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)

Cytotoxicity of thaliblastine (thalicarpine, TBL; NSC-68075) and/or cisplatin (DDP) in DDP-sensitive (O-342) and-resistant (O-342/DDP) rat ovarian tumor cell lines was comparatively determined using the MTT assay. The 50% inhibitory dose (ID50) of DDP was found to be 6.2 microM in O-342 cells and 23.4 microM in O-342/DDP cells, while, vice versa, the ID50 of TBL was 39.3 micrograms/ml in the sensitive line and 27.3 micrograms/ml in the resistant line. Furthermore, simultaneous exposure of cells to DDP and TBL showed a significant superiority over DDP alone in O-342 cells, as evaluated with variance analysis (P less than 0.001). This enhancing effect of TBL on DDP cytotoxicity, however, was not observed in the resistant cells.
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PMID:Antitumor activity of thaliblastine (NSC-68075) in experimental ovarian tumor cell lines sensitive and resistant to cisplatin. 153 81

The flavoenzyme DT-diaphorase has the potential either to bioactivate or to detoxify different bioreductive cytotoxins. Elucidation of structural features governing the ability to act as a substrate for DT-diaphorase should facilitate rational optimization or elimination of this reductive pathway for a particular class of bioreductive drug. We have examined structure-activity relationships governing both the cytotoxicity and the DT-diaphorase mediated reduction of two groups of bioreductive alkylating agents: (1) Indoloquinones related to EO9 [3-hydroxy-methyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)prop-beta - en-alpha-ol]; and (2) derivatives of diaziridinyl benzoquinone or diaziquone [2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone]. The rat U.K. 256 Walker tumor cell line and the human HT29 colon carcinoma line were studied because of their high DT-diaphorase content. Enzyme activity was measured spectrophotometrically by dicoumarol inhibitable cytochrome c reduction in the presence of drug, and aerobic cytotoxicity was assessed by the MTT assay. EO9 acted as a good substrate for both enzyme preparations and was highly potent in each cell line, especially in Walker tumor cells (ID50 0.039 nM). AZQ was also reduced efficiently and gave an ID50 of 6 nM in the Walker tumor line. Slight modifications in structure resulted in large variations in both DT-diaphorase metabolism and toxicity for both types of agent. There was a clear tendency for the most efficiently reduced analogues to exhibit greater cytotoxic potency. Inclusion of an aziridine moiety in the structure appears to be desirable, but not essential, for both rapid reduction and cytotoxicity. There was no evidence of active site-directed enzyme inhibition.
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PMID:Structure-activity relationships for DT-diaphorase reduction of hypoxic cell directed agents: indoloquinones and diaziridinyl benzoquinones. 154 32

This study compares the toxic effects of the carotenoids, beta-carotene and canthaxanthin, and alpha-tocopherol (vitamin E) on human tumor cells and their normal counterparts in vitro. Seven different malignant cell lines were examined: oral carcinoma (two cell lines), breast (two cell lines), lung carcinoma (two cell lines), and malignant melanoma. The in vitro cell culture assays showed a consistent morphologic change in the affected tumor cells following treatment with carotenoid or vitamin E. A rounding of the tumor cells and eventual lifting off the tissue culture plate were observed. These changes were apparent after 1 to 5 hours of treatment depending on the tumor cell line. Associated with these observable cellular changes were quantitative reductions in proliferation (3H-thymidine proliferation) and succinic dehydrogenase activity (MTT assay). In addition, there was a noticeable change in protein expression, with an increased expression of a 70-kD protein following treatment with beta-carotene. This protein was associated with tumor cells showing a decrease in proliferation (oral carcinoma, malignant melanoma) but not with normal keratinocytes or melanocytes. These studies substantiate a selective cytotoxic effect on human tumor cell growth by carotenoids and alpha-tocopherol in vitro, and may provide an explanation of the therapeutic activity of these agents and their possible use in the treatment of premalignancy or early oral carcinoma.
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PMID:The selective cytotoxic effect of carotenoids and alpha-tocopherol on human cancer cell lines in vitro. 154 92

