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)

A recently developed colony-formation assay has been used to evaluate in vivo 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) therapy of a transplantable rat brain-tumor model. A comparison of the in vitro colony-forming capacity of treated and untreated tumor cells permits calculation of the fraction of clonogenic tumor cells surviving in vivo therapy; The plateau that we previously observed o the BCNU dose-response curve is not the result of repair of potentially lethal damage, since no change in the 0.1% of surviving clonogenic tumor cells occurs during the first 2 to 4 days after treatment. Although reanalysis of the dose-response curve indicates that sublethal damage exists, its repair is probably minimal. The most likely explanation for the observed limitation of the BCNU effect is the drug's failure to reach all clonogenic cells. A dose of BCNU that kills more than 99.9% of clonogenic tumor cells within 30 minutes of treatment results in only a 60% decrease in tumor weight by Day 14. This disparity is explained by retarded removal of dead cells, and, along with a previously determined 90% cell-kill threshold necessary to appreciate increased animal survival, demonstrates the inherent limitations of measurements of tumor size (including brain scans and clinical patient evaluations) in evaluating the efficacy of brain-tumor therapy. Following at LD10 dose of BCNU the surviving clonogenic tumor cells increase in number after latency period of 2 to 4 days; during regrowth the cell doubling time is 40 hours. Marked variability in tumor response and regrowth was noted. The determination of information regarding disturbed tumor cell kinetics and tumor heterogeneityis essential for the proper planning of combination chemotherapy and multimodality regimens.
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PMID:Brain-tumor therapy. Quantitative analysis using a model system. 83 32

An in vitro colony formation assay was modified to determine the effects of in vivo 1,3-bis(2-chloroethyl)-1-nitrosourea therapy on tumor cell kill and subsequent clonogenic cell kinetics. The measured surviving fraction must be multiplied by the relative total number of tumor cells for each posttreatment interval in order to eliminate inaccuracies caused by dead cell removal in vivo and the lysis of damaged cells by the disaggregation procedure. The assumptions, limitations, and applications of the technique are discussed. 1,3-Bis(2-chloroethyl)-1-nitrosourea doses of 0.25, 0.50, and 1.00 X dose lethal to 10% of animals resulted in approximately at 1-, 2-, and 3-log cell kill, respectively. Significant proliferation of surviving clonogenic cells was observed after a latency period of approximately 2 days, and the rate of tumor regrowth was dose dependent. The cell-doubling times following treatment with 0.25, 0.50, and 1.00 X doses lethal to 10% of animals were 15, 21, and 38 hr, respectively. The interval to complete repopulation of the clonogenic pool corresponds to the observed increase in animal life-span for the 2 larger doses and further validates the assay as a true measure of in vivo chemotherapeutic efficacy.
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PMID:In vivo clonogenic tumor cell kinetics following 1,3-bis(2-chloroethyl)-1-nitrosourea brain tumor therapy. 95 98

The rapid analysis of in vivo chemotherapy on the L1210 ascites tumor grown in C57BL/6 X DBA/2F1 mice has been shown by means of an electronic volume analysis. The drugs were injected on the 4th day of tumor growth, and the cells in the peritoneal cavity were studied at 24-hr intervals on the 5th through 7th day. Using the electronic cell volume distributions, combined with labeling indices, cell morphology, and cell counts, it was found that the alkylating agents. 1,3-bis(2-chloroethyl)-1-nitrosourea and cyclophosphamide, at the dosages used, were more effective than the S-phase-specific drugs, palmitoyl ester of 1-beta-D-arabinofuranosylcytosine, vincristine, and methotrexate.
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PMID:Electronic volume analysis of L1210 chemotherapy. 100 Apr 92

