generated from tumor-bearing dogs. Cytotoxicity was greater against allogeneic tumor than against Raji. Lectin-dependent cellular cytotoxicity, tested by including PHA in the assay medium with lymphocytes and Raji cells, by ASL and LAK was greater than cytotoxicity of Raji without PHA. Because ASL were more cytolytic than LAK against all targets in vitro, they may be more beneficial than LAK for immunotherapy of canine tumors.
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PMID:Cytotoxicity against autologous, allogeneic, and xenogeneic tumor targets by human recombinant interleukin-2-activated lymphocytes from healthy dogs and dogs with lung tumors. 189 69

The cellular mechanism by which PTH and other osteotropic substances stimulate bone resorption is unclear. One hypothesis is that PTH-stimulated osteoblasts release cytokines which activate osteoclasts or osteoclast precursors. To examine whether cytokines are released by osteoblast-like cells in vitro, medium conditioned by a clonal rat osteosarcoma cell line 17/2.8 (ROS) was examined for mitogenic activity using a helper T lymphocyte line HT-2. This line proliferates in response to interleukin-2 (IL-2), IL-4, and granulocyte-macrophage colony-stimulating factor (GM CSF). Conditioned medium (CM) from untreated ROS cells caused proliferation of HT-2 cells. Treatment of ROS cells with PTH or lipopolysaccharide (LPS) caused a dose-dependent increase in the secretion of this mitogenic activity. To further define the nature of this mitogenic activity, we examined the effect of incubation of CM with neutralizing antibodies to IL-2, IL-4, and GM CSF. Mitogenic activity induced by both PTH- and LPS-treated ROS cell CM was completely inhibited by anti-GM CSF antibody, whereas there was no reduction in activity in the presence of antibodies to IL-2 or IL-4. Partial purification of both PTH- and LPS-treated CM using reverse phase HPLC resulted in a single peak of HT-2 mitogenic activity, which in both cases was completely inhibited by anti-GM CSF antibody. These findings suggest that PTH- and LPS-treated ROS cells secrete a T cell mitogenic activity which, by functional, serological, and biochemical criteria, is indistinguishable from GM CSF.
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PMID:Osteoblast-like cells secrete granulocyte-macrophage colony-stimulating factor in response to parathyroid hormone and lipopolysaccharide. 264 12

Human T-cell leukemia virus (HTLV), American PL isolate, was transmitted by cocultivation and by cell-free filtrates to a nonlymphoid human osteogenic sarcoma (HOS) cell line, designated HOS/PL, but not to nine other lines bearing receptors for HTLV. HOS and HOS/PL cells are not dependent on interleukin-2 and do not express interleukin-2 receptors that are recognized by anti-Tac monoclonal antibody. HTLV released by the Japanese MT2 cell line was also transmitted to HOS cells. The infected HOS cells release substantial titers of progeny HTLV which is antigenically indistinguishable from parental virus and is able to transform T cells.
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PMID:Productive infection and cell-free transmission of human T-cell leukemia virus in a nonlymphoid cell line. 631 2

