Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1522282 (EMT)
 2,868 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytotoxicities of D,L-tetraplatin and D-tetraplatin were evaluated at 37 degrees C, 42 degrees C and 43 degrees C at normal pH, at pH 6.45 and under normally oxygenated and hypoxic conditions in EMT-6 cells in vitro. The D-isomer was also tested in FSaIIC cells in vitro. Under these various conditions the pure D-isomer was very similar in cytotoxicity with the racemic mixture. Like cisplatin, both D,L- and D-tetraplatin were selectively cytotoxic toward normally oxygenated cells under acidic pH (6.45) conditions at 37 degrees C. In both cell lines the cytotoxicity of D,L- and D-tetraplatin was markedly increased at hyperthermic temperatures. Under the same conditions platinum levels in EMT-6 cells exposed to D,L- or D-tetraplatin were higher than in cells exposed to cisplatin, and unlike cisplatin there was an increase in intracellular platinum levels when the cells were exposed to D,L- or D-tetraplatin at 42 degrees C compared with 37 degrees C. The tumour growth delay of the FSaIIC fibrosarcoma was the same for D,L- and D-tetraplatin. A dose of 10 mg/kg intraperitoneally of tetraplatin produced a tumour growth delay of about 4.3 days which was increased to about 6 days with the addition of local hyperthermia (43 degrees C, 30 min) to the drug treatment. The tumour cell survival assay also showed no difference between D,L- and D-tetraplatin and a log-linear increase in tumour cell killing with increasing drug dose which was increased 1.5-3-fold with local hyperthermia. D,L- and D-tetraplatin were relatively much more cytotoxic toward bone marrow colony forming units of granulocyte-macrophage progenitors (CFU-GM) than was cisplatin and this cytotoxicity was increased about 5-10-fold under hyperthermic conditions. There was an increase in DNA crosslink formation in tumours when hyperthermia accompanied tetraplatin treatment. Overall, D,L- and D-tetraplatin produced very similar responses under hyperthermic conditions in both tumour and normal tissues, and may be a useful agent in combination with local hyperthermia.
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PMID:Interaction of D,L- and D-tetraplatin with hyperthermia in vitro and in vivo. 152 97

Nitroimidazoles are good quenchers of triplet state porphyrins in chemical systems, thereby inhibiting singlet oxygen formation and type II photodynamic reactions. Photobiological studies were performed with EMT-6 tumor cells in vitro utilizing Photofrin II (PII) in combination with etanidazole (ETAN), misonidazole (MISO), and trifluoromisonidazole (TF-MISO). After short-term (1 h) exposure of cells to PII, 5 mM ETAN and MISO had no effect on photoinactivation while 5 mM TF-MISO had a small but significant protective effect. When the intracellular oxygen level was equilibrated with 0.3% oxygen in the gas phase, all three nitroimidazoles produced significant photoprotection at concentrations as low as 0.3 microM. After long-term (24 h) exposure of cells to PII, all three nitroimidazoles demonstrated large photoprotective effects under both aerobic and 0.3% oxygen conditions. At equal concentrations of nitroimidazole, photoprotection was greatest for the most lipophilic compound (TF-MISO) and least effective for the most hydrophilic compound (ETAN). These studies suggest that nitroimidazoles can quench triplet state porphyrins (within cells) to reduce intracellular concentrations of singlet oxygen, the putative toxin in PII photoinactivation. In addition, after long-term exposures to PII when porphyrins have partitioned into cellular membranes and lipid environments, the lipophilicity of this class of photoprotector correlates with effectiveness in these mammalian cells.
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PMID:Protection against light-activated photofrin II killing of tumor cells by nitroimidazoles. 153 56

Hyperthermia can strikingly enhance tumor necrosis factor-alpha (TNF-alpha) cytotoxicity in vitro and in vivo. Other forms of TNF may have tumor therapeutic applications and their interaction with hyperthermia should also be assessed. We have compared the effect of heat on the in vitro cytotoxic response of murine L929 and EMT-6 and human T24 tumor cells to three TNF forms; recombinant human TNF-alpha, TNF-beta (lymphotoxin), and TNF-SAM2. A neutral red assay was used to measure toxicity at 18-20 h after initiating the heat treatment. TNF treatment preceded heating by 0-4 h or followed it by 2 h. Heating was done at 39 or 40.5 degrees C for 24 h, 40.5 or 42 degrees C for 1 h, or 43 degrees C for 1-1.5 h. We found that both TNF-beta and TNF-SAM2 toxicities, like that of TNF-alpha, were markedly enhanced by hyperthermia. Neither EMT-6 nor T24 cells responded consistently to any of these TNFs at heat doses up to 1 h at 43 degrees C, but an increment of only 15 min more at 43 degrees C sensitized EMT-6 cells and 1.5 h at 43 degrees C resulted in extensive EMT-6 cell killing. The T24 cells remained resistant except for variable responses at the highest TNF and heat doses. If TNF treatment was begun immediately before or 2 h after beginning to heat the EMT-6 cells, sensitization was reduced or eliminated, respectively, for all three TNF forms relative to protocols in which TNF was added 1, 2, or 4 h before heating.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative in vitro studies of the potentiation of tumor necrosis factor (TNF)-alpha, TNF-beta, and TNF-SAM2 cytotoxicity by hyperthermia. 157 35

