Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study the potential of minocycline, a semisynthetic tetracycline that inhibits collagenase activity in vivo, as an adjuvant to standard anticancer therapies was explored in vitro and in vivo. In EMT-6 cells, minocycline proved to be only minimally cytotoxic, producing a 50% cell kill at concentrations of 132 and 220 microM in normally oxygenated and hypoxic cells, respectively, after 24 h exposure to the drug. In vitro, there appeared to be no interaction between minocycline and cisplatin (CDDP), melphalan, 4-hydroperoxycyclophosphamide, or radiation. In tumor-cell survival studies using the FSaIIC murine fibrosarcoma, short-term treatment with minocycline (5 x 5 mg/kg given over 24 h) was only minimally cytotoxic and did not alter the tumor response to a range of radiation doses. However, when minocycline (5 x 5 mg/kg given over 24 h) was added to treatment with cyclophosphamide, there was a 4-fold increase in FSaIIC tumor-cell killing across the dose range of cyclophosphamide doses tested, whereas the killing of bone marrow granulocyte macrophage colony-forming units (CFU-GM) remained unchanged. The Lewis lung carcinoma was used to assess the response of both the primary tumor and metastatic lung disease to treatment with minocycline (14 x 5 mg/kg) given alone or in combination with several cytotoxic anticancer drugs or with radiation delivered locally to the primary tumor. Of the various therapies tested, minocycline proved to be especially effective as an addition to treatment with cyclophosphamide both in increasing the response of the primary tumor and in reducing the number of lung metastases. The tumor growth delay produced by melphalan, radiation, Adriamycin, and bleomycin was also increased by the addition of minocycline to these therapies. These results indicate that minocycline given in clinically achievable doses may be an effective addition to some standard therapeutic regimens and that the mechanism of modulation by minocycline is likely to involve an effect of the drug on the host and not its direct interaction with other therapeutic modalities at the level of the tumor cell.
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PMID:Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo. 150 76

A tumor cell-derived, collagenase stimulatory factor (TCSF), previously isolated and purified from LX-1 human lung carcinoma cells and judged by immunoblotting and SDS-PAGE to contain a single protein of approximately 58 kDa, has been further analyzed for its biological activity and composition. Three significant new findings have been made. First, the biological activity of TCSF preparations was shown definitively to reside in the 58-kDa protein. This was achieved in two ways: (a) a polyclonal antibody was raised against the 58-kDa protein, after excision from an SDS-PAGE gel, and shown to inhibit the stimulation of fibroblast collagenase production by TCSF preparations; (b) the 58-kDa protein was eluted from a transblot of purified TCSF and shown to stimulate fibroblast collagenase production. Second, partial sequencing of the 58-kDa protein revealed no significant homologies with other known collagenase stimulatory factors. Third, purified TCSF was found, on transblotting to Immobilon, to contain a doublet of 58 kDa (TCSF1) and 54 kDa (TCSF2) proteins; the former was present in higher concentration than the latter. N-terminal amino acid sequencing of the two intact proteins and of four corresponding pairs of tryptic peptides derived from the two proteins showed identity in each case, indicating that TCSF1 and TCSF2 are very similar in composition. However, TCSF1 but not TCSF2 stimulated fibroblast collagenase production, confirming that the 58-kDa protein is the major active component of TCSF preparations.
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PMID:Partial sequencing and characterization of the tumor cell-derived collagenase stimulatory factor. 184 36

Tumor cells from several sources produce a factor(s) which stimulates fibroblast collagenase production. Monoclonal antibodies have been raised against the tumor cell collagenase-stimulatory factor from LX-1 human lung carcinoma cells and have been used for purification of the factor from LX-1 cell membranes. These purified preparations stimulated fibroblast collagenase production, and 80% of these preparations contained a single Mr approximately 58,000 protein detectable by immunoblotting; the other 20% contained an additional minor component with a molecular weight of 35,000. A single protein with a molecular weight of approximately 58,000 was also detected in radiolabeled preparations of the purified factor by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Conditioned media from LX-1 cells contain several species with molecular weights lower than 58,000 which are immunologically cross-reactive with the membrane-derived factor. Immunofluorescence analysis indicates that the tumor cell collagenase-stimulatory factor is distributed on the outer surface of LX-1 cells and is absent from the cell surface of fibroblasts. These and previous results indicate that the factor is present on the tumor cell surface, is released into conditioned media possibly after proteolytic cleavage, and appears to have an important role in inducing collagenolysis of host stroma during tumor invasion.
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PMID:Monoclonal antibody preparation and purification of a tumor cell collagenase-stimulatory factor. 254 2

