Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-11(rhIL-11) is a cytokine that has been shown to enhance the recovery of bone marrow and intestinal crypt cells after cytotoxic insult with radiation or anticancer drugs. The current study examined the effects of rhIL-11 on the response of CEM human lymphoblastic leukemia cells and on the EMT-6 murine mammary carcinoma in vivo to cytotoxic anticancer therapies. Exposure of CEM cells to rhIL-11 for 24 hr did not alter the cytotoxicity of melphalan or radiation, increased the cytotoxicity of CDDP (100 muM) and 4-hydroperoxycyclophosphamide (50 betaM) and decreased the cytotoxicity of 5-fluorouracil and ara-C toward the cells. Treatment of mice bearing the EMT-6 tumor with rhIL-11 twice daily for 4 days prior to and the day of cytotoxic therapy resulted in no significant change in the tumor cell killing or bone marrow CFU-GM killing by melphalan, cyclophosphamide, thiotepa, CDDP, radiation, 5-fluorouracil or ara-C. Administration of rhIL-11 twice per day on days 7-18 to EMT-6 tumor bearing animals receiving high dose chemotherapy (melphalan, thiotepa or cyclophosphamide) as a single dose on day 7 followed by mobilized peripheral blood cells on day 8 and rhG-CSF on days 8-20, tended to prolong the tumor growth delay produced by the drugs. This rhIL-11 treatment also resulted in a more rapid recovery of white blood cells and granulocytes in the animals. Furthermore, animals treated with rhIL-11 had improved survival rates compared with animals receiving all other normal tissue support without rhIL-11.
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PMID:Interaction of interleukin-11 with cytotoxic therapies in vitro against CEM cells and in vivo against EMT-6 murine mammary carcinoma. 882 60

Directed motion toward and infiltration of tumor masses by effector cells is essential for successful adoptive immunotherapy. A human/SCID mouse chimeric system was used to examine whether an antitumor antibody and recombinant human monocyte colony-stimulating factor (rhM-CSF) could promote human T-cell infiltration of a human tumor in vivo. Fourteen days after subcutaneous injection of the human melanoma cell line M-14 into SCID recipients, several adoptive immunotherapy regimens were initiated using activated human T cells, an anti-melanoma monoclonal antibody (MoAb) (R24), and rhM-CSF. Effects on tumor growth and human T-cell infiltration into the tumor were assessed. Compared with other treatment groups, only mice treated with the combination of activated human T cells, anti-tumor MoAb, and rhM-CSF demonstrated a significant cellular infiltrate in the melanoma. Immunohistology demonstrated human T cells present in the tumor up to 7 days after injection. Groups treated with rhRANTES or rmGM-CSF in place of rhM-CSF exhibited markedly less human T-cell infiltration. Additionally, only mice treated with human T cells, R24, and rhM-CSF demonstrated a significant antitumor response in vivo. This model suggests that activated human T cells can be specifically targeted to in vivo tumor sites by combined treatment with an antitumor antibody and rhM-CSF.
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PMID:Adoptive immunotherapy involving recombinant human M-CSF and R24 anti-melanoma antibody induces human T-cell infiltration into human melanoma xenografts. 894 71

Murine epidermis contains 2 distinct cell populations which contribute to the skin immune system, Langerhans cells (LC), and dendritic epidermal T cells (DETC). LCs are important in the induction of immunity against a wide range of antigens; however, the function of DETC is unclear. To investigate the roles of these epidermal cells (EC) in protective antitumor immunity, an in vivo model of an ultraviolet radiation-induced fibrosarcoma, UV-13-1, was used. Mice were immunized with tumor antigen-pulsed EC followed 10 days later by an injection into the ear of 10(5) tumor cells, which did not lead to formation of a detectable tumor, but was intended to simulate the influence of a developing tumor on the ensuing immune response. The mice were then challenged with 2 x 10(6) viable tumor cells in each flank, sufficient to result in growth of a measurable tumor. Protective immunity was induced by DETC, and shown to be long-lasting, with tumors inoculated 160 days after immunization being effectively rejected. The effector cells responsible for protective immunity were CD8+ T cells. Delayed-type hypersensitivity generated by tumor antigen-pulsed EC was dependent on LCs, with no involvement of DETCs. This response, in contrast to that of DETC, required prior culture of EC with GM-CSF, but failed to inhibit tumor growth or incidence. Thus DETC and LC can both activate antitumor immune responses, although only the DETC-dependent response results in protective immunity in the presence of a developing tumor.
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PMID:Dendritic epidermal T-cell involvement in induction of CD8+ T cell-mediated immunity against an ultraviolet radiation-induced skin tumor. 898 97