Aluminium phthalocyanines substituted to different degrees with hydrophilic sulphonic acid and hydrophobic phthalimidomethyl groups were investigated in vivo as new agents for the photodynamic therapy of malignant tumours. Parameters studied included the photodynamic action on EMT-6 mammary tumours in BALB/c mice, the therapeutic window and the potential for direct cell killing, assayed via an in vivo/in vitro test. Although the efficiency of photoinactivation of the EMT-6 tumour increases by a factor of ten with reduction of the number of sulphonic acid groups from four to two, no further effect was seen with the addition of the hydrophobic phthalimidomethyl groups. Addition of the latter groups however increased the potential for direct cell killing by a factor of two and expanded the therapeutic window by a factor of four, thus improving the usefulness of the dye as a photosensitiser for the photodynamic therapy of cancer.
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PMID:Biological activities of phthalocyanines. XIV. Effect of hydrophobic phthalimidomethyl groups on the in vivo phototoxicity and mechanism of photodynamic action of sulphonated aluminium phthalocyanines. 161 52

Radiation-reduced chromosomes provide valuable reagents for cloning and mapping genes, but they require multiple rounds of x-ray deletion mutagenesis to excise unwanted chromosomal DNA while maintaining physical attachment of the desired DNA to functional host centromere and telomere sequences. This requirement for chromosomal rearrangements can result in undesirable x-ray induced chromosome chimeras where multiple non-contiguous chromosomal fragments are fused. We have developed a cloning system for maintaining large donor subchromosomal fragments of mammalian DNA in the megabase size range as acentric chromosome fragments (double-minutes) in cultured mouse cells. This strategy relies on randomly inserted selectable markers for donor fragment maintenance. As a test case, we have cloned random segments of Chinese hamster ovary (CHO) chromosomal DNA in mouse EMT-6 cells. This was done by cotransfecting plasmids pZIPNeo and pSV2dhfr into DHFR-CHO cells followed by isolation of a Neo + DHFR + CHO donor colony and radiation-fusion-hybridization (RFH) to EMT-6 cells. We then selected for initial resistance to G418 and then to increasing levels of methotrexate (MTX). Southern analysis of pulsed-field gel electrophoresis of rare-cutting restriction endonuclease digestions of DNA from five RFH isolates indicated that all five contain at least 600 kb of unrearranged CHO DNA. In situ hybridization with the plasmids pZIPNeo and pSV2dhfr to metaphase chromosomes of MTX-resistant hybrid EMT-6 lines indicated that these markers reside on double-minute chromosomes.
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PMID:Double-minute chromosomes as megabase cloning vehicles. 162 62

Two types of pacing leads with different insulation material, polyurethane, and polyethylene, were followed for 44 months with respect to their electrophysiological characteristics and complications. In 48 patients, 32 polyurethane leads (Lifeline 493-03) and 16 polyethylene leads (EMT 588 D) were implanted and connected in all cases to the same type of programmable ventricular inhibited (VVI) pulse generator (Programalith, Pacesetter). There was a significant fall during the follow-up in lead impedance with the polyurethane leads (495 +/- 62 to 444 +/- 58 ohms, P less than 0.01), whereas the corresponding measurements for the polyethylene leads were essentially unchanged (360 +/- 58 to 378 +/- 71 ohm, ns). The energy of the stimulation threshold tended to increase in the polyurethane group, whereas an opposite tendency was observed in the polyethylene group. Pacing and/or lead failures were not observed in any case. The observed fall in impedance with the polyurethane leads was seemingly of no clinical significance.
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PMID:Long-term comparison of the electrical characteristics of polyurethane and polyethylene insulated ventricular leads. 169 94

