Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on promising results with 5-FU/FA or 5-FU/IFN-alpha in colorectal cancer, a pilot study was initiated to evaluate the effects of the combination 5-FU/FA/interferon alfa (IFN-alpha) in patients with advanced pancreatic cancer. Patients received 9 million units (MU) IFN-alpha subcutaneously three times a week or 6 MU IFN-alpha once a week; 500 mg/m2 5-FU via an intravenous bolus 1 hour after the initiation of a 2-hour infusion of 500 mg/m2 of FA, once a week. Fourteen patients, all previously untreated with chemotherapy, were enrolled; 13 (two females/11 males) were evaluable for response and toxicity (one too early). The median performance status was 80% (range, 60 to 100) and the median age 62 years. Besides the inoperable primary tumor, metastatic sites were liver, lung, and peritoneum. Three of 13 patients had a partial remission, three of 13 patients a minor response, and four of 13 patients no change. Three patients had progressive disease. Until now, no complete remission was seen. Median duration of response was 4+ months; median survival has not been reached yet. Of all patients there were three instances of World Health Organization grade 3 toxicity: fatigue (one of 13), nausea (one of 13), and diarrhea (one of 13); grade 4 toxicity did not occur. Although overall toxicity was moderate, most patients experienced a reduction of well-being. Therefore in all patients the dose of IFN was reduced (from 3 x 9 MU/week to 1 x 6 MU/week). Our preliminary data suggest that biochemical modulation of 5-FU with FA and IFN-alpha (reduced dosage) is effective in pancreatic cancer with moderate toxicity, warranting further study.
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PMID:Combination fluorouracil, folinic acid, and interferon alfa-2a: an active regimen in advanced pancreatic carcinoma. 155 50

Previous studies have suggested that structural abnormalities involving the short arm of chromosome 9 are frequently associated with gliomas. The alpha-, beta-, and omega-interferon (IFNA, IFNB1, and IFNW, respectively) and the methylthioadenosine phosphorylase (MTAP) genes have been mapped to the short arm of chromosome 9, band p22. Homozygous deletions of these genes have been reported in many leukemia- and glioma-derived cell lines. In this report, we present a detailed analysis of partial and complete homozygous or hemizygous deletions of DNA sequences on 9p in human cell lines and primary tumor samples of glioma patients. Ten of 15 (67%) glioma-derived cell lines had hemizygous or homozygous deletion of IFN genes or rearrangement of sequences around these genes, while 13 of 35 (37%) primary glioma tumor samples had hemizygous (8 tumors) or homozygous (5 tumors) deletion of the IFN genes. The shortest region of overlap of these deletions maps in the interval between the centromeric end of the IFN gene cluster and the MTAP gene. In the cell lines and primary tumors examined, these gross genomic alterations were seen only in association with high grade or recurrent gliomas. Our observations confirm that loss of DNA sequences on 9p, particularly the IFN genes, occurs at a significant frequency in gliomas, and may represent an important step in the progression of these tumors. These results are consistent with a model of tumorigenesis in which the development or progression of cancer involves the loss or inactivation of a gene or several genes that normally act to suppress tumorigenesis. One such gene may be located on 9p; this gene may be closely linked to the IFN genes. Nevertheless, loss of the IFN genes, when it occurs, may play an additional role in the progression of these tumors.
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PMID:Molecular analysis of deletions of the short arm of chromosome 9 in human gliomas. 156 21

Human lymphoblastoid interferon (IFN-alpha MOR-22; OIF) was administered to forty-two patients suffering from renal cell carcinoma. Twenty-six patients with metastatic lesions or primary tumor were treated in a clinical trial with either MOR-22 alone or combination of MOR-22 and UFT (or FT-207). The efficacy was assessed in ten of twenty patients who had received MOR-22 alone for more than eight weeks, but objective response was not observed. The efficacy was done in eight of fourteen patients with MOR-22 and UFT (or FT-207) in combination. Complete response was achieved in one, and partial response in two, with an objective response rate of 37.5%. But the difference was no statistically significant in the survival rate of each therapy. In evaluable twenty patients with MOR-22 prophylactically, there was only one case who had occurred lung metastases with a refractory rate of 8.3%. Forty-one patients were examined for side effects to drugs. The main side effects were fever, anorexia, general fatigue, hematologic toxicities, and hepatic dysfunction in both therapy. These side effects occurred with more increased frequency in combination therapy of UFT (or FT-207) compared to MOR-22 alone.
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PMID:[Combination therapy of renal cell carcinoma with interferon-alpha and UFT (or FT-207)]. 250 5

