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)

Pirarubicin (THP) is a derivative of adriamycin (ADM) which has been reported to have a lower cardiotoxicity than ADM. The authors investigated the in vivo antitumor effect of THP against human colon cancer cells (RPMI 4788) xenografted into nude mice. In the model of intra-abdominal carcinomatosis, intraperitoneal administration of THP (6 mg/kg) resulted in a significant prolongation of the survival compared with the saline control group (p less than 0.01). Intravenous administration of THP (8 mg/kg) significantly inhibited tumor growth compared with the saline control group. Labeling index with bromodeoxyuridine (BrdU) of RPMI 4788 tumors treated with THP was smaller than that in the control group. Mitotic index was also smaller in the group treated with THP. Labeling index with BrdU indicates the proportion of cells in the S phase. Thus, the tumor cells in both S and M phases have decreased after treatment with THP. This change in the cell cycle progression may be due to the accumulation of G2 phase similar to in vitro study. From these results, it was suggested that the change in cell cycle progression revealed in vitro might be caused by THP in vivo.
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PMID:[Antitumor effect of pirarubicin (THP) against human colon cancer transplanted into nude mice and the mechanism of cell cycle progression]. 154 63

Intravesical instillation of pirarubicin (THP) was performed on 66 patients with superficial bladder cancer after transurethral resection to evaluate the prophylactic effect against tumor recurrence. Intravesical chemotherapy was carried out at the concentration of 20mg/40ml. THP was initially instilled three times for one week, following instillation of every two weeks for ten times, and then every one month for seven times. Bladder irritability was demonstrated 21 of 66 cases (31.8%). Although there was a case of contracted bladder, generalized side effect was no case. Eligible cases for evaluation of efficacy were 43 out of 66 patients. The non-recurrence rate (by Kaplan-Meier's method) at one and two years were 90.4% and 77.8%, respectively. Intravesical THP instillation seems to be effective for the purpose of prophylaxis against the recurrence of superficial bladder tumor.
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PMID:[Postoperative intravesical instillation of THP for superficial bladder tumor: clinical results of prophylactic effects on the recurrence. Fukushima THP Research Group]. 155 1

From January, 1987 through January, 1990, partial cystectomy was performed for 4 (18%) of 22 patients with invasive bladder cancer who had received neoadjuvant intra-arterial chemotherapy. The criteria of patient selection for partial cystectomy were: 1) invasive bladder cancer showing good response (greater than or equal to PR) to neoadjuvant chemotherapy, 2) solitary or localized tumor that can be eradicated by segmental resection, and 3) tumor of stage T3 or less. As a rule, cisplatinum (100 mg/m2) and THP-adriamycin (40 mg/m2) were administered selectively to the internal iliac artery by one-shot infusion. Concurrently, sodium thiosulfate (10 g/m2), a neutralizing agent against cisplatinum, was administered intravenously. All four patients had achieved clinical complete responses by one or two courses of intra-arterial chemotherapy, and then underwent partial cystectomy with pelvic lymphadenectomy. Pathological examination revealed pTONO in two patients, and the remains were pT3aNO and pT3bN1. After the mean follow-up of 24 months, three of them are alive with no evidence of disease, and also with normal bladder and sexual functions. However, one with pT3bN1 tumor underwent total cystectomy 5 months later for local recurrence (pT4b) and had died of cancer 18 months later. Neoadjuvant intra-arterial chemotherapy followed by partial cystectomy should be the most applicable conservative therapy with high radicality for invasive bladder cancer, when: 1) the patient has localized invasive cancer showing good response (greater than or equal to PR) to neoadjuvant chemotherapy, 2) the tumor is stage T3a or less and without findings of tentacular invasion (INF gamma) by pre-operative biopsy, and 3) pre-operative multiple biopsy is performed as deeply as possible along the prearranged incision line.
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PMID:[Neoadjuvant intra-arterial chemotherapy followed by partial cystectomy for invasive bladder cancer]. 156 48