Although IL-6 has been identified as a major growth factor in multiple myeloma (MM), it is believed that maintenance of tumor growth in vivo depends on one or more additional stroma-derived factors. We describe a new human myeloma cell line (MM5.1) that can be maintained in the presence of bone marrow-derived stromal cell layers, and not only when cultured with exogeneous IL-6. This cell line expresses the same immunoglobulin kappa light chain RNA sequence as the patient's original tumor cells, has a plasma cell morphology and expresses plasma cell antigens (cytoplasmic kappa light chain, CD38, BB4). Without the presence of stromal factors, MM5.1 cells become apoptotic. A low proliferative effect was observed in the presence of oncostatin M (OSM) but other cytokines (IL-10, IL-11, stem cell factor (SCF) and leukemia inhibitory factor (LIF)) had no effect at all. We observed that MM5.1 cells also grow when physically separated from stromal cell layers by a 0.45 microm microporous membrane or when cultured in conditioned medium from stromal marrow cells. Unexpectedly, the growth in stromal supernatants was markedly inhibited by an anti-IL-6 antiserum and an anti-IL-6 receptor transducer chain (gp130) mAb in a dose-dependent manner. This implies that MM5.1 cells are IL-6 responsive only when exposed to one or more additional soluble factor(s) derived from bone marrow stroma. Coculturing MM5.1 cells with IL-6 and cytokines that were described to increase the IL-6 responsiveness of myeloma cells (G-CSF, GM-CSF and IL-3) had no effect on the growth or survival. A strong proliferative effect was observed when MM5.1 cells were cultured with IL-6 and soluble IL-6 receptor (sgp80). However no sgp80 could be detected in stromal supernatants using a sensitive immunoassay. This indicates that sustained proliferation of the MM5.1 cell line depends on a combination of IL6 and at least one, thus far unidentified, stroma-derived factor. After more than 1 year in continuous culture, we could obtain a variant of the line (MM5.2) that shows an improved growth rate and grows stroma independently. Molecular analysis revealed clonal identity with the early passage form and Epstein-Barr virus antigen expression was negative. The two variants of this cell line offer a useful model to identify molecular mechanisms involved in clonal evolution towards stroma-independent growth of myeloma cells.
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PMID:Establishment and characterization of a human stroma-dependent myeloma cell line (MM5.1) and its stroma-independent variant (MM5.2). 900 94

The molecular mechanisms that regulate the production and/or functional activity of intratumoral tumor necrosis factor-alpha (TNF-alpha) remain poorly defined. To begin to address this issue we have examined the level of TNF-alpha mRNA and protein produced by macrophages present within immunogenic Fsa-R and non-immunogenic Fsa-N tumors grown in syngeneic Lps(d) C3H/HeJ and Lps(n) C3H/HeN mice. The results obtained indicate that macrophages isolated from tumors grown in Lps(d) C3H/HeJ mice express 5-10-fold less TNF-alpha than equivalent cells present in tumors grown in Lps(n) C3H/HeN mice. These data suggest that the mechanisms that operate within the tumor microenvironment to induce the production of TNF-alpha act, at least in part, via the same signal transduction pathway that is defective in Lps(d) C3H/HeJ mice. Interestingly, despite such differences in TNF-alpha production, tumors inoculated into C3H/HeJ and C3H/HeN mice grew at a similar rate and contained an almost identical proportion of macrophages. Moreover, tumor cells purified from tumors grown in C3H/HeJ and C3H/HeN mice produced similar quantities of the TNF-alpha-inducible cytokine GM-CSF. Thus, although differences in the level of TNF-alpha produced within tumors grown in C3H/HeN and C3H/HeJ mice are readily demonstrable, such differences appear to have little direct impact on the outcome of tumor growth.
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PMID:Molecular mechanisms regulating TNF-alpha production by tumor-associated macrophages. 902 25

