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)

EMT-6/UW tumours were treated in vivo with X-rays, cyclophosphamide, or bleomycin. Cell survival was assayed in vitro following tumour disaggregation with trypsin or an enzyme cocktail (EC) consisting of pronase, collagenase and DNase which gives a 10-20 x higher cell yield. Surviving fraction was lower after cyclophosphamide treatment for cells isolated with EC than for cells prepared with trypsin. The opposite result was obtained with bleomycin; trypsin-isolated cells appeared more sensitive. In attempting to determine the basis for this discrepancy, it was found that both dissociation methods isolate a non-representative cell sample with fewer cells in DNA synthesis (12-13%) than in the original tumour (approximately 22%). The specific nature of the interaction between the injury caused by drug and enzyme remains to be elucidated.
Br J Cancer Suppl 1980 Apr
PMID:Response of an in vivo-in vitro tumour to X-rays and cytotoxic drugs: effect of tumour disaggregation method on cell survival. 615 76

We studied the tumor uptake of [67Ga]citrate, [59Fe]citrate, and 125I-labeled transferrin (TF) by the in vitro growth form of EMT-6, a sarcoma-like mammary tumor of BALB/c mice. In analyzing the binding experiments, we developed a new mathematical model based on a formulation originally used to express the interaction of hormones with specific tissue receptors. The uptake of both carrier-free 67Ga and 59Fe by tumor cells was mediated by kinetically identical TF receptors. We also studied teric acid extracts of the stroma of EMT-6 tumors grown both in vivo and in vitro. Chromatography of these extracts on Sephacryl S-200 SF demonstrated that the cellular stroma contained specific TF-binding macromolecules. On the basis of these findings, we proposed the "transferrin receptor hypothesis" for the mechanism of 67Ga uptake by tumors. According to this view, a tumor-associated TF receptor is the functional unit responsible for the affinity of gallium for certain neoplasms. This receptor was also active in the uptake of iron by tumors.
J Natl Cancer Inst 1980 Jan
PMID:Common pathway for tumor cell uptake of gallium-67 and iron-59 via a transferrin receptor. 624 76

The bioreductive alkylating agent mitomycin C (mitomycin) has been shown to have greater activity under hypoxic than oxic conditions on murine cell lines such as the EMT-6 fibrosarcoma cell line. Solid tumors are known to contain hypoxic cells and are relatively resistant to ionizing radiation and some chemotherapeutic agents. We tested the cytotoxicity of mitomycin against fresh biopsies of human carcinomas under both hypoxic and oxic conditions in the human tumor clonogenic assay (HTCA). Additionally, we examined the metabolism of mitomycin by sonicates of the murine EMT-6 cells and the human WiDR colon carcinoma cells. We confirmed that under our clonogenic assay conditions the EMT-6 cell line was more sensitive to mitomycin under hypoxic than oxic conditions. Additionally, we established that EMT-6 cells also metabolize mitomycin at a more rapid rate under hypoxic than oxic conditions. However, these effects of hypoxia on mitomycin activity were not demonstrable for the human WiDR colon cancer cell line. In addition to these findings, the cytotoxicity of mitomycin was either unchanged or reduced under hypoxic conditions for ten fresh human tumors tested for mitomycin sensitivity in HTCA. Based on these observations, we conclude that the potentiating effect of hypoxia on mitomycin metabolism and biological activity may be peculiar to the murine EMT-6 and S-180 cell lines and that mitomycin C is not likely to have differential efficacy against hypoxic human carcinoma cells.
Cancer Chemother Pharmacol 1984
PMID:Cytotoxicity of mitomycin C on clonogenic human carcinoma cells is not enhanced by hypoxia. 642 4