Both bacterial and mammalian heat shock proteins (HSP) are recognized by some T cells, and hsp60 recognition has been implicated in rheumatoid arthritis. We have developed a model to study the induction of hsp60 in human monocytic cell lines. An anti-mycobacterial hsp65 mAb (ML30), cross-reacting with human hsp60 was used to screen 21 human tumor cell lines in Western blot analysis. All T cell and B cell lymphomas constitutively expressed hsp60 protein at moderate to high levels, while little or no hsp60 protein was detected in two monocytic leukemia lines. Moderate to high levels of hsp60 mRNA and protein could be induced in the THP-I monocytic leukemia cell line by heat shock, retinoic acid, interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha treatment, the highest levels obtained with a combination of IFN-gamma/TNF-alpha. This was also seen using two rabbit anti-hsp60 antisera directed against the N-terminal or C-terminal part of the human hsp60 protein. The determinants detected by the ML30 mAb or the two rabbit anti-hsp60 antisera were not cell surface expressed, as measured with immunofluorescence (FACS) analysis on control cultured or cytokine treated cell lines. This could be a useful model for studies related to the induction of hsp60 in human cells.
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PMID:Induction of human hsp60 expression in monocytic cell lines. 156 88

Focused high-energy shock waves (6,000 to 10,000 shots) were targeted under ultrasound guidance onto implanted urinary bladder cancer in rabbits to elucidate its effect. Although only focal necrosis of the tumor was seen following 6,000 to 10,000 shots daily for 3 days or following chemotherapy (THP-adriamycin) alone, almost total tumor necrosis was observed following a combined shock-wave therapy for one day and THP-adriamycin administration, demonstrating an additive and/or synergetic effect on rabbit urinary bladder cancer.
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PMID:Shock wave and THP-adriamycin for treatment of rabbit's bladder cancer. 158 86

Previous studies have demonstrated that the selective toxicity of leucyl-leucine methyl ester (Leu-Leu-OMe) for cytotoxic lymphocytes and myeloid cells is dependent on intracellular conversion to membranolytic metabolites by the acyl transferase activity of the granule enzyme dipeptidyl peptidase I (DPPI) that is enriched in these cells. The mechanism of cell death remained unclear, however, and was the subject of the experiments reported here. When human U937, HL60, or THP-1 myeloid tumor cell lines or murine CTLL-2 cells were treated with Leu-Leu-OMe, early release of both cytosolic 51Cr and soluble [3H]TdR labeled DNA fragments was observed, whereas antibody + C treatment of these cells caused only 51Cr release. Killing of U937 or THP-1 cells by incubation with the lysosomotropic amino acid methyl ester, Phe-OMe also induced only 51Cr release without evidence of DNA fragmentation. Preincubation with Zn2+, a known inhibitor of endonuclease activity prevented Leu-Leu-OMe-induced 51Cr or [3H]TdR release from these cell lines, but had no effect on antibody + C or Phe-OMe-induced 51Cr release. Zn2+ also prevented Leu-Leu-OMe-mediated killing of normal human CD16+ NK cells. Zn2+ had no inhibitory effect on Leu-Leu-OMe uptake or intracellular conversion to (Leu-Leu)n-OMe metabolites by these cell lines. Moreover, Zn2+ did not inhibit 51Cr release from nonnucleated E or nucleated U937 targets induced by extracellular production of DPPI-generated metabolites of Leu-Leu-OMe. Thus, killing of cytotoxic lymphocytes and myeloid cells by Leu-Leu-OMe appears to be dependent on generation of metabolites with membranolytic properties, but cell death induced by this process does not involve simple lysis of the plasma membrane. Rather, intracellular production of DPPI generated (Leu-Leu)n-OMe metabolites appears to trigger, an additional Zn(2+)-sensitive process that is associated with induction of apoptosis in cells with cytolytic potential.
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PMID:Apoptosis is induced in cells with cytolytic potential by L-leucyl-L-leucine methyl ester. 160 38