Cocultures of human fibroblasts and LX-1 human lung carcinoma cells expressed 8-10 fold higher levels of collagenase mRNA than the sum of the individual cells, in parallel with similar increases in collagenase activity. Addition of the tumor cell collagenase stimulatory factor, TCSF, purified from LX-1 cells, to these fibroblasts also gave a 3-4 times increase in collagenase mRNA level. However, various fibroblast cell lines differed in their response to TCSF stimulation. Thus one cell line, GM 1391, did not respond to TCSF but responded to another potent collagenase stimulator, tetradecanoyl phorbol ester. Another cell line 5383 did not respond significantly to either agent. In each case collagenase activity and mRNA levels responded in a parallel fashion.
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PMID:Coordinate increase in collagenase mRNA and enzyme levels in human fibroblasts treated with the tumor cell factor, TCSF. 255 7

Recent studies of murine tumor models and certain human tumor cell lines have provided evidence for intratumor heterogeneity in expression of extracellular matrix receptors and in the elaboration of matrix-degrading enzymes. However, little is known about possible intratumoral heterogeneity in the production of matrix macromolecules. We have, therefore, examined the biosynthesis and secretion of matrix proteins by cells derived from a polyclonal human cell line (JH-17) established from a large cell undifferentiated carcinoma of the lung. For the present studies, we focused on the production of collagens and structural glycoproteins by two phenotypically different aneuploid clones, designated C13 and C22. These clones were distinctive in their inability to grow in soft agar or to form tumors in nude mice and had identical DNA contents. Tumor cells were labeled with [3H]proline and the newly synthesized proteins accumulating in the culture medium were identified using biochemical and immunologic techniques. Clone C13 secreted at least three genetically distinct collagens, including type V procollagen (PC), type IV procollagen, and a type VIII-like collagen. By contrast, the clone C22 synthesized fibronectin, and a single bacterial collagenase-sensitive and pepsin-resistant component consistent with type I trimer. These studies emphasize the potential diversity of matrix proteins synthesized by neoplastic cells and suggest that there is intratumoral heterogeneity in matrix protein biosynthesis in vivo. These studies further suggest that tumor-derived matrix may be altered during tumor progression or cell selection in vivo.
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PMID:Heterogeneity in the production of collagens and fibronectin by morphologically distinct clones of a human tumor cell line: evidence for intratumoral diversity in matrix protein biosynthesis. 282 40

Cocultures of human fibroblasts with 3 different human tumor cell lines exhibited high levels of collagenase activity against type I collagen compared to individual cultures of each cell type. For LX-1 lung carcinoma cells maximum stimulation occurred at a ratio of tumor cells to fibroblasts of 0.5:1. These cocultures contained 15-50 times more collagenase activity than the sum of the individual cultures. Conditioned medium from the LX-1 cells stimulated the fibroblasts to an extent similar to that obtained in the cocultures. Conditioned medium from the fibroblasts did not stimulate the tumor cells. Thus human tumor cells secrete a factor(s) which stimulates collagenase production by human fibroblasts.
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PMID:Collagenase stimulation in cocultures of human fibroblasts and human tumor cells. 609 11

The proteolytic activity in homogenates and extracts of subcellular fractions prepared from subcutaneous Lewis lung carcinoma was determined using proteins and synthetic peptides as substrates. The presence of cathepsin D, plasminogen activator, cathepsin B-, cathepsin G- and elastase-like enzymes was observed. No difference was revealed between the proteolytic activity in homogenates of Lewis lung carcinoma, at the growth stage examined, and in homogenates of normal lung. High specific activities were found in the lysosomal extract, whereas decreasing activities were found in the nuclear extract, the homogenate and the postlysosomal mitochondrial supernatant; no active or trypsin-activatable collagenase activity was detected. The presence in the tumor tissue of these enzymatic activities is in agreement with their proposed role in the process of metastasis. The lack of differences between homogenates of tumor and normal lung tissue suggests that the use of whole cells is required to selectively study tumor proteinases specifically involved in tumor malignancy.
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PMID:Methodologic problems encountered in the assay of proteinases in Lewis lung carcinoma, a mouse metastasizing tumor. 629 35

