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)

Imbalance in the Kb and Db region encoded molecules is observed in Lewis lung carcinoma clones. The uncloned metastatic population and the D122 high-metastatic clone show no expression of H-2Kb products, while the nonmetastatic A9 clone expresses Kb products. Twenty-nine new subclones of 3LL and A9 were analyzed for D-end and K-end membrane expression, primary growth rate and metastatic spread. We show that the imbalance in H-2Kb to H-2Db is correlated with metastatic properties of a given clone, but local tumor growth is not. A "low Kb/low Db" phenotype is nonmetastatic as is a "high Kb/high Db" phenotype; a "low Kb/high Db" is highly metastatic and a "medium Kb/high Db" is moderately metastatic. We find support for this notion of imbalance in experiments on MHC modulation by interferon and retinoic acid. Interferon increases both Kb and Db expression of A9 and D122 clones yet the net increase of Db was greater than Kb. This was associated with an increase in metastasis formation. Retinoic acid increases the expression of the Db gene product on the nonmetastatic A9, clone, without apparent changes in Kb expression. This treatment shifts the A9 to a high-metastatic phenotype. The significance of this imbalance to the tumor--host relationship is discussed.
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PMID:MHC imbalance and metastatic spread in Lewis lung carcinoma clones. 686 90

The antitumor effect of human fibroblast interferon (HuIFN-beta) was examined using a nude mouse-human tumor xenograft group. Eight subcutaneously transplanted tumors--one line each of ovarian carcinoma, laryngeal carcinoma, carcinoma of the nasopharynx and hepatoma, and two lines each of lung carcinoma and melanoma--were used. HuIFN-beta at 1 X 10(5) IU/mouse was injected subcutaneously around the tumor or into the tumor itself. In the former case, statistically significant growth-suppressive effects were observed in one lung carcinoma (PC-12) and both melanomas (AM-1 and SK-14), but no effect was seen on the other five tumors. Further studies were made to ascertain the effects of intratumoral injections. Increased growth inhibition was observed in both melanomas (AM-1 and SK-14), but not in lung cancer (PC-12). Complete regression was seen in 3 of 8 mice carrying SK-14. The sensitivity of tumors to HuIFN-beta was correlated to the inhibitory effect of HuIFN-beta on cell division detected by histological observation.
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PMID:Effects of human fibroblast interferon on human tumors transplanted into nude mice: sensitivity of human tumors to interferon. 716 May 83

Ubiquitin cross-reactive protein (UCRP), a 15-kDa interferon-induced protein, is a sequence homolog of ubiquitin that is covalently ligated to intracellular proteins in a parallel enzymatic reaction and is found at low levels within cultured cell lines and human tissues not exposed to interferon. Ubiquitin and UCRP ligation reactions apparently target distinct subsets of intracellular proteins, as judged from differences in the distributions of the respective adducts revealed on immunoblots. In this study, successive passages of the human lung carcinoma line A549 in the presence of neutralizing antibodies against alpha and beta interferons had no effect on the levels of either free or conjugated UCRP, indicating that these UCRP pools are constitutively present within uninduced cells and are thus not a consequence of autoinduction by low levels of secreted alpha/beta interferon. In an effort to identify potential targets for UCRP conjugation, the immunocytochemical distribution of UCRP was examined by using affinity-purified polyclonal antibodies against recombinant polypeptide. UCRP distributes in a punctate cytoskeletal pattern that is resistant to extraction by nonionic detergents (e.g., Triton X-100) in both uninduced and interferon-treated A549 cells. The cytoskeletal pattern colocalizes with the intermediate filament network of epithelial and mesothelial cell lines. Immunoblots of parallel Triton X-100-insoluble cell extracts suggest that the cytoskeletal association largely results from the noncovalent association of UCRP conjugates with the intermediate filaments rather than direct ligation of the polypeptide to structural components of the filaments. A significant increase in the sequestration of UCRP adducts on intermediate filaments accompanies interferon induction. These results suggest that UCRP may serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments.
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PMID:Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. 752 57

Immunomodulatory substances have been used as antineoplastic agents in experimental and human systems. Many of these agents were derived from microorganisms. Several biologically active fractions have been isolated from Nocardia. These derivatives were shown to induce interferon production, to activate natural killer cells and macrophages and to exert an antitumoral effect. We attempted to examine the mechanism of the antitumoral activity of the Nocardia water-soluble mitogen (NWSM). The tumor tested was the Lewis lung carcinoma (3LL). Regular histological examination and identification of the cellular immune reaction by monoclonal antibodies against macrophages (Mac 1 antigen), B- (IgG expressing) and T-lymphocytes (anti-Lyt-1), analysed by flow cytometry, were performed on samples of the tumor site and of the spleen. Intratumoral administration of the immunomodulators resulted in a massive accumulation of inflammatory cells around the tumor in mice treated with NWSM. The thick rim of infiltrating cells consisted of macrophages and lymphocytes, while the nontreated tumor was found to provoke only a scanty lymphocyte infiltration. Macrophages were, therefore, present at the tumor site and were directly implicated in the antitumoral effect of the Nocardia immunomodulator. T-lymphocytes were also observed at the site of the tumor. The spleen reaction consisted of marked extramedullary hematopoiesis and enlarged follicles containing prominent germinal centres (assessed also by a FACS-demonstrated increase in B-lymphocytes). In view of the inefficiency of chemotherapy in the treatment of advanced cancer, it is of major importance to explore alternative cancer treatment modalities. Immunotherapy is a particularly interesting alternative since it can potentially affect metastatic disease.
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PMID:Antitumoral activity of an immunomodulatory fraction of Nocardia opaca: mechanism of action. 792 96