The induction of proteolytic enzymes is an important mechanism in the migration of monocytes into tissues and body fluids. The monocytic cell line THP-1 was used as a model system to study the production of a particular gelatinase. Upon stimulation with phorbol myristate acetate (PMA) the cells differentiated to the adherent phenotype and produced significant amounts of a 96-kD gelatinase in a dose-dependent way. The secretion rate was maximal between 12 and 24 h after induction. Study of gelatinase mRNA steady state levels showed that the synthesis of THP-1 gelatinase is regulated by PMA at transcriptional or posttranscriptional levels. Stimulation of signal transduction pathways with other substances, including calcium ionophore A 23187, dibutyryl cyclic AMP, and dexamethasone, were ineffective in inducing gelatinase mRNA or enzyme activity. However, THP-1 cells were responsive to the cytokine interleukin (IL)-1 beta, to bacterial lipopolysaccharide (LPS), and the lectin concanavalin A (Con A), the kinetics of gelatinase induction being similar to those of induction by PMA. The THP-1 cells did not synthesize and/or secrete detectable levels of IL-6 after stimulation with PMA, Con A, LPS, or IL-1 beta. The 96-kD monocytic THP-1 gelatinase was shown to be a neutral metalloproteinase that cross-reacted with hepatoma-derived and neutrophil gelatinases in immunoprecipitation experiments. The active enzyme produced by THP-1 cells consistently showed, however, a molecular mass different from that of normal granulocyte-, monocyte-, and tumor cell-derived gelatinases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The cytokine-protease connection: identification of a 96-kD THP-1 gelatinase and regulation by interleukin-1 and cytokine inducers. 165 55

L-leucine methyl ester (Leu-OMe), Leu-Leu-OMe, Phe-OMe, and Glu-(OMe)2 are toxic to mononuclear phagocytes (M phi) and neutrophils. In the present studies, the mechanism of this toxicity was examined. A concentration of NH4Cl known to neutralize lysosomal pH and to block conversion of Leu-OMe to the dipeptide condensation product Leu-Leu-OMe inhibited Leu-OMe- or Glu-(OMe)2- but not Leu-Leu-OMe-mediated M phi toxicity. Leu-OMe-, Glu-(OMe)2-, or Leu-Leu-OMe-mediated killing of M phi was prevented by Gly-Phe-CHN2, a specific inhibitor of the thiol protease, dipeptidyl peptidase I (DPPI). Neither NH4Cl nor Gly-Phe-CHN2 prevented Phe-OMe-mediated M phi toxicity. In contrast, inhibition of M phi serine esterase activity prevented Phe-OMe- but not Leu-OMe- or Glu-(OMe)2-mediated killing of M phi. The myeloid tumor lines U937, HL60, and THP-1 were found to be uniformly enriched in DPPI and susceptible to Leu-Leu-OMe but not Leu-OMe toxicity. Whereas HL60 were resistant to Phe-OMe, THP-1 cells were killed by this agent. Incubation of peripheral blood mononuclear cells with Leu-OMe resulted in loss of natural killer (NK) functions and cytotoxic T lymphocytes (CTL) precursors, a process that requires the DPPI-dependent generation of membranolytic polymerization products. Phe-OMe had no toxic effects on NK cells or CTL precursors. These results indicate that Leu-OMe and Glu-(OMe)2 toxicity for M phi is related to the production of higher molecular weight hydrophobic polymerization products via the sequential action of two nonserine esterase lysosomal enzymes. In contrast, Phe-OMe toxicity for myeloid cells was found to correlate with serine esterase-mediated intracellular trapping of high concentrations of the free amino acid Phe. These distinct enzymatic mechanisms may provide a unique means of targeting agents capable of selectively deleting cells of myeloid lineage.
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PMID:Spectrum of toxicities of amino acid methyl esters for myeloid cells is determined by distinct metabolic pathways. 173 5