Human brain tumor cell strains were previously found by others to be sensitive to growth inhibition by human interferon-beta (HuIFN-beta). We noticed that the sensitive strains were some that we had found deficient in the repair of O6-methylguanine (O6MeG), a characteristic of 20% of the human tumor cell strains we have studied. We confirmed this sensitivity to HuIFN-beta, and have further shown that human brain tumor cells which repair O6MeG are resistant to the growth inhibitory effects of HuIFN-beta. In addition, treatment with HuIFN-alpha or HuIFN-beta resulted in more killing (reproductive inactivation) of six human tumor cell strains deficient in repairing O6-methylguanine in DNA than did such treatment of six strains of cells proficient in such repair. Further, we found two human lines, altered to become O6MeG repair deficient after establishment of the primary tumor cell culture, that were resistant to interferon. IFN treatment produced no DNA damage detectable by either chemical or biological assays. It is suggested that the genes responsible for resistance to IFN treatment and to agents that produce O6MeG are often coordinately shut down.
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PMID:Human tumor cell strains both unable to repair O6-methylguanine and hypersensitive to killing by human alpha and beta interferons. 400 75

The antitumor effect of human leukocyte interferon was investigated on ten patients with malignant brain tumor. In eight cases of primary tumor, IFN alone was administered when their recurrent sign was evident. A dose of 3 X 10(6) IU or 1 X 10(6) IU of IFN was injected intramuscularly two or three times a week in high-dose group, while a dose of 5 X 10(4) IU once a week in low-dose group. No remarkable side effects including bone marrow depression were noted. Natural killer activity was enhanced and immunologic skin reaction manifested. Partial remission of more than 50% decrease of tumor volume calculated on CT scan was seen in two cases in the low-dose group for about 3-6 months. Complete remission could not be obtained by IFN alone. Our pilot study has shown that IFN alone will not be effective against progressive malignant brain tumors by general administration. Further investigation should be carried out to improve the use of IFN therapy in malignant brain tumor.
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PMID:Effect of human leukocyte interferon on malignant brain tumors. 683 90

The prognosis and the quality of life of patients with carcinoid tumors is related either to symptoms from the substances secreted or to progressive tumor growth. Medical treatment with cytotoxic agents is of marginal value for increasing life expectancy and reducing clinical symptoms. Recent studies with interferon have shown interesting results. In the present investigation, 22 patients with carcinoid tumors and syndrome were treated with recombinant interferon alpha-2a (r-IFN alpha-2a) at the dose of 6 x 10(6) IU intramuscularly daily for 8 weeks and three times weekly thereafter. The primary tumor was localized in the foregut (n = 11), midgut (n = 7), hindgut (n = 1), and unknown site (n = 3). Most cases had liver metastasis. Seventeen patients had elevated 5-hydroxyindoloacetic acid (5-HIAA) excretion and 5 had flushing and/or diarrhea as the only clinical manifestation. Six cases presented a complete syndrome (flushing, diarrhea and 5-HIAA excretion). Control of symptoms was obtained in 80% and a 5-HIAA level reduction in 58% of the patients. The interferon treatment was more effective for control of the carcinoid syndrome than for control of tumor growth. The treatment was well tolerated and fever, myalgia, anorexia and fatigue were the most frequent side-effects.
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PMID:Treatment of carcinoid syndrome with recombinant interferon alpha-2a. 768 66

Observations during the last several years on the relationships between bone marrow-derived dendritic cells (DC) and the cells which are in direct contact with them led to the idea that DC may have regulatory properties. Such regulatory properties exerted by DC were noted in experimental cancers in murine systems as well as in human cancers. It was noted that patients with the same type of cancer in which DC are present in the tumor survive longer than patients without DC in the tumor. It is not known how DC can abrogate the development of the metastatic tumor cells in the primary tumor, nor how the tumor cells are capable of abrogating the anticancer activity of the DC and allowing the development of tumor metastases. Studies on the anticancer activity of macrophages revealed that these cells have an inducible Nitric Oxide (NO) synthase (NOS) which utilizes arginine to produce NO. Suppressor macrophages release NO, which inhibits the ribonucleotide reductase and mitochondrial oxidation in tumor cells in vitro. It was also reported (4) that Interferon gamma (IFN-gamma), produced by murine T helper 1 cells, induces NOS activity in macrophages, while T helper 2 cells which produce Interleukin-4 (IL-4) inhibit the expression of NOS in macrophages. The hypothesis presented in this paper suggests that DC have a gene for NOS which is inducible by immunomodulators (e.g. IFN gamma, OK432, LPS) and can be suppressed by cytokines produced by tumor cells (e.g. IL-4, IL-10).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Success and failure of dendritic cell (DC) anticancer activity may be modulated by nitric oxide synthetase (NOS) gene expression: a hypothesis. 768 49