Previous studies showed that gammaIFN decreases metastatic hepatic tumor growth by stimulating Kupffer cells (KC). The present studies examine whether lymphocyte stimulation via cells engineered to secrete GM-CSF or IL-2 decreases hepatic tumor growth, and whether stimulation of both macrophages and lymphocytes is more effective than either individually. Rats were immunized with irradiated hepatoma cells transduced by herpes viral amplicon vectors containing the genes for GM-CSF, IL-2 or LacZ. On day 18, half of each group was treated with 5 x 10(4) U gammaIFN, or saline intraperitoneally for 3 d. On day 21, all rats received 5 x 10(5) hepatoma cells intrasplenically. On day 41, rats were killed and tumor nodules were counted. Separate rats underwent splenocyte and KC harvest for assessment of lymphocyte- and macrophage-mediated tumor cell kill in vitro. GM-CSF or IL-2 vaccines or gammaIFN decreased tumor nodules significantly (GM-CSF 13+/-4, IL-2 14+/-6 vs. control 75+/-24, P < 0.001). Combination therapy was more effective, and completely eliminated tumor in 4 of 12 IFN-GM-CSF and 8 of 11 IFN-IL-2 animals. Additional rats underwent partial hepatectomy, an immunosuppressive procedure known to accelerate the growth of hepatic tumor, following tumor challenge. Therapy was equally effective in this immunosuppressive setting. Vaccination is associated with enhancement of splenocyte-mediated tumoricidal activity, whereas the effect of gammaIFN is mediated by KC. GM-CSF and IL-2 vaccine therapy and pretreatment with gammaIFN represent effective strategies in reducing hepatic tumor. Combination therapy targets both lymphocytes and macrophages, and is more effective in reducing tumor than either therapy alone.
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PMID:Prevention of hepatic tumor metastases in rats with herpes viral vaccines and gamma-interferon. 904 85

This report characterizes the immunological host response to a syngeneic murine mammary carcinoma along with variants genetically modified to express B7-1 or secrete GM-CSF and interleukin-12 (IL-12). MT-901 is a subline of a mammary adenocarcinoma that was chemically induced in the Balb/c host. It was found to be weakly immunogenic by immunization/ challenge experiments, and it induced tumor-specific T-cell responses in lymph nodes (LN) draining progressive subcutaneous tumors. Tumor clones expressing B7-1 or secreting GM-CSF exhibited reduced tumorigenicity without completely abrogating tumor growth, whereas IL-12 elaboration lead to complete tumor growth inhibition. In vivo subcutaneous inoculation of a transgenic cell clone secreting GM-CSF (240 ng/10(6) cells/24 hours) resulted in significantly enhanced T-cell reactivity of tumor-draining lymph node (TDLN) cells as compared to wild-type TDLN cells. This finding was obtained from observations assessed by several different methods, including: 1) in vitro cytotoxicity, 2) in vitro interferon-gamma release, and 3) adoptive transfer in mice with established tumor. Moreover, the transfer of activated LN cells derived from mice inoculated with GM-CSF-secreting tumor cells resulted in the prolonged survival of animals with macroscopic metastatic disease, which was not evident utilizing LN cells from mice inoculated with wild-type tumor. By contrast, clones that expressed B7-1 or IL-12 (4 ng/10(6) cells/24 hours) did not elicit enhanced tumor-reactive TDLN cells compared with wild-type tumor when assessed in the adoptive transfer model. The autocrine secretion of GM-CSF by transduced tumor cells was found to serve as an effective immune adjuvant in the host response to this weakly immunogenic tumor.
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PMID:Immune responsiveness to a murine mammary carcinoma modified to express B7-1, interleukin-12, or GM-CSF. 917 34