Decreased activity of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), responsible for the conversion of 6-mercaptopurine and 6-thioguanine (6-TG) to their cytotoxic nucleotides, may cause resistance to these thiopurines in experimental leukemic systems. The clinical significance of this mechanism is as yet unclear. In 83 children with untreated acute lymphoblastic leukemia (ALL), we determined the prognostic value of HGPRT activity and the relation between HGPRT activity and resistance to thiopurines. HGPRT activity was determined radiochemically; in vitro resistance to 6-TG with the MTT assay. HGPRT level was significantly lower in T-ALL than in B-lineage ALL; no differences were found between sequential differentiation stages of B-lineage ALL. HGPRT activity was inversely related to the white-blood-cell count (WBC). Among patients with cALL and pre-B-ALL with WBC less than 50 x 10(9)/l, cases with a low HGPRT had a significantly poorer prognosis than those with a high HGPRT. WBC, age, sex, organomegaly and differentiation stage were comparable in both patient groups. No correlation was found between HGPRT activity and in vitro 6-TG resistance in cALL and pre-B-ALL patients. T-ALL cases were not more 6-TG-resistant than cALL and pre-B-ALL cases. Cells from 6 relapsed ALL cases did not show decreased HGPRT activity. We conclude that: (a) HGPRT is lower in T- than in B-lineage ALL and is constant in sequential differentiation stages of B-lineage ALL; (b) HGPRT activity is inversely related to tumor load; (c) low HGPRT activities are correlated with a poorer prognosis in precursor B-ALL but this cannot be explained by thiopurine resistance because (d) there is no relation between HGPRT activity and in vitro 6-TG resistance.
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PMID:Hypoxanthine-guanine phosphoribosyl-transferase in childhood leukemia: relation with immunophenotype, in vitro drug resistance and clinical prognosis. 156 89

The in vitro sponge-gel-supported three-dimensional histoculture chemosensitivity assay (Hoffman assay) allows the in vivo-like culture of human tumors. In this study, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) end point was applied to the Hoffman assay in an attempt to increase in vitro-in vivo correlation. The chemosensitivities of 16 human tumor lines were determined in vitro by the histoculture assay, and retrospectively correlated to their in vivo chemosensitivity as xenografts in nude mice. The in vitro test was considered to be positive if tumor-cell MTT reduction activity was lowered by more than 50%. The cutoff drug concentrations to determine sensitivity in vitro were determined for mitomycin C, doxorubicin, 5-fluorouracil and cisplatin. Using these cutoff drug concentrations in vitro we found, as a function of time of exposure, a strong correlation between serum drug concentrations found in nude mice given maximum tolerated doses and drug concentrations found in the histoculture media in vitro, thereby establishing a relationship between the amounts of drugs to which tumors were exposed in vivo and in vitro. The overall correlation rate of the efficacy results of the drug-response assay to in vivo chemosensitivities was 89.8%, with 90.0% true-positive and 89.7% true-negative rates, 81.7% sensitivity and 94.6% specificity, thereby indicating potential clinical use for tumor histoculture with the MTT end point.
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PMID:High in vitro-in vivo correlation of drug response using sponge-gel-supported three-dimensional histoculture and the MTT end point. 159 40

Since the prognosis of patients with malignant ascites is generally poor, the establishment of a therapeutic plan should be done as soon as possible. In order to select the most suitable antitumor agent, a drug-sensitivity test was done by MTT assay using fresh autologous tumor cells as targets. Autologous tumor cells were collected from their ascitic fluids. Results obtained here indicate a possible strategy for the treatment of patients with malignant ascites by MTT assay.
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PMID:[Strategy for therapy of malignant ascites using MTT assay]. 160 58

Two new cell lines were established from a single human uterine cervical adenocarcinoma which had been successfully transplanted into nude mice. They were subcultivated more than 70 times over a period of 46 months and designated as TCO-1 and TCO-2, respectively. Growth characteristics, modes of chromosomes and specific tumor makers were different in TCO-1 and TCO-2. The plating efficiency of TCO-1 was greater and its doubling time was shorter than those of TCO-2. Modes of chromosomes were 77 in TCO-1 and 94 in TCO-2. Their chemosensitivities to 13 anticancer drugs were studied by MTT assay. Only the mitomycin C (MMC) was an effective agent for both TCO-1 and TCO-2 cell lines which were characteristically different from each other. The results suggest that MMC would be a promising agent for chemotherapy of human uterine cervical adenocarcinoma. The influences of 6 hormones (estradiol, progesterone, dihydrotestosterone, medroxyprogesterone acetate, human menopausal gonadotropin, human chorionic gonadotropin) on their proliferation were studied by MTT assay and dye exclusion assay. TCO-1 and TCO-2 showed no significant changes in proliferation in any of them. It is suggested that hormone replacement therapy could be indicated even for postoperative patients with cervical adenocarcinoma.
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PMID:[Characterization of two novel cell lines established from a single human uterine cervical adenocarcinoma, and their chemosensitivities and hormonal effects on their proliferation]. 160 68