C57BL/6 mice (H-2b) were immunized with lethally x-irradiated Moloney virus-induced lymphoma cells of BALB/c origin (H-2d) on Days 0 and 10 and received rug on Days 11 and 14. Their spleen cells were then tested for reactivity against Moloney virus-induced lymphoma of BALB/c origin by the 51Cr-release cytotoxicity assay. In non-drug-treated mice the secondary cytotoxic response was maximal on Days 14 to 15, declined rapidley, and recurred after Day 21. The cytotoxic effector cells were shown to be theta-bearing T-lymphocytes. Cyclophosphamide (CY), 180 mg/kg, given on Day 11, totally prevented the development of a cytotoxic response and when given on Day 14 abolished the response already established. CY, 48 mg/kg, as well as 1,3-bis(2-chloroethyl)-1-nitrosourea 33 mg/kg, were almost as suppressive. Immune mice given CY on Day 14 and reimmunized on Day 36 exhibited a normal tertiary response. Mice similarly immunized on Days 1 and 10 and given drugs on Day 14 were challenged on Day 15 with up to 3.5 x 10-8 viable Moloney virus-induced lymphoma cells of BALB/c origin. Despite H-2 incompatibility, all nonimmune control mice developed ascites and died, whereas all mice immunized but not given drug failed to develop ascites. By contrast, 17 of 34 immunized mice given CY, 180 mg/kg, and 7 of 34 given 1,3-bis(2-chloroethyl)-1-nitrosourea developed ascites. The ascites eventually regressed. THE RESULTS SHOW THAT CY and 1,3-bis(2-chloroethyl)-1-nitrosourea can suppress a secondary cellular immune response as measured by the T-cell-mediated 51Cr-release cytotoxicity assay in vitro and by viable tumor challenge in vivo.
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PMID:Suppression of secondary cellular immunity to a tumor allograft by cyclophosphamide and 1,3-bis(2-chloroethyl)-1-nitrosourea. 107 84

L-2,3,5,6-Tetrahydro-6-phenylimidazo[2,1-beta]thiazole hydrochloride (LMS), when used in concert with 1,3-bis(2-chloroethyl)-1-nitrosourea, resulted in a significantly higher percentage of long-term leukemic-free survivors. The additive effect provided by LMS treatment was evident during the immunosuppressed period induced by 1,3-bis(2-chloroethyl)-1-nitrosourea treatment and when tumor load was minimal. Treatment with LMS alone did not appear to possess any significant antitumor effect. The beneficial effect of LMS treatment may be attributable to the immunostimulatory activity reported for this drug. LMS appears to possess characteristics that make it an excellent candidate for use as an immunostimulant in cancer combined modality treatment.
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PMID:Prolongation of chemotherapeutically induced remission of a syneneic murine leukemia by L-2,3,5,6-tetrahydro-6-phenylimidazo[2.1-BETA]thiazole hydrochloride. 111 50

Survival curves are presented for the treatment of B16 melanomas with a range of single doses of cyclophosphamide (CY), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), or 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitro-sourea (MeCCNU). When these four drugs are assessed in terms of the tumor cell kill at the lethal dose to 10% of the mice, MeCCNU is found to be much the most effective, followed by CCNU, and then CY and BCNU together. The superiority of MeCCNU is possibly related to the fact that it seems to be longer lived in the mice than are the other drugs. Combined drug and irradiation experiments have indicated that CY kills both oxygenated and hypoxic cells in the tumor, leaving proportions equal to those in the tumor prior to treatment, whereas BCNU preferentially spares the hypoxic cells. Since hypoxic cells constitute a population of cells that is at a distance from blood vessels, this result suggests that CY treatment of B16 melanomas is not limited by an inability of the drug to diffuse to cells away from blood vessels.
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PMID:The response of hypoxic B16 melanoma cells to in vivo treatment with chemotherapeutic agents. 112 Mar 4

An in vitro colony formation assay was used to determine the efficacy of in vitro therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on a rat brain tumor. The fraction of clonogenic cells surviving in vivo therapy was determined by a comparison between the in vitro colony-forming capacity of cells derived from previously treated and untreated tumors. With this intracerebral solid tumor a direct correlation was found between the surviving fraction of cells and animal survival, implying that the in vitro assay system is a reliable test of therapeutic effect. The BCNU dose-response curve was exponential up to a dose of 0.75 times the LD10 dose with little additional cell kill noted at higher drug levels. This plateau does not appear to represent a resistant subpopulation of cells, since retreatment of tumors derived from cells surviving an LD10 dose were as sensitive to BCNU as those with no prior drug exposure. Instead, it may represent, at least in part, failure of the drug to reach and/or enter cells in all parts of solid tumors. On the average BCNU doses of 0.75 times the LD10 dose or greater resulted in slightly more than a 3-log cell kill and doubled the life-span for our tumor-bearing animals. The finding that an increase in animal life-span requires at least a 1-log tumor cell kill indicates that survival studies with intracranial tumor models may be insensitive to single courses of many chemotherapeutic agents with modest but significant antitumor activity.
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PMID:In vitro evaluation of in vivo brain tumor chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea. 113 13

