Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cell survival assay in the FSaIIC murine fibrosarcoma demonstrated that when the modulator Fluosol-DA (0.3 ml; 12 ml/kg i.v.) was administered just prior to an alkylating agent plus carbogen breathing for 6 h or the modulator etanidazole (1 g/kg i.p.) was administered just prior to an alkylating agent, the combination treatment produced significantly more tumor cell killing across the dosage range of each alkylating agent tested compared with the alkylating agent alone. Each alkylating agent produced a dose-dependent log-linear tumor cell survival curve. There was an increase in tumor cell killing of 5-10-fold when either Fluosol-DA/carbogen or etanidazole was added to treatment with the alkylating agent. For cis-diamminedichloroplatinum(II) (CDDP) and N,N',N''-triethylenethiophosphoramide, the modulators used in combination increased tumor cell killing by only 2-3-fold over that obtained with a single modulator, but for the other alkylating agents, tumor cell killing was increased by 10-50-fold when the combination of modulators was used. Bone marrow granulocyte-macrophage colony-forming unit survival assays showed that the combination of modulators with the alkylating agents resulted in only small increases in bone marrow toxicity of the alkylating agents except for N,N',N''-triethylenethiophosphoramide and L-phenylalanine mustard (L-PAM), for which the toxicity to the bone marrow granulocyte-macrophage colony-forming unit was increased by 5-10-fold compared with the alkylating agents alone. The Hoechst 33342 dye diffusion defined tumor cell subpopulation assay, also in the FSaIIC tumor, demonstrated that the combination of modulators increased the toxicity of CDDP, cyclophosphamide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea by 9-55-fold compared with the alkylating agent alone in both the bright (euxoic-enriched) and dim (hypoxic-enriched) cells. For each alkylating agent except 1,3-bis(2-chloroethyl)-1-nitrosourea, the increase in tumor cell killing was greater in the dim cells than in the bright cells. Finally, tumor growth delay studies in both the FSaIIC tumor and the EMT-6 murine mammary adenocarcinoma confirmed that the combination of modulators significantly increased the tumor growth delay caused by CDDP, carboplatin, cyclophosphamide, N,N'N"-triethylenethiophosphoramide, L-PAM, and 1,3-bis(2-chloroethyl)-1-nitrosourea. The greatest increases (4-5-fold) were observed for carboplatin and L-PAM in the FSaIIC tumor and CDDP and cyclophosphamide in the EMT-6 tumor. These results suggest that Fluosol-DA/carbogen together with etanidazole may be an effective modulator combination of alkylating agents in the clinic.
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PMID:Modulation of alkylating agents by etanidazole and Fluosol-DA/carbogen in the FSaIIC fibrosarcoma and EMT6 mammary carcinoma. 182 74

Enzyme activity measurements of alkaline phosphatase in surgically removed human liver tumors showed elevated level of the enzyme in 6 focal nodular hyperplasias, reduction in 8 primary hepatocellular carcinomas, and no change in the 4 adenoma samples. The activity represented liver type of alkaline phosphatase nearly in all cases because it could be inhibited by L-homoarginine more extensively than by L- phenylalanine. Studies on polyacrylamide gel electrophoresis indicated the presence of a variant type isoenzyme only in one focal nodular hyperplasia and in two hepatocellular carcinomas, one of which showed a fibrolamellar structure whereas the other was associated to cirrhosis. The importance of the elevated amount of connective tissue in the tumor, resulting in an isoenzyme shift of alkaline phosphatase, received substantial support upon comparing chemically induced rat liver tumors with and without cirrhosis.
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PMID:Alkaline phosphatase activity in human and rat liver tumors. 184 42