Tumor concentrations of the chemotherapeutic drug, bleomycin, labeled with cobalt-57 (Co-bleo) were compared in mouse tumor models and in human lung tumors using quantitative single-photon emission computed tomography. Drug concentrations in histologically similar human tumors showed marked variability for the same injected dose (ID). Small cell carcinomas showed concentrations between 1.09 and 8.85 %ID/cc x 10(-3) while non-small cell lung tumors showed a concentration variation between 0.36 and 6.75 %ID/cc x 10(-3). In contrast to the situation in human tumors, uptake in mouse tumors showed only slight variability in animals with the same tumor model. EMT-6 tumors in mice showed at 6 hr significantly higher uptake of Co-bleo (p less than 0.001) and significantly higher tumor-to-lung ratio (p less than 0.001) when compared to murine fibrosarcomas. The EMT-6 tumors in contrast to the fibrosarcomas responded to bleomycin treatment in a dose dependent manner. The results indicate that while in mice the tumor dose closely follows the administered dose, in humans, the tumor dose and the tumor-to-lung ratio in the individual patient cannot be predicted from the administered dose.
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PMID:Administered dose and tumor dose of bleomycin labeled with cobalt-57 in mice and men. 170 87

5-Chlorodeoxycytidine (CldC), coadministered with modulators of pyrimidine metabolism, is an effective radiosensitizer of murine tumors. Past studies that utilized RIF-1 tumors in C3H mice and Lewis lung carcinoma (LLC) in BDF1 mice have been extended with an emphasis on using multiple cycles of drug administration followed by irradiation of LLC and the use of two additional tumor models. Four of seven cures of BDF1 mice bearing LLC were obtained with three doses of 20 Gy irradiation, in which the first and third dose were preceded by a "Standard Protocol" that includes N-(phosphonacetyl)-L-aspartic acid (PALA), 5-fluorodeoxycytidine (FdC), tetrahydrouridine, and the radiosensitizer, 5-chlorodeoxycytidine. No cures were obtained in groups of mice receiving radiation alone or drugs alone, and there were no "no takes" in untreated control groups (six mice/group). Extensive tumor inhibition, exceeding that obtained with drugs or radiation alone, was obtained with two cycles of drugs and radiation combined when a dimethybenzanthracene-induced mammary adenocarcinoma was used in BALB/c mice. With the EMT-6 tumor in BALB/c mice, doses of 10 and 20 Gy were administered 9 and 16 days after tumor implantation, each preceded with the Standard Protocol; this resulted in a tumor growth delay of 24 days. No tumor growth delay occurred with drugs or radiation alone. The omission of PALA, FdC or CldC from the Standard Protocol resulted in loss of tumor control, which was obtained with the complete protocol. The fact that 5-chlorodeoxycytidine is an effective radiosensitizer in four rodent tumor systems is compelling evidence that it has potential as a radiosensitizer of human tumors, especially in view of its tumor selectivity and its resistance to catabolism when used with modulators of its metabolism, and in view of the high levels of the key enzymes in human tumors, which can convert 5-chlorodeoxycytidine to 5-chlorodeoxyuridine triphosphate, the proximate radiosensitizer.
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PMID:5-chlorodeoxycytidine, a radiosensitizer effective against RIF-1 and Lewis lung carcinoma, is also effective against a DMBA-induced mammary adenocarcinoma and the EMT-6 tumor in BALB/c mice. 173 88

Several analogues of PtCl4(Rh-123)2 in which the metal may be Pt or Pd and the coordinated ligand may be -Cl, -CN or -NO2 were prepared and tested in cell culture with EMT-6 cells at normal (37 degrees C) and hyperthermic (42 degrees C and 43 degrees C) temperatures and various environmental conditions (normally oxygenated vs. hypoxic and pH 7.40 vs. pH 6.45). Pd is a much more reactive metal than Pt, while -CN and -NO2 are more tightly bound ligands than is -Cl. The goal of these studies was to define the complex with the least cytotoxicity at 37 degrees C and the greatest enhancement in cytotoxicity under hyperthermic conditions. The Pt complexes Pt(CN)4(Rh-123)2 and Pt(NO2)4(Rh-123)2 were much less cytotoxic than PtCl4(Rh-123)2 under both normothermic and hyperthermic conditions. The Pd complexes were, in general, more cytotoxic than the corresponding Pt complexes. The level of metal (Pt or Pd) in the cells did not appear to be a major factor in the level of cytotoxicity obtained. Complexes which were not cytotoxic at 37 degrees C regardless of oxygenation level or pH did not become cytotoxic at hyperthermic temperatures. In conclusion, the optimal members of this series were the complexes with chloro ligands, indicating that aquation is probably a necessary step in the cytotoxic mechanism and cytotoxicity at 37 degrees C was necessary to obtain cytotoxicity at higher temperatures.
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PMID:Effect of hypoxia and acidosis on the cytotoxicity of six metal(ligand)4(rhodamine-123)2 complexes at normal and hyperthermic temperatures. 180 41

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


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