Cells of the monocytic leukemia line, THP-1, mimic several of the functional characteristics of activated monocytes and macrophages following incubation in the tumor promoting agent, mezerein. The current paper explores the nature of the factors in medium conditioned by THP-1 cells which inhibit cell growth and the effects of interferon-gamma (IFN gamma) on their synthesis. Activity inhibiting the growth of the MDA-MB-415 mammary carcinoma line migrated in a pH range of 6.5 to 7.5 and could be resolved into 2 peaks, one corresponding to interleukin-1 beta (IL-1 beta) and the other with an apparent average molecular weight of 43 Kd. Antisera against tumor necrosis factor alpha and beta (TNF alpha and beta) and monocyte colony stimulating factor (M-CSF) had no effect on the 43 Kd inhibitor. IFN gamma enhanced the secretion of IL-1, but decreased the production of the 43 Kd inhibitor. The L-929 cell cytotoxicity assay and an ELISA were used to show that the amount of TNF alpha present was less in medium from IFN gamma treated cells. THP-1 cells also produced an IFN gamma repressed activity separating at pH 4.8 to 6.1 which inhibited the response of T cells to IL-1 in a thymocyte co-mitogenic assay. The inhibitors expressed by THP-1 cells may be comparable to the cytotoxic and cytostatic activities expressed by activated human monocytes and macrophages.
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PMID:Characterization of inhibitory activities secreted by THP-1 leukemia cells and regulation by interferon-gamma. 184 67

Lipopolysaccharide (LPS) endotoxin is implicated as the bacterial product responsible for the clinical syndrome of Gram-negative septicemia. Although the lipid A domain of LPS appears to be responsible for the toxicity of endotoxin, lipid A from the photosynthetic bacterium Rhodobacter sphaeroides (RSLA) and a disaccharide precursor of lipid A from enteric bacteria, termed lipid IVA, have little activity on human cells. Using the human promonomyelocytic cell line THP-1 and human monocytic cells, we now show that both lipid IVA and RSLA are antagonists of LPS. Complete, apparently competitive, inhibition of LPS activity is possible at a 10-100-fold excess of antagonist, as judged by measuring the release of cytokines and prostaglandin E2. Both antagonists prevent monocyte stimulation by endotoxin extracted from a variety of Gram-negative bacteria. Cells pretreated with either inhibitor and subsequently washed still show attenuated responses to LPS. Stimulation of monocytes by whole Gram-negative bacteria is also antagonized in a dose-dependent manner. Lipid X has no inhibitory effect in the same dose range as lipid IVA and RSLA. These findings rule out LPS sequestration as the explanation for the observed antagonism. Neither inhibitor alters monocyte stimulation by phorbol 12-myristate 13-acetate, Staphylococcus aureus, or purified protein derivative, demonstrating specificity for LPS. Although RSLA appears to inhibit LPS when tested with macrophages from both humans and mice, lipid IVA had the unique ability to act as an LPS antagonist with human-derived cells but to exhibit LPS-like effects with murine-derived cells. Like LPS, lipid IVA stimulated the release of both tumor necrosis factor alpha and arachidonic acid from murine-derived RAW 264.7 macrophage tumor cells. The range of concentrations necessary for lipid IVA to induce LPS-like effects in murine cells was similar to that necessary to antagonize the actions of LPS in human monocytes. The agonist activities of lipid IVA were completely inhibitable by RSLA. This unique species-dependent pharmacology observed with lipid IVA may reflect differences between human and murine LPS receptors. RSLA and lipid IVA may be useful in defining the role of LPS in Gram-negative bacterial infections and may prove to be prototypical therapeutic agents for the treatment of Gram-negative septicemia.
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PMID:Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes. 191 61


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