Calcium- and phospholipid-dependent protein kinase (protein kinase C; PKC) may be an important mediator in transduction of some of the cellular actions of insulin. We studied PKC activity in freshly isolated circulating mononuclear cells obtained from healthy subjects and patients with non-insulin-dependent (type II) diabetes mellitus (NIDDM). The kinase activity was measured using a specific nonapeptide substrate, Ala-Ala-Ala-Ser-Phe-Lys-Ala-Lys-Lys-amide. There was negligible calcium- and phospholipid-independent kinase activity in cytosolic and particulate fractions of cells from both control and diabetic subjects. Total (cytosolic and particulate) PKC activity of mononuclear cells from poorly controlled diabetic patients was significantly reduced compared with controls; this reduction was mainly due to a decrease in the cytosolic kinase activity. Tumor-promoting phorbol ester (TPA, 0.1 mumol/L) induced translocation of PKC activity in control cells; in contrast, this subcellular redistribution was not observed in cells from a majority of poorly controlled diabetic subjects. Increased calcium influx into the cells caused by the calcium ionophore A23187-triggered translocation of PKC activity in control cells, while it was ineffective in cells from poorly controlled diabetic patients. Cells from well-controlled diabetic patients demonstrated TPA-induced translocation of the PKC activity approaching that of control cells. The total PKC activity in cells from patients with good glycemic control was normal. Impaired activation of PKC is thus associated with the insulin resistance found in patients with poorly controlled NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired translocation of protein kinase C activity in human non-insulin-dependent diabetes mellitus. 186 31

We have previously shown that while spleen cells from untreated mice bearing a large MOPC-315 tumor are not cytotoxic in vitro for MOPC-315 tumor cells, spleen cells obtained from such mice on day 7 after low-dose melphalan (L-phenylalanine mustard); L-PAM therapy exert a substantial anti-MOPC-315 cytotoxicity [Mokyr et al. (1989) Cancer Res 49: 4597]. Here we show that this anti-MOPC-315 lytic activity is evident by day 5, and peaks on day 7 after the low-dose chemotherapy, at a time when the mice are actively engaged in tumor eradication. Short-term exposure of spleen cells from mice bearing a MOPC-315 tumor and treated with low-dose L-PAM (L-PAM TuB mice) to phorbol 12-myristate 13-acetate (PMA) was found to enhance greatly the ability of these spleen cells to lyse MOPC-315 tumor cells. The highest level of anti-MOPC-315 cytotoxicity was obtained when spleen cells from tumor-bearing mice that had received chemotherapy 7 days earlier were exposed to PMA at a concentration of 1-10 ng/ml. The exertion of the enhanced anti-MOPC-315 lytic activity by L-PAM TuB spleen cells exposed to PMA was found to require CD8+, but not CD4+, T cells. The apparent specificity of the lytic activity exerted by the PMA-stimulated L-PAM TuB spleen cells was illustrated not only by the inability of the spleen cells to lyse an allogeneic, antigenically unrelated thymoma (EL4), but also by their relatively weak lytic activity for two antigenically related syngeneic plasmacytomas. In addition, when EL4 target cells were admixed with MOPC-315 tumor cells, the lytic activity triggered in the L-PAM TuB spleen cells by the MOPC-315 tumor cells plus PMA was not effective in lysing the antigenically unrelated target cells. Moreover, even in the presence of the calcium-specific ionophore, ionomycin, L-PAM TuB spleen cells exposed to PMA were unable to lyse the EL4 target cells. Thus, fresh CD8+ splenic T cells from L-PAM TuB mice that are in the process of eradicating a large MOPC-315 tumor as a consequence of low-dose L-PAM therapy can be triggered with PMA to exert enhanced lytic activity against MOPC-315 tumor cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phorbol ester-induced enhancement in lytic activity of CD8+ splenic T cells from low-dose melphalan-treated MOPC-315-tumor bearers. 190 Oct 31

Mosmann's method for measuring the number of viable cells, examination of their growth and function by tetrazolium test, "MTT assay", is widely thought to be reliable. For the purpose to establish a rapid, accurate, in vitro drug sensitivity test, MTT assay was applied and evaluated for clinical application. Based on Mosmann's original MTT assay, optimal and adequate conditions for (1) the number of the cells examined at the starting of cultivation, (2) concentration of anti-tumor agents, doxorubicin, cisplatin, mitomycin C, L-phenylalanine mustard, (3) incubation time with anti-tumor agents, were determined using established cell lines, T-24, RMUG, HeLa, Vero, P 388, and Colon 26 in 96 well microplates. Conclusions are as below: (1) Number of the cells in each well of microplate is 1 x 10(3)-1 x 10(6) cells/ml, that seemed to be theoretically and technically adequate. (2) Anti-tumor agents should be added at the peak plasma concentration. (3) Incubation for 4 to 5 days is preferable. (4) HCl-isopropanol seemed to be advantageous compared to 10% sodium dodecyl sulfate for solubilization of MTT formazan crystal. (5) Results of MTT assay and colony assay were well correlated.
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PMID:[Sensitivity test of anti-tumor agents. 2. Application of MTT assay]. 190 12

