Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The host's immune system discriminates tumor cells from normal cells by recognizing the major histocompatibility complex (MHC) class I antigen expressed on the tumor cell membrane. However, the role of MHC class I antigen in tumor cells has not yet been clarified. In this study, the influence of MHC class I antigen expression on the tumorigenicity of a human glioblastoma cell line (KMG4) is examined. Barely detectable levels of MHC class I messenger ribonucleic acid were found to express in KMG4 cells by Northern blot analysis using mouse MHC class I (H-2Ld) and human leukocyte antigen (HLA)-B7 genes as probes. The H-2Ld gene connected at the downstream end of murine mammary tumor virus (MMTV)-promoter was cotransfected with the neomycine-resistant gene pSV2-neo into KMG4 cells, and the drug-resistant cells were selected. The KMG4 cells (KMG4-MMTV-Ld), which acquired the MHC class I gene were detected by Northern blot analysis with H-2Ld as the probe, and by immunohistochemistry using the H-2Ld-specific monoclonal antibody. Tumorigenicity, as determined by colony-forming ability in soft agar, was then compared between MHC class I-expressing KMG4-MMTV-Ld and nonexpressing control cells. The MHC class I-expressing cells were found to be deprived of colony-forming ability, indicating that MHC class I antigen could negatively influence the anchorage-independent cell growth of the human glioblastoma cell line KMG4.
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PMID:Suppression of anchorage-independent growth of human glioblastoma cell by major histocompatibility complex class I gene-transfection. 156 45

Forphenicinol (FPL) is a low molecular immunomodifier derived from forphenicine, a microbial product found by Umezawa and co-workers. We studied the antitumor effect of FPL, cyclophosphamide (CY), and the combination of the two on several syngeneic murine tumors. The tumors used were mammary carcinoma, L1210 leukemia, B16 melanoma, Lewis lung carcinoma, and glioblastoma. A single ip injection of CY on Day 1 followed by eight consecutive daily oral doses of FPL beginning 6 days after tumor inoculation showed strong cooperation in curing syngeneic mammary carcinoma inoculated intradermally in C3H/HeN mice, most mice being cured of the tumor by the combination therapy and subsequently having acquired strong specific immunity. Treatment with FPL alone (either pre- or post-treatment) also significantly inhibited the growth of the mammary tumor. FPL and CY also showed cooperation in inhibiting the growth of L1210 leukemia transplanted intradermally into CDF1 (BALB/c X DBA/2) mice and markedly prolonged the survival time but FPL treatment alone had no effect. The FPL-CY treatment also affected Lewis lung carcinoma and glioblastoma in syngeneic C57BL/6 mice and produced therapeutic synergism. FPL alone significantly inhibited the growth of B16 melanoma in C57BL/6 mice as well as the syngeneic mammary carcinoma in C3H/HeN mice. These findings suggest that oral administration of FPL in combination with chemotherapeutic agents can be used for treating cancer without causing toxicity, because of the synergistic efficacy of the combination.
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PMID:Effect of forphenicinol, a small molecular immunomodifier, in combination with cyclophosphamide on growth of and immunity to syngeneic murine tumors. 397 57

Protein kinase C (PKC) promotes cell survival in response to ionizing radiation in a variety of experimental models including human carcinoma, human glioblastoma, and transformed mouse embryo fibroblast cell lines. We have introduced specific antisense oligonucleotides into human mammary tumor cell lines in vitro to analyze the role of individual PKC isoforms in radiation-induced cell death in breast cancer. MDA-MB-231 and MCF-7 cells treated with oligonucleotide directed against the PKC delta isoform exhibited impaired survival in response to 5.6 Gy gamma-radiation as measured by mitochondrial metabolism of tetrazolium dye. The role of PKC delta in the breast tumor cell lines was of particular interest, because contradictory reports exist in the literature regarding the role of PKC delta in cell survival and apoptosis. A comparison of the effects of the PKC delta antisense oligonucleotide and a nucleotide scrambled version of this nucleotide revealed only the antisense oligonucleotide decreased cell survival. The PKC delta antisense oligonucleotide decreased cell survival after exposure to low (1.5 Gy) radiation doses and in the absence of radiation insult. We found 3 micro M rottlerin, a selective PKC delta inhibitor, to reduce MCF-7 and MDA-MB-231 cell survival. Furthermore, MCF-7 cells transformed to express a dominant-negative mutant of PKC delta exhibited reduced survival. Comet analysis showed that PKC delta oligonucleotide treatment caused an accumulation of cells containing damaged DNA similar to that seen in 1.5 Gy radiation-treated cells. We conclude that PKC delta acts as a prosurvival factor in human breast tumor cells in vitro.
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PMID:Protein kinase C delta is a prosurvival factor in human breast tumor cell lines. 1265 22

