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PubMed1988

A 20-year study of endocardial pacing lead EMT 588. Lead durability and nature of failure.

A report is presented of 1253 EMT 588 endocardial leads implanted in 1063 patients. The electrode surface area was large (47 mm2) in the 473 leads implanted during 1962-1973, and small (8-12 mm2) in the 780 leads implanted in 1974-1981. Replacement of 245 leads was necessary, in 187 cases due to lead failure and in 58 because of problems with normally functioning leads, such as infection. The highest lead failure rate occurred within the first 6 months after implantation, and was mostly caused by displacement and threshold increase. The dominating cause of late failure was lead lesion. The cumulative lead survival rates for the first and the second series were 88 and 94%, respectively after 1 year, 80 and 91% after 5 years, and 72 and 84% after 9 years. The polyethylene insulation proved to be the most vulnerable part of this lead. Insulation lesions could result in corrosion and/or fracture of the steel conductors. The chronic thresholds were largely stable.

Electrodes↗

PubMed1999

MTA (LY231514) in combination treatment regimens using human tumor xenografts and the EMT-6 murine mammary carcinoma.

An important component in the development of a new anticancer drug is an understanding of its potential for inclusion in combination treatment regimens. LY231514, a multitargeted antifolate (MTA), was tested in combination with cisplatin, methotrexate, 5-fluorouracil, paclitaxel, docetaxel, doxorubicin, LY329201 (a glycinamide ribonucleotide formyltransferase [GARFT] inhibitor), and fractionated radiation therapy in vivo using EMT-6 mammary carcinoma, human HCT 116 colon carcinoma, and human H460 nonsmall cell lung carcinoma grown as xenografts in nude mice. Isobologram methodology was used to determine the additivity or synergy of the combination regimens. MTA administered with cisplatin, paclitaxel, docetaxel, or fractionated radiation therapy produced additive to greater than additive tumor response by tumor cell survival assay and tumor growth delay. While an additive tumor response was observed when MTA was administered with methotrexate, synergistic tumor responses were seen when MTA was administered with the GARFT inhibitor, LY329201, or with the topoisomerase I inhibitor, irinotecan. MTA was administered in combination with full doses of each anticancer agent studied, with no evidence of increased toxicity resulting from the combination.

Animals↗

PubMed1979

[Electrophoresis mobility inhibition test (emt) in immunological early diagnosis of gynaecological malignomas (author's transl)].

The electrophoresis mobility inhibition test (EMT) was employed in the examination of a total of 74 woman patients with various gynaecological malignomas, 50 women with non-malignant diseases and 41 healthy female controls. In the group of patients with malignoma, 78.4% of the test results agreed with the histological diagnosis, 21.6% of the results were false negative. In the group of patients with benign diseases, 78.0% of the test results were correct, whereas 22.0% were false-positive. One false-positive test result was seen among the healthy controls. Extensive tumour growth, chronic infections and virus diseases seem to falsify the test result. Significance, perspectives and limitations of this test system within the framework of tumour diagnosis, are discussed.

Bacterial Infections↗

PubMed1981

Flow cytofluorometric analysis of the effects of new nitrosourea derivatives on proliferation of EMT 6 tumor cells "in vitro".

Examined by flow cytofluorometric analysis, the DNA distribution of EMT 6 tumor cells was highly perturbed after one hour of in vitro incubation with: RPCNU, RFCNU, chlorozotocin (CZT) or 185 (CNCC), four new nitrosourea derivatives. After the treatment with chlorozotocin (20 micrograms/ml) and CNCC (50 micrograms/ml), most of cells were in G2 + M phase and this accumulation lasted more than 48 hours without any restoration before 72 hours. RPCNU (20 micrograms/ml) and RFCNU (50 and 65 micrograms/ml) induced and accumulation of cells in G2 + M phase during 24 hours. The normal state was regained after 48 hours. These reduced rate of progression of the cells through S phase and the G2 block observed after exposure to the new compounds, should, in part, explain their antitumoral activity.