Three nitrosourea analogs, 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and 1-trans-(2-chloroethyl)-3-cyclohexyl-1-(4-methylcyclohexyl)-1-nitrosourea, were examined for effects on survival and cell cycle traverse capacity in exponentially growing (cycling) populations of line CHO Chinese hamster cells and in cultures arrested in G1 by isoleucine deprivation during treatment with drugs, then returned to the cycling mode by restoration of isoleucine (noncycling cells). Among parameters studied were survival, cell division, DNA initiation capacities, cell cycle distributions, and rates of cell cycle traverse in drug-treated cycling and noncycling cells utilizing a protocol combining autoradiography, cell number enumeration, and flow microfluorometry. The results obtained were in generally good agreement with results obtained in vivo in other studies and included the following. Cells treated with any of these agents accumulated preferentially in late S and G2, primarily the result of a gross increase in duration of these phases of the cell cycle. There was also a prolongation of doubling time during the early stages following drug treatment and return to the proliferating mode of cells which ultimately survived. All three drugs induced mitotic nondisjunction in cells capable of dividing and also induced polyploidy by allowing multiple rounds of progression through the cell cycle in the absence of an intervening cell division. In treated populations, the G2-arrested and polyploid cells were among the first cells to die. Treated, noncycling cells that were returned to cycle exhibited a lower survival capacity than did treated, cycling cells. Finally, 1-(2-chloroethyl-3-cyclohexyl)-1-nitrosourea and 1-trans(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea induced a dramatic alteration in clonal morphology and growth patterns in surviving cells that persisted for at least a week after drug removal. The results obtained suggest that our model system may be useful as a predictive guide for determining response of susceptible tumor cells to treatment with chemotherapeutic agents.
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PMID:Comparative effects of three nitrosourea derivatives on mammalian cell cycle progression. 116 49

B16 melanoma cells sterilized in vitro with 1,3-bis(2-chloroethyl)-1-nitrosourea or in vivo with trans-1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, have been used to enhance the percentage of tumor takes with small s.c. implants of viable cells and to reduce the latent period between tumor implantation and palpability. The admixture of trans-1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea-inactivated cells with viable cell implants reduced the number of cells required to produce tumors in 50% of the animals by approximately 3 log10 units and markedly reduced the time of tumor appearance from implants of up to 10(6) cells. Similar results were obtained with 1,3-bis(2-chloroethyl)-1-nitrosourea-sterilized cells. The growth-supporting effect obtained with the nitrosourea-inactivated cells appeared to be as pronounced as that previously reported, for this tumor system, with radiation-inactivated cells.
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PMID:Growth support of small B16 melanoma implants with nitrosourea-sterilized fractions of the same tumor. 126 54

Treatment of isolated mitochondria from rat hepatoma tumor cells (AS-30D) with the oxidant, t-butyl hydroperoxide (tBuOOH, 1 or 5 mumol/ml) resulted in the oxidation of glutathione (GSH to GSSG) and the formation of protein-glutathione mixed disulfides (ProSSG). The GSSG was retained inside of the hepatoma mitochondria. In the presence of ADP+succinate (5 or 10 mM), or ketoglutarate (10 mM) or malate (5 mM), the GSSG was reduced to GSH, but the amount of ProSSG stayed constant. With saline or ADP+glutamate (10 mM)/malate (0.1 mm) no reduction of GSSG to GSH occurred. The presence of antimycin (5 micrograms/ml) with ADP+succinate inhibited reduction. At a concentration of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, 0.5 mM) which inhibited a major portion of the glutathione reductase activity, the reduction of GSSG to replenish GSH was also inhibited. NADPH may play a critical role as well, for the addition of 2.4 mM NADPH to permeabilized hepatoma mitochondria fostered the reduction of GSSG after tBuOOH treatment. Therefore, hepatoma mitochondria possess a glutathione reductase-dependent system to reduce GSSG to GSH. The reaction only occurs with actively respiring mitochondria.
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PMID:Glutathione disulfide reduction in tumor mitochondria after t-butyl hydroperoxide treatment. 139 20


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