Interactions between cancer cells and host macrophages might have important regulatory roles in controlling the expression of the metastatic phenotype, particularly by regulating the production of proteases necessary for tissue invasion. To investigate that possibility, mouse macrophages and Lewis lung carcinoma (LLC) cells from four clonal subpopulations with either low or high metastatic ability were cultured on [14C]collagen (type l)-coated plates. They did not degrade collagen when they were cultured independently on that substrate, but they were induced to do so when macrophages and cancer cells were cultured together. An increased production of neutral collagenase and other neutral protease activities was observed simultaneously. The degree of stimulation of collagen degradation varied according to the cancer cell subpopulation present in the cocultures. For a given LLC cell subpopulation, similar degrees of stimulation of collagen degradation were achieved with either bone marrow-derived or resident peritoneal macrophages, either syngeneic (from C57BL/6 mice) or allogeneic; lower stimulations were obtained with thioglycolate-elicited peritoneal macrophages. Macrophage-conditioned culture media could be substituted for living macrophages to stimulate collagen degradation or collagenase secretion by LLC cells, but LLC cell-conditioned media did not stimulate collagen degradation by macrophages. This suggests that, in the cocultures, collagen degradation is achieved mainly by the cancer cells, not by the macrophages, and that it is induced by a soluble factor, a monokine, produced by the macrophages. That factor might be identical to a recently identified rabbit monokine that stimulates fibroblasts or synovial cells to degrade collagen and proteoglycan and to activate plasminogen, because rabbit macrophage-conditioned media containing that monokine also stimulated collagen degradation by LLC cells.
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PMID:Collagen degradation by metastatic variants of Lewis lung carcinoma: cooperation between tumor cells and macrophages. 635 18

5'-deoxy-5-fluorouridine (5'-FUdR) is a cytostatic that is biotransformed to 5-fluorouracil (5-FUra) by pyrimidine nucleoside phosphorylase (PyNPase), the expression of which is up-regulated by tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interferon gamma (IFN gamma). In Lewis lung carcinoma (LLC) cell cultures, these inflammatory cytokines up-regulated the expression of type-IV collagenase, metastatic factor, as well as PyNPase and consequently enhanced the antiproliferative activity of 5'-FUdR. However, the activity of 5-FUra was not enhanced. It appears that 5'-FUdR selectively kills highly metastatic cells which are exposed to these intrinsic cytokines in tumor tissues, because of their high PyNPase activity. In fact, 5'-FUdR inhibited the spontaneous metastasis of LLC from the s.c. inoculation site to the lung. When 5'-FUdR was given during the process of metastasis it greatly reduced the number of tumor nodules in the lung even at doses 46 times lower than those inhibiting the primary tumor growth. In addition, 5'-FUdR, but not 5-FUra, lowered type-IV collagenase levels in the tumors at the low dose showing only anti-metastatic activity. On the other hand, 5-FUra showed anti-metastatic activity at doses similar to or only several times lower than those inhibiting the primary tumor growth.
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PMID:Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine. 775 57

The tumor cell-derived collagenase-stimulatory factor (TCSF) was previously purified from human lung carcinoma cells (S. M. Ellis, K. Nabeshima, and C. Biswas, Cancer Res., 49: 3385-3391, 1989). This protein is present on the surface of several types of human tumor cells in vitro and in vivo and stimulates production of interstitial collagenase in human fibroblasts. In this study it is shown that TCSF stimulates expression in human fibroblasts of mRNA for stromelysin 1 and 72-kDa gelatinase/type IV collagenase, as well as for interstitial collagenase. Measurement of enzyme protein by immunoassay showed that the amounts of interstitial collagenase and stromelysin 1 were increased in TCSF-treated fibroblasts; gelatin zymography indicated that there was an increase in the 72-kDa gelatinase. These results indicate that tumor cell interaction with fibroblasts via TCSF could lead to increased degradation of interstitial or basement membrane matrix components and thus to enhanced tumor cell invasion.
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PMID:Tumor cell-derived collagenase-stimulatory factor increases expression of interstitial collagenase, stromelysin, and 72-kDa gelatinase. 831 25


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