Antineoplastic Agents↗

PubMed1982

[KCl-tumor extracts in the electrophoretic mobility test [EMT]. - Clinical relevance to diagnosis of gastric cancer (author's transl)].

Using KCl-tumor extracts from various human carcinomas we tried to improve the reliability of the electrophoretic mobility test (EMT). 25 of 26 patients with histologically proven gastric cancer showed a correct positive reaction if tested with gastric cancer tumor extracts. 44 of 50 healthy controls showed negative test results when tested with the same tumor extracts. Migration inhibition in the tumor patients differed significantly from that of the healthy controls (p less than or equal to 0,05). Specificity was verified by testing gastric cancer patients with extracts from tumors of the same organ as well as different carcinomas: the most pronounced migration inhibition was observed, when gastric carcinoma extracts were used. Tumor extracts of different histogenesis showed weaker or negative reactions. Inflammatory lesions reduce the reliability of the test system: of 17 patients with ulcers or erosive gastritis 9 had false positive reactions.

Adult↗

PubMed1993

Phototoxicity, redox behavior, and pharmacokinetics of benzophenoxazine analogues in EMT-6 murine sarcoma cells.

Structural modifications to the photoinactive benzophenoxazine Nile blue A have led to three novel derivatives which include 5-ethylamino-9-diethylaminobenzo[a]phenoxazinium (EtNBA), 5-ethylamino-9-diethylaminobenzo[a]phenothiazinium (EtNBS), and 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium (EtNBSe) chlorides. The incorporation of sulfur and selenium into the benzophenoxazine moiety results in lipophilic, red-absorbing (650-660 nm) chromophores which possess significantly increased singlet oxygen yields (0.025 and 0.65, respectively, compared to 0.005 for EtNBA). This study examines the photosensitizing efficacies and pharmacokinetics in vitro in the EMT-6 murine mammary sarcoma cell line as well as the physicochemical, photochemical, and redox properties of these new analogues. Comparisons with Photofrin II, the only photosensitizer available clinically, were made in an attempt to high-light their different pharmacological characteristics. The photodynamic activity of the benzophenoxazine dyes correlates with their ability to generate the phototoxin singlet oxygen and increases in the following order: EtNBA < EtNBS << EtNBSe. At an extracellular dye concentration of 0.5 microM, the light dose required to kill approximately 50% of the cells was 2.0 and < 0.5 J/cm2 for the sulfur and selenium dyes, respectively. The light dose required to kill approximately 50% of the cells for both EtNBA and Photofrin II could not be determined because of their weak phototoxic effect under these conditions. At a light dose of 3.3 J/cm2, EtNBSe is approximately 1000 times more phototoxic than Photofrin II. All three benzophenoxazine derivatives are characterized by a similar uptake/efflux pattern in vitro consisting of a rapid and extensive cellular accumulation followed by a slow efflux rate. Contrary to their rapid uptake, 50% of the accumulated EtNBS and EtNBSe is retained intracellularly after a 6-h period in dye-free medium. Video-enhanced fluorescence microscopy corroborates the rapid uptake measurements as well as indicating the intracellular localization of the dyes in both living and thermally inactivated cells. Low extracellular dye concentrations (0.05 microM) result in a punctate fluorescence pattern in the perinuclear region, while higher dye concentrations (> 0.1 microM) lead to additional fluorescence in the cytoplasm, cytomembranes, and other organelles but apparently not the nucleus. Absorption spectrometry revealed that living cells rapidly reduce the dyes to their colorless leuko form (photoinactive) if oxygen is not readily available in the environment. It is shown that the cellular reduction is an enzymatic process and that an oxygen-free and cell-free medium containing both the coenzyme NADH and the hydride transfer enzyme diaphorase is capable of reducing the dyes to the colorless leuko form.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

Biological activities of phthalocyanines. XVII histopathologic evidence for different mechanisms of EMT-6 tumor necrosis induced by photodynamic therapy with disulfonated aluminum phthalocyanine or photofrin.