Metastatic Lewis lung carcinoma (LLC-LN7) cells have previously been shown to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) which induces the appearance of immunosuppressive granulocytic-macrophage progenitor cells (GM-suppressor cells). The present in vitro studies showed that treatment of LLC-LN7 tumor cells with 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] plus low dose gamma-interferon (IFN-gamma) resulted in a synergistic reduction in tumor GM-CSF secretion and a blockage in the capacity of the tumor cells to induce GM-suppressor cells. The production of GM-CSF by bulk cultures of enzymatically dissociated LLC-LN7 tumors that had been excised as s.c. tumors from mice was also blocked when the dissociated tumor was cultured with 1,25(OH)2D3 plus IFN-gamma. Our previous and present studies showed that GM-suppressor cells persist in bulk cultures of dissociated LLC-LN7 tumors after a 1-week period of culture. Addition of either 1,25(OH)2D3 or IFN-gamma did not diminish the persistence of GM-suppressor cells. However, when tumor production of GM-CSF was inhibited by culture with both 1,25(OH)2D3 and IFN-gamma, the ability of the dissociated tumor culture to sustain the presence of GM-suppressor cells was blocked. This elimination of GM-suppressor cells by treatment of the dissociated tumor with 1,25(OH)2D3 and IFN-gamma coincided with increased expansion of CD8+ tumor-infiltrating leukocytes and increased cytotoxic T-lymphocytes activity of tumor-infiltrating lymphocytes. These results suggest that blocking tumor production of GM-CSF can interrupt the suppressor-inducing cascade of the tumor and enhance expansion and anti-tumor cytolytic reactivity of tumor-infiltrating leukocytes.
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PMID:1 alpha,25-dihydroxyvitamin D3 plus gamma-interferon blocks lung tumor production of granulocyte-macrophage colony-stimulating factor and induction of immunosuppressor cells. 826 14

We assessed the antiproliferative effect of human recombinant interferon -alpha (IFN-alpha) or -beta in combination with 5-fluorouracil (5-FU), cisplatin, or cis- or trans-retinoic acid on two human nonsmall cell lung carcinoma cell lines (SK-LU-1 and SK-MES-1) and on one human small cell lung carcinoma cell line (NCI-H69). Results were obtained by direct cell count and/or by the clonigenic assay. The three cell lines differed in their sensitivities to the antiproliferative effects of the different agents. However, both NSCLC cell lines were more responsive to IFN-beta than to IFN-alpha. The SK-MES cell line was more resistant to both IFNs than the SK-LU-1. The NCI-H69 cells were resistant to all the drugs tested, except trans-retinoic acid. The dose and time of exposure were found to be important factors in the case of IFNs and cytotoxic agents, with lower surviving fractions obtained with the higher doses and longer exposures. This finding, however, did not hold true for the retinoic acids, which showed no antiproliferative effect. Within the sensitivity of our system, we did not identify any synergistic interaction in any of the cell lines with IFN-alpha or IFN-beta and 5-FU or cisplatin. A slight synergistic interaction was observed with IFN and cis- or trans-retinoic acid in the SK-LU-1 cell line which was not thought to be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antiproliferative effects of interferons -alpha and -beta in combination with 5-fluorouracil, cisplatin, and cis- and trans-retinoic acid in three human lung carcinoma cell lines. 838 34

The biological effect of type 1 interferons is proposed to arise in part from the conjugation of ubiquitin cross-reactive protein (UCRP), the ISG15 gene product, to intracellular target proteins in a process analogous to that of its sequence homolog ubiquitin, a highly conserved 8.6-kDa polypeptide whose ligation marks proteins for degradation via the 26 S proteasome. Inclusion of CoCl2 during the purification of recombinant UCRP blocks the proteolytic inactivation of the polypeptide occurring by cleavage of the carboxyl-terminal glycine dipeptide required for activation and subsequent ligation. Intact UCRP supports a low rate of ubiquitin-activating enzyme (E1)-dependent ATP:PPi exchange but fails to form a stoichiometric E1-UCRP thiol ester or undergo transfer to ubiquitin carrier protein (E2). The binding affinity of E1 for UCRP is significantly diminished relative to that of ubiquitin. These results suggest that UCRP conjugation proceeds through an enzyme pathway distinct from that of ubiquitin, at least with respect to the step of activation. This was confirmed for an in vitro conjugation assay in which 125I-UCRP could be ligated in an ATP-dependent reaction to proteins present within an A549 human lung carcinoma cell extract and could be competitively inhibited by excess unlabeled UCRP but not ubiquitin. Other results demonstrate that 125I-UCRP conjugation is significantly increased in cell extracts after 24 h of incubation in the presence of interferon-beta, consistent with the late induction of UCRP conjugating activity. Thus, interferon-responsive cells contain a pathway for UCRP ligation that is parallel but distinct from that of ubiquitin.
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PMID:Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. 855 May 81