The treatment of multiple myeloma is multidisciplinary and requires attention not only to the primary disease itself but to its secondary manifestations. Melphalan remains the single most effective oral chemotherapeutic drug used to treat multiple myeloma. A major problem with the oral administration of the drug is its variable bioavailability. The presence of an L-phenylalanine moiety in the structure of melphalan makes it likely that gastrointestinal absorption occurs through the normal amino acid transport mechanisms and that the presence of food influences the drug's uptake. Another factor that complicates the bioavailability of this agent is the fact that melphalan undergoes spontaneous hydrolysis at physiologic pH. One of the controversies in myeloma therapy is the continuing debate over the possible superiority of complex, multiagent chemotherapy regimens compared with single melphalan and prednisone or cyclophosphamide and prednisone. It does appear that response frequencies are considerably greater with combination chemotherapy than with standard oral melphalan and prednisone treatment. It is probable that both approaches--single-agent chemotherapy with melphalan and prednisone versus combination chemotherapy--can play a role in remission induction therapy. It may be appropriate to treat the patient with a low tumor burden with melphalan and prednisone and treat more aggressive myeloma patients with triple alkylator therapy or other combinations of chemotherapy agents. The most promising activity of interferon alfa-2b (rIFN alpha 2b) in induction of myeloma remission appears to occur when rIFN alpha 2b is combined with multiple alkylating agents. Analysis of clinical trials suggests that sequential use of rIFN alpha 2b with cytotoxic therapy may be more active than when IFN alpha 2b is given concomitantly with cytotoxic therapy. It may be most plausible to use rIFN alpha 2b in maintenance of remission of myeloma. In the laboratory, interferons have the capacity to modulate oncogene expression and to decrease both in vitro colony formation and the labeling index of myeloma cells. Further, it has been shown that interferon can reduce the capacity for self-renewal in myeloma-forming cells. The following concepts will be discussed: 1. There is promising evidence that rIFN alpha 2b may improve the frequency and quality of remission in multiple myeloma when administered in an alternating schedule. There is some evidence that rIFN alpha 2b, when combined with cytotoxic therapy and given concomitantly, may be less active.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A review of the clinical studies of alpha-interferon in the management of multiple myeloma. 194 25

Irradiation of whole blood with 137Cs gamma rays intensifies the oxidative burst. Oxidant production was used as an indicator of inflammatory cell reactions and was measured by luminol-amplified chemiluminescence after treatment with inflammatory activators including bacteria, the neutrophil taxin formyl-Met-Leu-Phe, the Ca2+ ionophore A23187, the detergent saponin, and the tumor promoter phorbol ester. The irradiation response is dose-dependent up to about 100 microGy, is detectable within minutes, persists at least 1 h, and is transmitted intercellularly by a soluble mediator. The response is completely inhibited by Ca2+ sequestration in the presence of A23187 or by adenosine, indicating its Ca2+ dependency, and by the phospholipase A2 blocker p-bromphenacyl bromide. However, inhibition by the cyclooxygenase blocker aspirin is sporadic or absent. Blood taken after diagnostic examination of lungs with X rays also exhibited intensified chemiluminescence. These reactions implicate a role for specific amplifying mediator pathways, especially metabolites of the arachidonic acid cascade, in the response: "damage and repair" to cells or DNA plays little or no role. Our results provide evidence for a new mechanism of radiation action with possible consequences for the homeostasis of reactions involving inflammation and second messengers in human health and early development.
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PMID:Ionizing radiation at low doses induces inflammatory reactions in human blood. 196 21

