Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several studies have established a link between blood coagulation and cancer, and more specifically between tissue factor (TF), a transmembrane protein involved in initiating blood coagulation, and tumor metastasis. In the study reported here, a murine model of human melanoma metastasis was used for two experiments. (i) The first experiment was designed to test the effect of varying the level of TF expression in human melanoma cells on their metastatic potential. Two matched sets of cloned human melanoma lines, one expressing a high level and the other a low level of the normal human TF molecule, were generated by retroviral-mediated transfections of a nonmetastatic parental line. The metastatic potential of the two sets of transfected lines was compared by injecting the tumor cells into the tail vein of severe combined immunodeficiency (SCID) mice and later examining the lungs and other tissues for tumor development. Metastatic tumors were detected in 86% of the mice injected with the high-TF lines and in 5% of the mice injected with the low-TF lines, indicating that a high TF level promotes metastasis of human melanoma in the SCID mouse model. This TF effect on metastasis occurs with i.v.-injected melanoma cells but does not occur with primary tumors formed from s.c.-injected melanoma cells, suggesting that TF acts at a late stage of metastasis, after tumor cells have escaped from the primary site and entered the blood. (ii) The second experiment was designed to analyze the mechanism by which TF promotes melanoma metastasis. The procedure involved testing the effect on metastasis of mutations in either the extracellular or cytoplasmic domains of the transmembrane TF molecule. The extracellular mutations introduced two amino acid substitutions that inhibited initiation by TF of the blood-coagulation cascade; the cytoplasmic mutation deleted most of the cytoplasmic domain without impairing the coagulation function of TF. Several human melanoma lines expressing high levels of either of the two mutant TF molecules were generated by retroviral-mediated transfection of the corresponding TF cDNA into the nonmetastatic parental melanoma line, and the metastatic potential of each transfected line was tested in the SCID mouse model. Metastases occurred in most mice injected with the melanoma lines expressing the extracellular TF mutant but were not detected in most mice injected with the melanoma lines expressing the cytoplasmic TF mutant. Results with the extracellular TF mutant indicate that the metastatic effect of TF in the SCID mouse model does not involve products of the coagulation cascade. Results with the cytoplasmic TF mutant indicate that the cytoplasmic domain of TF is important for the metastatic effect, suggesting that the TF could transduce a melanoma cell signal that promotes metastasis.
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PMID:Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. 766 69

B-78-H1 melanoma cells were stably transfected with cDNAs encoding human IL-6, human LIF, murine sIL-6R and murine sLIFR. The mock transfected and transfected cells demonstrated no detectable H-2Kb molecules. B-78 transfected cells were subcutaneously (s.c.) and intravenously (i.v.) injected to B57BL/6 x C3H mice. Control B-78 cells formed tumors and lung metastases in injected animals. Cells transfected with IL-6, LIF and sIL-6R showed greatly reduced tumor and metastases formation. Transfection of IL-6, sIL-6R or LIF had similar protective effects while the combination of IL-6 and sIL-6R was most effective. In contrast, cells transfected with sLIFR showed reduced metastasis formation but increased tumor growth compared to mock transfected cells. Kinetic analysis demonstrated a 3 weeks lag period between the formation of tumors by B-78 cells and the combination of B-78 cells transfected with IL-6 and sIL-6R. No such lag phase was seen when B-78-IL-6 or B-78-sIL-6R cells were injected alone. Mice primarily injected s.c. with a mixture of IL-6 and sIL-6R transfected cells and rechallenged after 2 weeks with parental B-78 cells demonstrated long-lasting antitumor immunity. IL-6 and sIL-6 transfected cells used alone for immunization had only limited effect. Injection of transfected cells into SCID mice which are characterized by greatly reduced number of T and B cells, showed a protective effect of sIL-6R on metastasis formation by B-78 cells. beta 2m knockout mice lacking CD8+ T cells, injected with B-78 cells developed tumors and died after 2 weeks. However, B-78 cells transfected with IL-6 developed tumors in only 50% of animals. Mice without tumors rechallenged with B-78 cells demonstrated required immunity against parental melanoma cells. The results obtained indicate that studied IL-6-type cytokines and their respective soluble receptors affect murine melanoma growth and metastasis formation. The major finding of these studies is that IL-6 complexed with sIL-6R demonstrated qualitatively different biological activity than IL-6 alone especially in stimulating long lasting anti-melanoma immunity. The proposed mechanism of action of such complexes beside activation of cytotoxic T lymphocytes is activation of NK cells.
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PMID:Interleukin-6-type cytokines and their receptors for gene therapy of melanoma. 766 37