The efficacy of several potential antiangiogenic agents, TNP-470, minocycline, suramin, genistein, interferon delta 4, 14(sulfated)-beta-cyclodextrin and tetrahydrocortisol, alone and in combination with cytotoxic therapies was examined against primary and metastatic Lewis lung carcinoma. The antiangiogenic agents when administered as single agents or in two-agent combinations were only modestly active as antitumor agents. Three antiangiogenic agent combinations, TNP-470/minocycline, TNP-470/14(SO4)beta-CD/THC and minocycline/14(SO4)beta-CD/THC, produced significant increases in tumor growth delay and decreases in the number of lung metastases when administered along with cyclophosphamide compared with cyclophosphamide alone. Two antiangiogenic agent combinations, minocycline/interferon delta 4 and minocycline/14(SO4)beta-CD/THC, produced significant decreases in the number of lung metastases when administered alone with adriamycin compared with adriamycin alone. The antiangiogenic combinations of TNP-470/minocycline, TNP-470/suramin, TNP-470/genistein, TNP-470/interferon delta 4 and TNP-470/l4(SO4)beta-CD/THC, resulted in increased tumor growth delays when administered along with CDDP, BCNU, fractionated radiation or 5-fluorouracil. There was not always a direct correlation between the antiangiogenic regimen that was most beneficial against the primary tumor as compared with disease metastatic to the lungs. These studies establish that a broad range of antiangilogenic therapies can interact in a positive manner with cytotoxic therapies.
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PMID:Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma. 861 8

Because adjuvant chemotherapy has resulted in only modest prolongation of survival for patients with lung cancer, investigators have turned to the evaluation of alternative treatment strategies for this patient population. Immunotherapy with Bacillus Calmette Guerin, Corynebacterium parvum, and levamisole has been evaluated in several prospective randomized trials, and no study has shown a statistically significant difference in overall survival. Interferon has been evaluated in three trials of adjuvant therapy after response to chemotherapy for small cell lung cancer. Different interferon preparations were used, but none of the trials showed a significant prolongation of survival. The retinoids have been evaluated as adjuvant treatment after complete resection of stage IN-SCLC. One trial showed a reduction in second primary tumors, and in particular, tumors to tobacco smoking in patients treated with retinyl palmitate. A second trial using 13-cis retinoic acid is ongoing in North America. In the last decade, several inhibitors of angiogenesis have been identified, and they are now beginning to be evaluated in the clinical setting. The National Cancer Institute of Canada Clinical Trials Group and the European Organization for Research and Treatment of Cancer have initiated a study of adjuvant marimastat, a metalloproteinase inhibitor, for patients who have responded to induction chemotherapy for small cell lung cancer. This is the first adjuvant antiangiogenesis factor trial to be initiated for any tumor type. Other investigational agents which are currently undergoing Phase I and Phase II testing include monoclonal antibodies which may inhibit tumour cell growth by binding to growth factors, or which may be conjugated to toxins or chemotherapeutic agents which result in tumour cell death. In the last decade, we have witnessed an explosion in our knowledge and understanding of the regulation of normal and neoplastic cell growth at the molecular level. It remains only speculative at this time as to whether manipulation of abnormal genes in malignant cells will be clinically possible, and whether treatment of this sort may be applied in an adjuvant setting.
Lung Cancer 1997 Jun
PMID:Alternatives to chemotherapy and radiotherapy as adjuvant treatment for lung cancer. 921 9

A new preparation "subalin" developed on the basis of a recombinant saprophyte strain of Bacillus subtilis 2135/105 producing human interferon alpha-2 has been tested for its ability of increasing the effectiveness of antitumor therapy. The study used Lewis lung carcinoma bearing mice C57B1/6 treated with injections of 60 mg/kg body cyclophosphamide, intraperitoneally, on days 3 and 7 of tumor growth. Subalin was administered per as on days 1-14 after tumor transplantation. Combined treatment with cyclophosphamide and subalin resulted in a significantly higher inhibition of primary tumor growth and metastatic spreading as compared with control receiving cyclophosphamide alone. Also, there were fewer animals with metastasis; the average number of these lesions per animal and the total affected area were less. Subalin proved to exert a moderate antitumor and antimetastatic effect. The cytostatic activity of peritoneal macrophages was higher in mice treated with subalin. It is suggested that the chemo-sensitizing and antitumor effects of subalin are due to its ability to induce endogenous interferon production.
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PMID:[Modulation of the antitumor effect of cyclophosphamide by the recombinant probiotic Subalin]. 924 89


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