Hepatocyte growth factor/scatter factor-Met signaling has been implicated in tumor growth, invasion, and metastasis. Suppression of this signaling pathway by targeting the Met protein tyrosine kinase may be an ideal strategy for suppressing malignant tumor growth. Using RNA interference technology and adenovirus vectors carrying small-interfering RNA constructs (Ad Met small-interfering RNA) directed against mouse, canine, and human Met, we can knock down c-met mRNA. We show a dramatic dependence on Met in both ligand-dependent and ligand-independent mouse, canine, and human tumor cell lines. Mouse mammary tumor (DA3) cells and Met-transformed NIH3T3 (M114) cells, as well as both human and canine prostate cancer (PC-3 and TR6LM, human sarcoma (SK-LMS-1), glioblastoma (DBTRG), and gastric cancer (MKN45) cells, all display a dramatic reduction of Met expression after infection with Ad Met small-interfering RNA. In these cells, we observe suppression of tumor cell growth and viability in vitro as well as inhibition of hepatocyte growth factor/scatter factor-mediated scattering and invasion in vitro, whether Met activation was ligand dependent or not. Importantly, Ad Met small-interfering RNA led to apoptotic cell death in many of the tumor cell lines, especially DA3 and MKN45, but did not adversely affect MDCK canine kidney cells. Met small-interfering RNA also abrogated downstream Met signaling to molecules such as Akt and p44/42 mitogen-activated protein kinase. We further show that intratumoral infection with c-met small-interfering RNA adenovirus results in a substantial reduction in tumor growth. Thus, Met small-interfering RNA adenoviruses are reliable tools for studying Met function and raise the possibility of their application for cancer therapy.
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PMID:RNA interference reveals that ligand-independent met activity is required for tumor cell signaling and survival. 1552 Feb 3

We have identified an 85 kb BAC clone, 346J21, that carries a cell senescence gene (SEN16), previously mapped to 16q24.3. Transfer and retention of 346J21 in breast cancer cell lines leads to growth arrest after 8-10 cell doublings, accompanied by the appearance of characteristic senescent cell morphology and senescence-associated acid beta-galactosidase activity. Loss of transferred BAC results in reversion to the immortal growth phenotype of the parental cancer cell lines. BAC 346J21 restores senescence in the human breast cancer cell lines, MCF.7 and MDA-MB468, and the rat mammary tumor cell line LA7, but not in the human glioblastoma cell line T98G. We postulate that inactivation of both copies of SEN16 is required for the immortalization of breast epithelial cells at an early stage of tumorigenesis. Positional mapping of 346J21 shows that SEN16 is distinct from other candidate tumor suppressor genes reported at 16q24.
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PMID:Functional identification of a BAC clone from 16q24 carrying a senescence gene SEN16 for breast cancer cells. 1555 27

Increased numbers of tumor-infiltrating macrophages correlate with poor disease outcome in patients affected by several types of cancer, including breast and prostate carcinomas. The colony stimulating factor 1 receptor (CSF1R) signaling pathway drives the recruitment of tumor-associated macrophages (TAMs) to the neoplastic microenvironment and promotes the differentiation of TAMs toward a pro-tumorigenic phenotype. Twelve clinical trials are currently evaluating agents that target the CSF1/CSF1R signaling pathway as a treatment against multiple malignancies, including breast carcinoma, leukemia, and glioblastoma. The blockade of CSF1R signaling has been shown to greatly decrease the number of macrophages in a tissue-specific manner. However, additional mechanistic insights are needed in order to understand how macrophages are depleted and the global effects of CSF1R inhibition on other tumor-infiltrating immune cells. Using BLZ945, a highly selective small molecule inhibitor of CSF1R, we show that CSF1R inhibition attenuates the turnover rate of TAMs while increasing the number of CD8+ T cells that infiltrate cervical and breast carcinomas. Specifically, we find that BLZ945 decreased the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. Furthermore, we show that BLZ945 prevents tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. Our results demonstrate that TAMs undergo a constant turnover in a CSF1R-dependent manner, and suggest that continuous inhibition of the CSF1R pathway may be essential to maintain efficacious macrophage depletion as an anticancer therapy.
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PMID:CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. 2449 62