The human melanoma cell line M24met expresses tissue factor, the cellular initiator of the blood coagulation cascade. Blocking of the coagulation pathways at the level of tissue factor, factor Xa, or thrombin inhibits hematogenous M24met metastasis in SCID mice, implicating a role for thrombin generation in this process. Dependent on cell surface tissue factor activity, M24met cells generate thrombin in vitro. Thrombin and the thrombin receptor agonist peptide TRP-14 activate a signaling pathway in M24met cells that involves an increase in intracellular calcium and induces cell proliferation. Immunofluorescence evidences expression of the signaling thrombin receptor on these cells. Thus, M24met melanoma cells express both the initiating cell surface receptor for the coagulation pathways and the central signaling receptor of the coagulation system, suggesting the in situ generation of proliferative signals which can contribute to the malignant phenotype.
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PMID:Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells. 771 65

Doxorubicin (DOX) was conjugated to a monoclonal antibody (mAb 425) directed against the human epidermal growth factor receptor. The immunoreactivity of these conjugates, with an average of six to eight molecules of DOX per antibody, was largely conserved, and their in vitro cytotoxicity against metastatic human melanoma cells (M24 met) was improved over that of free DOX. An evaluation of the therapeutic efficacy of mAb 425-DOX indicated that this immunoconjugate suppressed the growth of primary and secondary M24 met tumors in mice with severe combined immunodeficiency and prolonged the life span of these animals, whereas an equivalent dose of free DOX was ineffective. Conjugation of DOX to an irrelevant mAb also increased its antitumor effect over that of equivalent amounts of free drug but to a lesser extent than that achieved by the mAb 425-DOX conjugate. These results demonstrate targeted delivery and striking antitumor activity of DOX immunoconjugates in a preclinical model of spontaneous, metastatic human melanoma that was insensitive to free DOX.
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PMID:Therapeutic efficacy of a doxorubicin immunoconjugate in a preclinical model of spontaneous metastatic human melanoma. 775 86

A cancer cell transfection model was used to evaluate biological activity of soluble IL-6 receptor (sIL-6R) in vivo. B-78 melanoma cells were stably transfected with cDNAs encoding human IL-6, murine sIL-6R and human leukaemia inhibitory factor (LIF). Control and transfected cells were intravenously (i.v.) and/or subcutaneously (s.c.) injected into B57BL/6 x C3H or SCID mice. Whereas B-78 cells formed tumours and lung metastasis in injected animals, transfected animals, transfected cells showed greatly reduced tumour and metastasis formation. Transfection of IL-6, sIL-6R or LIF had similar protective effects. The combination of IL-6 and sIL-6R was most effective. Kinetic analysis demonstrated a 3 week lag period between formation of tumours by B-78 cells and the combination of B-78 cells transfected with IL-6 and sIL-6R. No such lag phase was seen when B-78-IL-6 or B-78-IL-6 or B-78-sIL-6R were injected alone. These results indicate that IL-6 alone exhibits a different quality of activity when compared to the IL-6-soluble receptor complex. Our results demonstrate for the first time that sIL-6R is a biologically active molecule in vivo.
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PMID:Soluble interleukin 6 receptor is biologically active in vivo. 778 33

A metastatic human melanoma cell line that produces urokinase-type plasminogen activator was stably transfected with cDNA encoding human plasminogen activator inhibitor 2 (PAI-2). Transfected clones expressed PAI-2 at levels two to nine times higher than both the parental cell line and mock transfectants, as detected by ELISA of cell lysates and conditioned medium. The clone with the highest PAI-2 expression exhibited complete inhibition of soluble and cell-surface-bound plasminogen activator activity. The level of PAI-2 overexpression in these clonal cell lines correlated positively with the inhibition of their ability to degrade extracellular matrix in vitro. Parental, mock-transfected, and PAI-2-transfected cell lines produced rapidly growing tumors when injected s.c. into the skin of mice with severe combined immunodeficiency. The tumors producing the highest levels of PAI-2 were surrounded by a dense tumor capsule. Both parental cells and mock-transfected cells invariably metastasized from s.c. tumors to lymph nodes and lungs of mice. PAI-2-transfected cell lines produced significantly less or no metastases. Taken together, these data indicate a critical role for plasminogen activator activity in melanoma invasion and metastasis.
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PMID:Overexpression of plasminogen activator inhibitor 2 in human melanoma cells inhibits spontaneous metastasis in scid/scid mice. 781 18