Leptomeningeal (LM) cancer spread from either a primary brain tumor or a systemic cancer is rapidly fatal. Current therapies are ineffective and highly toxic to normal nervous system tissues. A xenograft model of LM neoplasia in nude rats using a diversity of tumor cell types was established in order to evaluate new treatment strategies and to study the pharmacokinetics and biological effects of treatments administered into the subarachnoid space. Consistent leptomeningeal engraftment and progressive tumor growth was seen after intrathecal injection of 9 of 13 tumor cells lines, including 2 melanomas, 2 neuroblastomas, 2 medulloblastomas, 2 gliomas, and 1 breast cancer. Clinical signs ranged from steady weight loss commencing from the day after tumor implantation to absence of any signs for three weeks until the sudden occurrence of major neurological deficits or death. Pathologic examination showed only leptomeningeal tumor growth with some cell lines and severe parenchymal invasion with others. CSF cytology consistently demonstrated tumor cells in animals with LM disease. Cranial magnetic resonance (MR) following intravenous (i.v.) administration of a contrast agent revealed enhancing lesions one week following melanoma tumor implantation. Reliable ventricular puncture was demonstrated by radiography following intraventricular (IVent) injection of an iodinated contrast material. IVent instillation of saline, albumin, or antibodies did not provoke clinical toxicity or an inflammatory response.
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PMID:A rat model of leptomeningeal human neoplastic xenografts. 925 14

Tumors are tolerated by the immune system notwithstanding the expression of tumor-associated antigens. PROb tumor cells, derived from a rat colon carcinoma, are rejected by tumor-immune hosts but give rise to progressive tumors in naive hosts. Paradoxically, these tumors are heavily infiltrated by dendritic cells that express MHC class II and ICAM-1. These tumor-infiltrating dendritic cells (TiDCs) could be expected to process and present to T cells the antigens released by the adjacent tumor cells. Indeed, we report here that TiDCs, compared with splenic dendritic cells, are poor stimulators of primary allogeneic T-cell proliferation and cytokine [interleukin-2 (IL-2) and interferon-gamma] production. Most of them (89-97%) do not express B7, an essential co-stimulatory signal for T cells, even after a culture period allowing B7 up-regulation on epidermal Langerhans cells. GM-CSF in association with tumor necrosis factor-alpha or IL-4, or cell-associated CD40-ligand, all known to be potent stimulators of B7 expression on other dendritic cells, did not restore B7 expression by TiDCs. After a first exposure to TiDCs, allogeneic T-cell response to a second challenge to splenic dendritic cells was decreased. The failure of most dendritic cells infiltrating PROb tumors to express B7, even after stimulation, may contribute to their poor capacity to stimulate T cells and could play a role in the immune tolerance allowing tumor growth.
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PMID:Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats. 925 1

There has recently been interest in the use of high-dose radiation with methods such as radiosurgery and brachytherapy for skull base tumors. Brachytherapy is believed to be effective for clival chordomas, but technical difficulties exist in stereotactic insertion of catheters into the clivus. We assessed the usefulness following improvement of implantation techniques in three patients with clival chordomas. All tumors were larger than 50 mm in diameter. Removable iridium-192 sources were held in catheters which were implanted through a transnasal approach under general anesthesia using a CT-guided stereotactic system in one patient and a CRW stereotactic system adapted to a magnetic resonance imaging (MRI) scanner in 2 patients. The implantation array was designed based on results of stereotactic 3-D MRI scanning, and coordinates were calculated for stereotactic implantation through twist drill holes. These catheters were introduced through the nares and directed into the clival chordoma under endoscopic visualization and X-ray fluoroscopy. No complications such as CSF liquorrhea, hemorrhage or infection were observed. Brachytherapy with a total dose of 43.2-58.0 Gy at the tumor periphery was administered for 7 to 10 days, and serial follow-up imaging studies demonstrated reduction in tumor size in two patients and no tumor growth in the other. Our results suggested that stereotactic brachytherapy is potentially useful for the control of clival chordomas and that computer-guided transnasal stereotactic insertion enables implantation of catheters less invasively and more accurately than does X-ray fluoroscopic guidance alone.
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PMID:[Stereotactic brachytherapy for clival chordoma]. 933 Mar 95


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