Traditionally, heat shock proteins (HSPs) are believed to be located intracellularly, where they perform a variety of chaperoning functions. Recently, evidence has accumulated that some tumor cells express HSPs on the cell surface. The present study confirms this finding and correlates HSP72 cell surface expression, induced by nonlethal heat shock, with an increased sensitivity to interleukin-2-stimulated CD3-natural killer (NK) cells. After nonlethal heat shock, a monoclonal antibody directed against the major heat-inducible 72-kD HSP (HSP72) stains the cell surface of sarcoma cells (ie, Ewing's sarcoma cells or osteosarcoma cells) but not that of normal cells (ie, peripheral blood lymphocytes, fibroblasts, phytohemagglutin-stimulated blasts, B-lymphoblastoid cell lines) or of mammary carcinoma cell line MX-1 carcinoma cells. In this study, we show for the first time a correlation of HSP72 cell surface expression with an increased susceptibility to lysis by NK effector cells. This finding is supported by the following points: (1) HLA-disparate effector cells show similar, elevated lysis of HSP72+ heat-treated sarcoma cells; (2) CD(3-) NK cells, but not CD3+ cytotoxic T lymphocytes, are responsible for the recognition of heat-shocked sarcoma cells; (3) by antibody-blocking studies, an immunogenic HSP72 determinant, which is expressed selectively on the cell surface of heat-treated sarcoma cells could be correlated with NK recognition; (4) the reported phenomenon is independent of a heat-induced, transient downregulation of major histocompatibility complex (MHC) class-I expression; and (5) blocking of MHC class-I-restricted recognition, using either MHC class-I-specific monoclonal antibody W6/32 on the target cells or alpha/beta T-cell receptor monoclonal antibody WT31 on effector cells, also has no inhibitory effect on the lysis of HSP72+ tumor cells. Finally, our in vitro data might have further clinical implications with respect to HSP72 as a stress-inducible, sarcoma-specific NK recognition structure.
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PMID:CD3- large granular lymphocytes recognize a heat-inducible immunogenic determinant associated with the 72-kD heat shock protein on human sarcoma cells. 763 45

The presence of a high number of activated T cells in the bloodstream and spontaneous proliferation of peripheral blood mononuclear cells in vitro are striking characteristics of human T-cell leukemia virus type I (HTLV-I) infection. The HTLV-I regulatory protein Tax and the envelope protein gp46 have been implicated in mediating the activation process. In this study, HTLV-I-producing cell lines and purified virus from the cell lines were examined for the ability to activate peripheral blood lymphocytes (PBLs) and Jurkat cells. Antisera and monoclonal antibodies against several cellular adhesion proteins involved in T-cell activation and against viral proteins were used to identify which molecules may be participating in the activation process. First, neither virus from a T-cell line, MT2, nor virus produced from the human osteosarcoma cell line HOS/PL was able to induce PBLs to proliferate. In contrast, both fixed and irradiated HTLV-I-producing T-cell lines induced proliferation of PBLs; HOS/PL cells did not activate PBLs. Second, HTLV-I-positive T-cell lines were capable of activating interleukin-2 mRNA expression in Jurkat cells. Induction of interleukin-2 expression was inhibited by anti-CD2 and anti-lymphocyte function-associated antigen 3 (LFA-3) monoclonal antibodies but not anti-human leukocyte antigen-DR, anti-CD4, anti-LFA-1, or anti-intercellular adhesion molecule 1. Similar results were obtained with PBLs as the responder cells. Furthermore, monoclonal antibodies and antisera against various regions of the HTLV-I envelope proteins gp46 and gp21 as well as p40tax did not block activation. These data indicate that HTLV-I viral particles are not intrinsically mitogenic and that infection of target T cells is not necessary for activation. Instead, the mitogenic activity is restricted to virus-producing T cells, requires cell-to-cell contact, and may be mediated through the LFA-3/CD2 activation pathway.
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PMID:The mitogenic activity of human T-cell leukemia virus type I is T-cell associated and requires the CD2/LFA-3 activation pathway. 768 60

We studied the efficacy of infusing human recombinant interleukin-2 (IL-2) through the splenic artery for generation of lynphokine activated killer (LAK) cells in vivo in a canine system. Catheters were inserted into the splenic artery, portal vein and inferior vena cava (IVC) in Beagle dogs. IL-2 was administered continuously through either the splenic artery or IVC by portable infusion pump and the cytotoxic activity of portal vein blood lymphocytes (PVBL) and peripheral blood lymphocytes (PBL) against canine osteosarcoma D-17 target cells was monitored. Following administration low-dose IL-2 (8 x 10(5) IU/day) for 6 days through the splenic artery, LAK precursor cells were present, but not following administration intravenously. Interestingly, when a high dose of IL-2 (4 x 10(6) IU/day on days 1-6 and 13-18) was administered through the splenic artery, strong cytotoxicity was detected in PVBL and PBL without subsequent culture in vitro with IL-2, suggesting that an infusion rate of 4 x 10(6) IU/day IL-2 may be sufficient for generation of LAK cells in vivo. These results suggest that continuous infusion of IL-2 through the splenic artery can generate LAK cells more easily and may prove especially useful for the immunotherapy of hepatic micrometastasis.
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PMID:Successful in vivo generation of canine lymphokine-activated killer cells by continuous recombinant interleukin-2 infusion through the splenic artery. 780 61