The necrosis of EMT-6 mammary murine tumors induced by photodynamic therapy (PDT) with Photofrin (PII) or disulfonated aluminum phthalocyanine (AlPcS2) was studied. Attention was given to the spontaneous evolution of angiogenesis and necrosis of such tumors in order to determine the most appropriate moment for treatment. On day 6 after tumor cell inoculation, mice were injected with photosensitizer followed by exposure to red light 24 h later, at which time optimal dye concentrations were reached in the tumor. Animals were sacrificed 3 h or 24 h after illumination and tissues were prepared for histology. Prominent cytopathic alterations were already observed at 3 h and there was massive necrosis at 24 h. In the case of PII vascular damage, congestion and hemorrhage were already present at 3 h and these changes account for the subsequent tumor necrosis through hemorrhagic infarction. With AlPcS2 these early vascular alterations were much less evident and only focal at 24 h, suggesting that AlPcS2-PDT mediated tumor necrosis involves to a large extent direct tumor cell damage.

Animals↗

PubMedDate not supplied

Evidence for different mechanisms of EMT-6 tumor necrosis by photodynamic therapy with disulfonated aluminum phthalocyanine or photofrin: tumor cell survival and blood flow.

A comparison was made of photodynamic therapy (PDT) mediated by two photosensitizers, the disulfonated aluminum phthalocyanine (AlPcS2) and Photofrin* (PII) with regard to their mechanism of action on murine tumors. Balb/c mice bearing intradermally growing EMT-6 tumors were injected intravenously with either 1 mumol kg-1 body weight of AlPcS2 or 5 mg/kg of PII 24 h prior to red light irradiation from a Xenon lamp (650-700 nm, 200 mW cm-2, for AlPcS2 and 600-650 nm, 400 J cm-2 for PII. Tumor cell survival following in vivo PDT was determined by an in vitro clonogenicity assay on the dissociated tumors. Immediately after the completion of light irradiation, a reduction of approximately 72% in the number of clonogenic cells was seen with AlPcS2-treated tumor versus approximately 24% of that for PII-treated tumor. Further loss of clonogenic cell survival progressed as a function of time following PDT, and was considered to be the consequence of indirect PDT action, however, the decline in cell viability was steeper in the first 6 h with PII-PDT than with AlPcS2-PDT. 24 h after PDT, the clonogenic capacity of both AlPcS2-and PII-PDT treated tumor fell to approximately 3% of the control tumor. The PDT effect on tumor blood flow as a measure of the tumor vascular damage was monitored by the retention of 99mTc-MIBI in the tumor. Little effect on tumor blood flow was seen with AlPcS2-PDT at 0 h after the completion of light treatment. Thereafter the blood flow declined slowly and remained at approximately 50% the level of the control by 24 h post-PDT. In contrast, PII provoked a approximately 40% reduction of tumor blood flow immediately after the completion of photo irradiation, which then fell to approximately 20% within 2 h and approximately 7% by 24 h post-PDT. These results indicate the involvement of both direct and indirect mechanisms in the PDT induced tumor necrosis. However, AlPcS2-PDT exerted a larger direct tumor cell phototoxic effect, whereas PII-PDT induced tumor cell death to a greater extent via an indirect effect that parallels the extensive damage to the tumor vasculature.

Animals↗

PubMed1996

THNLA-1 as radio/chemosensitiser of EMT-6 tumours in mice.