The aim of this study was to optimize the experimental conditions of the MTT assay for primary cultures of human brain tumors. This assay is based on the mitochondrial reduction of MTT-(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) salt to formazan crystals by living cells. Formazan can be quantified spectrophotometrically. This assay measures the antimetabolic and, by using an adequate recovery period for the cells, also the antiproliferative effects of cytotoxic drugs. Our results suggest the following experimental design for its application as an chemosensitivity assay for human brain tumors: 1-h drug exposure followed by a seven days recovery period without drugs. Then tumor cells are incubated 4 hours with 1 mg MTT/ml and final absorbance readings are performed at 550 nm and 630 nm as test and reference wavelengths respectively. In this way, the assay seems to be a reliable and simple method for rapid chemosensitivity testing in human brain tumors.
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PMID:The MTT assay for chemosensitivity testing of human tumors of the central nervous system. Part I: Evaluation of test-specific variables. 161 35

The present study was designed to analyse the cytotoxic effects of the combination of fotemustine with 5-fluorouracil (5-FU) plus folinic acid (FA). Two human tumor cell lines were used; one line was derived from colon cancer (WIDR) and the other, from a non-small-cell lung cancer (CAL 12). Cytotoxic effects were assessed using the MTT (tetrazolium bromide) semi-automated test in 96-well incubation plates. The effects of various drug combinations were evaluated by the isobologram method. The drug combinations tested included fotemustine concentrations of 20, 30, 40, 50 and 70 micrograms/ml, 5-FU concentrations of 5, 15 and 30 micrograms/ml, and a constant FA concentration of 10(-5) M. A total of 180 different experimental conditions were tested. When cells were exposed to fotemustine prior to treatment with 5-FU, the final cytotoxic effects on both cell lines were additive or synergistic in the majority of cases (P less than 0.001). The 5-FU concentration was a determinant factor that modified the effects of the drug combination from antagonism (at low 5-FU concentrations) to synergism (high 5-FU concentrations; P less than 0.001). The addition of FA (10(-5) M) resulted in a significant shift towards synergistic associations in both cell lines. Administration of 5-FU prior to treatment with fotemustine caused marked antagonism, which 10(-5) M FA could not significantly shift towards simple additivity.
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PMID:Sequence-dependent cytotoxic effects of the combination of a new nitrosourea, fotemustine, with 5-fluorouracil plus folinic acid. 165 24

Cytotoxic effects of vitamin K3 were evaluated utilizing the P388/S, L1210, EAT, S-180 and a multidrug-resistant variant of the P388 leukemia cells (P388/ADR). Antitumorigenic potential of vitamin K3 was assessed by MTT and DNA and RNA biosynthesis inhibition assay. A dose-dependent inhibition of P388/S and P388/ADR cell survival and [3H]thymidine and [3H]uridine incorporation (as a function of DNA and RNA biosynthesis) was observed in tumor cell types exposed to vitamin K3 concentrations ranging from 1 to 100 microM. One hundred mg/kg vitamin K3 caused a 32 and 52% increase in life span of the sensitive and resistant P388 leukemia tumor-bearing mice. Induction of DNA strand breaks at 100 microM vitamin K3 was greater in P388/S than in P388/ADR cells. In vitro treatment with vitamin K3 (100 microM) reduced the intracellular levels of GSH by 40, 47, 6, 15 and 14% in P388/S, P388/ADR, EAT, S-180 and L1210 tumor cells, respectively. In vivo treatment with 100 mg/kg vitamin K3 reduced the GSH content by 18 and 38% and increased the activity of the enzyme GSH-S-transferase and gamma-glutamyl transpeptidase. Effects of free radical scavengers and of compounds that modulate the GSH metabolism on the cytotoxicity of vitamin K3 were also investigated. Results indicate that vitamin K3 interacts with the tumor cell thiol pools while eliciting its antitumor effects and suggest the utility of vitamin K3 in dealing with the growing problem of multidrug resistance.
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PMID:Modulation of thiol pools by vitamin K3 and its effect on survival of sensitive and resistant murine tumor cells. 168 89


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