In order to assess the effect of oxygen on chemopotentiation by misonidazole (MISO), EMT-6/Ro tumor cells were exposed in vitro to combinations of CCNU and 1.0 mM MISO in culture medium equilibrated at various oxygen concentrations. The effect of oxygen on MISO cytotoxicity was similarly determined and compared with the relationship obtained for chemosensitization. MISO cytotoxicity and chemopotentiation were both oxygen sensitive, being maximal under anoxic conditions. Furthermore, the pattern of oxygen sensitivity was virtually identical for the two activities. These results suggest that a similar metabolic pathway, i.e., the oxygen-sensitive reduction of MISO to the nitroradical anion by cellular nitroreductases, is involved in the mechanism of both activities. The data further indicate that chemopotentiation can be expressed in cells treated at intermediate oxygen tensions. The implications of these findings with respect to the magnitude of chemopotentiation in vivo and the enhancement of normal tissue damage in animals treated with MISO and chemotherapy agents is discussed.
Cancer Res 1984 Oct
PMID:Effect of oxygen on misonidazole chemosensitization and cytotoxicity in vitro. 646 2

We have investigated the relationships between nitrosourea structure and physicochemical properties and the ability of misonidazole (MISO) to potentiate nitrosourea cytotoxicity in an in vitro model system. EMT-6/Ro tumour cells were exposed in suspension to each of 9 different nitrosourea anti-tumour drugs under hypoxic and aerobic culture conditions. Additional cultures were similarly treated with nitrosoureas in the presence of 1.0 mM MISO. Seven of the 9 nitrosoureas did not demonstrate any selective toxicity toward aerobic or hypoxic cells. In contrast, chlorozotocin (CHLZ) was slightly more toxic toward hypoxic cells while Bis-OH CyNU more effectively killed aerobic cells. The addition of MISO to the drug treatment enhanced the effectiveness of all the nitrosoureas under hypoxic conditions, with the exception of CHLZ which was uninfluenced by MISO. The magnitude of the MISO dose enhancement factor (DEF, defined as the ratio of drug doses required to reduce cell survival to S = 10(-3) in 4 hours in the absence and presence of 1.0 mM MISO) for each combination was examined as a function of the relative carbamoylating or alkylating activity of the nitrosourea included in that combination. Such an analysis revealed a significant (P less than 0.05) positive correlation between relative carbamoylating potency and DEF. No significant (P greater than 0.20) relationship could be established for DEF and alkylating activity.
Br J Cancer 1984 Mar
PMID:Enhancement of nitrosourea cytotoxicity by misonidazole in vitro: correlation with carbamoylating potential. 670 5

[14C]Misonidazole (MISO) becomes bound to macromolecules of mammalian cells upon hypoxic incubation. Intracellular enzyme processes are implicated since the temperature dependence for this process showed an activation energy of 33.5 kcal/mol. The sensitizer bound to both hypoxic and aerobic cells was associated with the macromolecular fraction and the soluble fraction in the proportion, 23 and 77%, respectively. The initial rate of binding of [14C]MISO to the macromolecular (acid-insoluble) fraction of hypoxic EMT-6 mouse tumor and V-79 hamster cells increased proportionally with the square root of extracellular concentration of MISO up to at least 5mM. High concentrations of dimethyl sulfoxide (an effective OH radical scavenger), allopurinol (an effective inhibitor of xanthine oxidase), and diamide (a chemical which can deplete cellular levels of glutathione) had little or no effect on this metabolism-induced binding process. The addition of high concentrations of exogenous cysteamine to hypoxic cell cultures resulted in almost complete inhibition of binding. Extracellular bovine albumin at high concentration in hypoxic cell cultures had little effect on the production of adducts to cell macromolecules and only small amounts of [14C]MISO were found to bind to the extra-cellular bovine albumin. This result suggests that MISO preferentially binds to molecules within the cell in which it is metabolically activated. In experiments where cells labeled under hypoxic conditions with [14C]MISO were subsequently permitted to proliferate in aerobic monolayers, a half-life of the acid-insoluble addition products of approximately 55 hr was measured. A large number of [14C]MISO adducts (approximately 10(9)/cell) can be generated in hypoxic cells without any evidence of cytotoxicity, and they are slowly cleared from cells. These are favorable characteristics as regards the development of this technique as a marker for hypoxic cells in solid tumors.
Cancer Res 1983 Apr
PMID:Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. 683 1