Prostate tumor cells preferentially metastasize to bony sites and lymph nodes at a frequency in excess of that which would be predicted by random tumor cell dissemination. In order to determine whether chemoattractants in these organs promote organ-specific metastasis, we utilized human cell lines derived from and/or related to these organs as sources of potential chemoattractants. Secretory proteins derived from the cell lines MG-63 (osteosarcoma), SK-ES-1 (Ewing's sarcoma), and KG-1 (leukemia) stimulated chemomigration of the TSU-pr1 prostate tumor cells in a dose-dependent manner in Boyden chambers. In addition, secretory proteins from a human prostatic stromal cell line (hPS) and from the TSU-Pr1 prostate tumor cell line were also able to stimulate chemomigration of the TSU-pr1 cells through Boyden chambers. Since lymph nodes and bony sites represent organs of hematopoietic/lymphoid proliferation and activation, we undertook identification of specific cytokines present at these sites which may promote the chemomigration of prostate tumor cells. In this context, the cytokines interleukin-1 alpha, interleukin-2, interleukin-6, tumor necrosis factor-beta, transforming growth factor-beta, interferon alpha 2-a, and granulocyte-macrophage colony-stimulating factor did not stimulate chemomigration of the TSU-pr1 prostate tumor cell line. In contrast, the cytokine epidermal growth factor (EGF) stimulated chemomigration of the TSU-pr1 prostate tumor cells through the Boyden chambers in a dose-dependent manner. Western blot analysis of secretory proteins from the cell lines KG-1, SK-ES-1, MG-63, hPS, and TSU-pr1 identified EGF-immunoreactive proteins in all cases. In addition, EGF immunoreactivity was localized to the stroma of the human prostate, the osteogenic stroma of pelvic medullary bone, and the stroma within the capsule and trabeculae of pelvic lymph nodes. Hence, these results demonstrate that the cytokine EGF promotes the chemomigration of the TSU-pr1 prostate tumor cell line, and that EGF within the stroma of pelvic lymph nodes and medullary bone may act as a chemoattractant for prostate tumor cells, thereby facilitating the preferential formation of metastatic foci within these organs.
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PMID:Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone. 854 75

Current treatment of osteosarcoma produces disappointing outcomes, and innovative therapies must be investigated. We have used retroviral vectors to transfer the herpes simplex virus thymidine kinase (HSVtk) and interleukin-2 genes to human osteosarcoma cells. Each gene was stably transduced and expressed; the HSVtk gene effectively conferred ganciclovir (GCV) susceptibility to transduced cells. A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to GCV killing. Human osteosarcoma cells were used to develop a series of experiments in athymic nude mice to treat experimental osteosarcoma. Subcutaneously implanted mixtures of tumor cells and HSVtk vector producer cells developed into tumors that completely regressed upon administration of GCV. Subcutaneously implanted mixtures of transduced and wild-type cells showed a potent bystander effect upon administration of GCV, with complete tumor ablation when as little as 10% of the cells were HSVtk+. A significant (P < .05) antitumoral response was seen against primary tumors composed of unmodified cells when a secondary tumor of transduced cells was implanted at a distance of 1 cm, suggesting a diffusible bystander factor. The presence of interleukin-2-transduced cells improved the efficacy of treatment. A significant (P < .03) antitumoral response was seen in the treatment of established osteosarcomas by the injection of HSVtk vector producer cells.
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PMID:Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes. 1077 Jun 26


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