Sodium ascorbate supplementation in drinking water inhibited subcutaneous tumor growth, enhanced levodopa methylester (LDME) chemotherapy, and increased survival of B16 melanoma-bearing mice. Antitumor activity was greatest in mice fed diets low in tyrosine and phenylalanine (restricted diet). Ascorbate partially protected against LDME-induced decrease in food intake. Primary tumor masses were smaller, more well defined, and less invasive in ascorbate-supplemented mice, and secondary tumor masses appeared encapsulated. Dehydroascorbate increased tumor growth and decreased survival. Ascorbate supplementation did not alter establishment of experimental B16-BL6 melanoma metastases but inhibited tumor outgrowth when combined with LDME chemotherapy and the restricted diet. Spontaneous metastasis was inhibited by ascorbate in mice fed the restricted diet. Ascorbate supplementation doubled plasma concentration in melanoma-bearing mice independent of diet and increased tumor concentration 3.7-fold (basal diet) and 5.6-fold (restricted diet) relative to unsupplemented mice. Tumor peroxidation also increased during ascorbate supplementation and LDME treatment.
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PMID:Ascorbate in the treatment of experimental transplanted melanoma. 196 84

We performed studies to determine whether tumor cells (TCs) produce 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE), and to determine the relationship between TC and endothelial cell (EC) 13-HODE and 15-HETE synthesis, and TC adhesion to ECs and their underlying extracellular matrix (ECM). We measured (1) the amounts and ratios of 13-HODE: 15-HETE in three different human TC lines and in three different murine TC lines under basal and stimulated conditions; and (2) the relationship between 13-HODE synthesis and cAMP levels in TCs and ECs. Under basal conditions, TCs produced both 13-HODE and 15-HETE, the intracellular ratios of which correlated with TC adhesivity. Stimulation of the TCs with the chemotactic tripeptide, N-formyl-methionyl-leucyl-phenylalanine, decreased 13-HODE synthesis, and increased 15-HETE synthesis and TC adhesion to ECs and to their ECM. Alternatively, enhancing 13-HODE synthesis in either TCs or ECs (by elevating the resting levels of intracellular cAMP) was associated with decreased TC adhesion to ECs and ECM. These results suggest that intracellular 13-HODE: 15-HETE ratio in TCs regulates TC adhesivity, and that an alteration in 13-HODE: 15-HETE ratio will markedly influence TC adhesion.
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PMID:Regulation of tumor cell adhesion by intracellular 13-HODE: 15-HETE ratio. 196 7

Many clinical approaches for the treatment of hormone-sensitive tumors are being developed based on analogs of LH-RH and somatostatin. Inhibition of the pituitary-gonadal axis forms the basis for oncological applications of LH-RH agonists like [D-Trp6]-LH-RH and new LH-RH antagonists free of edematogenic effects such as [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit6,D-Ala10]-LH -RH (SB-75). Agonists and antagonists of LH-RH have been used in patients with prostate cancer and might be also beneficial for the treatment of breast cancer and ovarian, endometrial and pancreatic carcinomas. Some of the effects of LH-RH analogs can be due to direct action since LH-RH receptors have been found in these cancers. The use of sustained delivery systems based on microcapsules of PLG, makes the treatment more efficacious. Octapeptide analogs of somatostatin such as D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and related analogs were designed specifically for antitumor activity. These somatostatin analogs, by virtue of having a wide spectrum of activities appear to inhibit various tumors through multiple mechanisms. Direct antiproliferative actions of somatostatin analogs appear to be mediated by specific receptors located on tumor cells. High affinity binding sites for RC-160 and related analogs have been found in human pancreatic, prostate, breast and ovarian cancers and brain tumors such as meningiomas. In vivo administration of analog RC-160 inhibits the growth of Dunning R-3327 prostate cancers in rats, MXT mammary tumors in mice and BOP-induced ductal pancreatic cancers in hamsters. Combination of microcapsules of RC-160 with [D-Trp6]-LH-RH results in synergistic potentiation of the inhibition of these cancers. Somatostatin analog RC-160 and LH-RH antagonist SB-75 are the object of further experimental studies and clinical trials aimed at the exploration of their inhibitory effects on the processes of malignant growth.
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PMID:Antitumor effects of analogs of LH-RH and somatostatin: experimental and clinical studies. 198 Oct 9


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