Magainin peptides and model amphipathic peptides exhibit antibiotic activity and are also cytolytic for transformed human cells. Here we demonstrate in vitro that MSI-511 (an all-D amino-acid model magainin peptide) and MSI-130 (a margainin analogue) were more lytic for 17 human melanomas than for normal melanocytes. Melanomas established s.c. in athymic nude mice and then injected once with the peptide MSI-511 completely disappeared in 6 out of 9 animals, whereas a control peptide had no effect. Murine skin at the tumor injection site was initially affected, but healed within 2 weeks with minimal scarring. Similarly, accelerated healing was seen in human skin grafted to SCID mice and injected with MSI-511. Our results indicate that lytic magainin peptides can be used for local tumor therapy with minimal long-term damage to normal tissues.
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PMID:Experimental local therapy of human melanoma with lytic magainin peptides. 782 29

We investigated the therapeutic potential of employing antisense oligodeoxynucleotides to target the disruption of MYB, a gene which has been postulated to play a pathogenetic role in cutaneous melanoma. We found that MYB was expressed at low levels in several human melanoma cell lines. Also, growth of representative lines in vitro was inhibited in a dose- and sequence-dependent manner by targeting the MYB gene with unmodified or phosphorothioate-modified antisense oligodeoxynucleotides. Inhibition of cell growth correlated with specific decrease of MYB mRNA. In SCID mice bearing human melanoma tumors, infusion of MYB antisense transiently suppressed MYB gene expression but effected long-term growth suppression of transplanted tumor cells. Toxicity of the oligodeoxynucleotides was minimal in mice, even when targeted to the murine Myb gene. These results suggest that the MYB gene may play an important, though undefined, role in the growth of at least some human melanomas. Inhibition of MYB expression might be of use in the treatment of this disease.
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PMID:Biologic and therapeutic significance of MYB expression in human melanoma. 818 37

The use of retroviral-mediated gene transfer to introduce a DNA label into T cells (TIL) being used in the immunotherapy of patients with malignant melanoma finally opened the door to the clinical application of gene therapy for a wide variety of inherited and acquired diseases. The gene therapy trial for ADA deficiency SCID has demonstrated that long term stable expression of exogenous genes can be achieved in human T lymphocytes using retroviral vectors for ex vivo treatment and that significant immune reconstitution can be achieved in these patients following periodic infusions with ADA gene-corrected autologous T cells. Newer clinical applications include the insertion of genes into CD34 enriched stem cell populations, the testing of autologous tumor vaccines employing cytokine gene-modified tumor cells and the direct transfer of the herpes thymidine kinase gene into brain tumors in situ in order to render those tumors sensitive to treatment with the ordinarily non-cytotoxic drug ganciclovir.
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PMID:Strategies for gene therapy. 829 Mar 10

An orthotopic model of human melanoma was developed in which malignant cells were injected into human skin grafted to nude and SCID mice. Melanoma cells proliferated and invaded the human skin grafts with characteristic patterns. Three of six melanomas grew as multiple nodules and infiltered the grafts without major architectural changes in the dermis, whereas the others invaded the dermis along collagen fibers with prominent endothelial vessels. By contrast, melanoma cells inoculated into mouse skin grew as diffusely expanding nodules that did not invade the murine dermis. In human skin grafts, human melanoma cells were angiogenic for human blood vessels, and murine vessels were only found at the periphery of grafts. Tumor cells invaded the human vessels, and four out of seven cell lines metastasized to lungs, suggesting that this model is useful to determine in vivo the interactions between normal and malignant human cells.
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PMID:Growth and invasion of human melanomas in human skin grafted to immunodeficient mice. 834


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