The cytotoxicity of citrated gallium nitrate (NSC 15200) to EMT-6/UW mouse sarcoma cells growing in vitro was assayed as growth inhibition in treated cultures as well as cell survival (colony-forming ability) after acute or chronic exposure to graded doses. Gallium nitrate is both cytostatic and lethal to cells, with some growth inhibition occurring after chronic exposure to low doses (10 micrograms/ml) which kill essentially no cells. Cell kill and growth inhibition were both observed if cells were exposed for 24 hr or more to doses greater than 50 micrograms/ml. The growth inhibitory and lethal effects of gallium nitrate were enhanced by the addition of human transferrin to the medium. This enhanced toxicity was consistent with, and proportional to, the increased gallium uptake in the presence of transferrin rather than a direct effect of this iron transport protein. The addition of ferric citrate greatly reduced the toxic effect of the gallium salt. Cells in stationary plateau phase cultures appear to be as sensitive to gallium nitrate as exponentially growing cells. Ga3+ may mimic Fe3+ in some aspects of cellular metabolism, and competition between the two metals occurs at the initial uptake step, binding to transferrin, and possibly at other points in cell metabolism.
Eur J Cancer Clin Oncol 1982 Jul
PMID:Tumor cell toxicity of stable gallium nitrate: enhancement by transferrin and protection by iron. 688 67

Isoeffect analysis of complete dose response curves can be used to study the interaction of agents in combined modality protocols. When such an analysis is applied to data from in vivo tumour model systems, the effects of the agents on factors such as tumour vasculature, growth or reoxygenation pattern also need to be considered. In this study the change in tumour size, which can occur during a long time-interval between agents, was used as an example of a factor which may influence the position of data points on an isoeffect plot. Assays of in vivo tumour growth delay and in vitro clonogenic survival were performed to demonstrate that the radiation response curves of EMT-6/Ro tumours were size dependent. These curves were used to illustrate that data points obtained from a combined modality treatment may fall outside of the envelope of additivity of an isoeffect plot, as a direct consequence of tumour growth. This finding indicates that it may not be possible to interpret the results from isoeffect analyses of in vivo data on the basis of cellular interactions between agents, and suggests that instead isoeffect analyses be applied primarily to assess the overall response of the tumour system.
Br J Cancer Suppl 1980 Apr
PMID:Tumour size: a factor influencing the isoeffect analysis of tumour response to combined modalities. 693 39

Enhancement of various antitumor drugs effects by inhibitors of radiation-induced potentially lethal damage (PLD) repair was studied in three murine tumors (EMT-6, RIF-1 and SQ-1). In EMT-6 tumors, PLD repair inhibitors, 3'-deoxyguanosine (3'-dG) and 7904 (a derivative of 3'-deoxyadenosine) showed a marked enhancement of tumor growth inhibition by anticancerous drugs (FT-207 (a derivative of 5-FU), bleomycin, Ara-C, ACNU). However, the effects of mitomycin-C and vincristine were not potentiated by the inhibitors. In SQ-1 carcinomas, another repair inhibitor, ara-A (1-beta-D-arabinofuranosyladenine) (32 mg/kg) potentiated the effect of ACNU. In RIF-1 sarcomas, in which a low PLD repair function has been reported after ionizing radiation exposure, the potentiation was not so marked as in EMT-6 or SQ-1 tumors. Thus, as a possibility, the potentiation by inhibitors of radiation-induced PLD repair might be a result of the inhibition of chemical-induced PLD repair. The study of this field may contribute to the improvement of cancer treatment not only by radiotherapy but also by chemotherapy.
 ...
PMID:Effects of inhibitors of radiation-induced potentially lethal damage repair on chemotherapy in murine tumors. 698 87

3-Deazaguanine (3-DG) is a new purine antagonist that is active against slow- and rapid-growing solid experimental tumors, especially those that are models for human breast carcinomas. These tumors include mammary adenocarcinomas 13762, R3230AC, and C3H/16C. 3-DG also showed positive activity against leukemias L1210 and L1210/araC, adenocarcinoma 755, and EMT-6 mammary adenocarcinoma. On the basis of its activity against these tumors, 3-DG is to undergo clinical trials.
Cancer Treat Rep 1982 Oct
PMID:3-deazaguanine, a candidate drug for the chemotherapy of breast carcinomas? 712 23


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