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

Interleukin (IL)-7 has been evaluated for its influence, alone or in combination with local hyperthermia (LH), on B16a melanoma-bearing mice. Six- to eight-week-old C57BL/6J male mice were inoculated s.c. with 5 x 10(5) tumor cells into the left hind limb. Mice were randomly divided into four groups, and treated s.c. with IL-7 (5 ng) or saline as control, twice a day for three weeks beginning eight days after tumor inoculation. LH, using hot water circulator at 43 +/- 0.2 degrees C for 30 min, was induced to the limb with tumor twice a week for two weeks. Size of the primary tumor was measured every other day for five weeks. Mice were sacrificed five weeks after tumor inoculation. The size of the primary tumor and the number of lung metastases were reduced in mice treated either with IL-7 or LH alone. As a control for IL-7, granulocyte colony stimulating factor (G-CSF) alone had no effect on primary tumor size or number of lung metastases. The greatest antitumor effect was observed in mice treated with IL-7 in combination with LH. Survival was prolonged significantly only in mice treated with IL-7 plus LH compared with that of mice treated with saline. Decreased natural killer (NK) cell activity, number of Thy1.2 cells, and ratio of L3T4+/Lyt2+ cells were associated with tumor growth. These parameters were restored in mice treated with IL-7 plus LH. Increases in levels of IL-1 alpha, IL-6, tumor necrosis factor (TNF alpha) and interferon (IFN gamma) were associated with an increase in the survival of tumor-bearing mice treated with IL-7 and/or LH. These results suggest that changes in T-cell, NK cell and cytokines such as IL-1 alpha, IL-6, TNF-alpha and IFN-gamma in response to IL7 and/or LH might account for prolonged survival of B16a melanoma-bearing mice and that IL-7 might be useful as a potential antitumor agent combined with other therapy in certain malignant solid tumors with metastases.
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PMID:Antitumor effect of interleukin 7 in combination with local hyperthermia in mice bearing B16a melanoma cells. 824 52

In some human tumors, reduced or defective MHC class I surface expression has been attributed to functional deficiencies of the genes of the antigen-processing machinery, the proteasome subunits low molecular weight (LMP)-2 and LMP-7, as well as the peptide transporters associated with antigen processing (TAP)-1 and TAP-2. Using normal epithelial kidney cells (MZ1851NN) and renal cell carcinoma cell lines established from the primary tumor (MZ1851RC) and a lymph node metastasis (MZ1851LN) of the same patient, we investigated whether the modulation of MHC class I antigens, TAP and LMP molecules, occurs during transformation and subsequent progression. The mRNA and protein expression of MHC class I heavy and light chain TAP and LMP was strongly reduced in MZ1851RC when compared to the corresponding normal kidney cells MZ1851NN, and this suppression was even more pronounced in the metastatic cell line MZ1851LN. In addition, the activity of the TAP molecules, as measured by peptide translocation assays, was also markedly diminished in MZ1851RC compared to MZ1851NN cells and was further down-regulated in cells of the metastatic lesion. MHC class I surface expression was enhanced by either culturing MZ1851RC and MZ1851LN cells at 26 degrees C instead of 37 degrees C or by incubation of both cell lines with class I-specific binding peptides, whereas MHC class I surface expression of MZ1851NN cells was not affected under these culture conditions. IFN-alpha and in particular IFN-gamma treatment enhances the steady-state mRNA and/or protein levels of TAP, LMP, and MHC class I genes of MZ1851 cell lines but had no additional effect on the stability of MCH class I surface expression. These data indicate that malignant transformation and subsequent in vivo selection of renal tubular cells can lead to the recovery of carcinoma cells that show stable expression of an immune escape phenotype. Deficiencies associated with this phenotype involve all levels of the MHC class I-restricted antigen presentation machinery, are at least partially reversible by IFN treatment, and are even more pronounced in cells that had acquired metastatic potential.
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PMID:Analysis of the major histocompatibility complex class I antigen presentation machinery in normal and malignant renal cells: evidence for deficiencies associated with transformation and progression. 862 Apr 89


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