THNLA-1 contains a 2-nitroimidazole tethered to 9-amino-1,2,3,4-tetrahydroacridine. Compared with its parent acridinic analogue, NLA-1, THNLA-1 is a weak DNA-affinic bioreductive compound with a greater mobility along the DNA backbone, decreased aerobic toxicity, greater hypoxic selectivity and a superior in vitro therapeutic index. Also, THNLA-1 behaves as a radio/chemosensitiser in vitro. In this report we have expanded our radio/chemosensitisation studies in vivo, using the EMT-6 mouse mammary tumour model in balb/c mice and the in vivo-in vitro assay. THNLA-1 was given i.p. ( < or = 0.5 ml in saline) at various time intervals before a single dose of 20 Gy whole-body irradiation. Tumours were excised immediately or 24 h after irradiation. Radiosensitisation studies with SR-2508 (i.v.) have been performed in a similar way for comparison purposes. THNLA-1 demonstrated the same radiosensitising effect as SR-2508 but with 19-fold less dose (mmol kg-1). The optimum effect was observed when THNLA-1 was given 1 h before irradiation and the tumours excised 24 h after irradiation. Chemosensitisation studies in the same tumour model and using cis DDP showed that the cytotoxic effect of cis-DDP (5 or 8 mg kg-1, i.p.) was significantly enhanced with 30 or 45 mg kg-1 THNLA-1 given approximately 3 h before cis-DDP. A similar potentiating effect was observed when NLA-1 (27 or 30 mg kg-1) was used, but toxicity was also observed at the higher dose. Limited toxicity studies showed that THNLA-1 is well tolerated up to at least 70 mg kg-1 as a single dose, for more than 40 days.

Animals↗

PubMed1998

Biochemical characterization of in vivo alkylating agent resistance of a murine EMT-6 mammary carcinoma. Implication for systemic involvement in the resistance phenotype.

While cancer drug resistance has been extensively studied in cell culture, little is known about more clinically relevant in vivo resistance. The in vivo resistance of a murine mammary carcinoma EMT-6 to alkylating agents was demonstrated in the present study to be associated with multiple biochemical changes. These included an up to 1.5-fold increase in activity of phase II drug metabolizing enzymes (DMEs), such as glutathione (GSH), glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPX) and aldehyde dehydrogenase (ALDH), and an up to 88% decrease of phase I DME activity [7-ethoxycumarin O-deethylase (ECOD), P450 reductase (PR)] in the resistant tumors compared with the parental tumor. Transplant of either parental or resistant tumors to mice was accompanied by a decrease of both phase I and phase II DME activity in the livers of female Balb/C mice compared with the non-tumor mice. Moreover, at the protein level, while cytochrome P450 (CYP) IIB1/2 in the liver of mouse bearing both the sensitive and the resistant tumor was significantly diminished compared to that in the liver of non-tumor control mouse in Western analysis, there was actually an increase of this protein in the liver of the host bearing either of the two resistant tumors compared to that of the sensitive tumor-bearing animal. Although this in vivo resistance phenotype is not expressed in cell culture, the profile of most of the enzyme changes in the resistant tumors remained similar in in vitro culture of the isolated tumor cells. Collectively, these results demonstrate that this in vivo alkylating agent resistance is associated with multiple changes of both phase I and phase II DMEs in the resistant tumors, and some of these, such as CYP IIB1/2 protein are further altered in the resistant tumor-bearing mouse liver, suggesting a potential role of systemic factors in this resistance phenotype.

7-Alkoxycoumarin O-Dealkylase↗

PubMed2025

Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state.

Mutations in "Ras-like in all tissues" (RIT1) occur in up to 2% of lung adenocarcinomas and are mutually exclusive with KRAS and EGFR mutations, suggesting that RIT1 may act as a non-canonical driver oncogene in lung cancer. However, the lack of a RIT1-mutant lung cancer model has hindered the development and testing of RIT1-targeted therapeutics. Here, we report a mouse model with conditional regulation of the cancer-associated RIT1M90I variant. We show that autochthonous expression of RIT1M90I and combined inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. Oncogenic cooperation between RIT1M90I and p53/Nf2 loss is driven by synergistic activation of AP-1 transcription factors and can be reversed by the combined inhibition of MEK and TEAD. These data identify YAP/TEAD as a mediator of RIT1's oncogenic capability and nominate TEAD as a potential drug target in RIT1-mutant lung cancer.

Animals↗

PubMed1976