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)

We have tested the tumoricidal potency of enzyme immunotoxins constructed of antibodies conjugated to glucose oxidase and to lactoperoxidase. Murine plasmacytoma cells were targeted in vitro with the use of affinity-purified rabbit anti-plasmacytoma membrane antibodies (conjugated to glucose oxidase or lactoperoxidase) or rabbit serum raised against plasmacytoma microsome membranes followed by goat anti-rabbit immunoglobulin conjugates (to glucose oxidase or lactoperoxidase). Cytotoxicity was generated subsequently by incubation of the washed cells in a medium supplemented with glucose and sodium iodide, which were the substrates of these enzymes. This resulted in the presumed metabolic release of highly toxic reduced oxygen species and iodinated derivatives. Targeting of tumor cells with both conjugates, as opposed to one of them alone, produced a synergistic killing effect. The gain of specific versus unspecific cytotoxicity was upwards of 10,000-fold. The killing rates were elevated (t10 values less than 30 min) and linear over time. The resultant reduction in tumor cell viability was in the order of 5 to 6 logs after only 20 to 90 min of incubation in the glucose/NaI medium. Cytotoxicity was enhanced by the gamma-glutamyl cysteine synthetase inhibitor buthionine-S,R-sulfoximine and by the glutathione reductase inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea, while catalase was inhibitory. The results suggest that these enzyme immunotoxins may be suitable for the ex vivo purging of autologous bone marrow grafts.
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PMID:Immunotoxins containing glucose oxidase and lactoperoxidase with tumoricidal properties: in vitro killing effectiveness in a mouse plasmacytoma cell model. 279 Jul 77

Drug-induced DNA hypermethylation was observed to constitute one component of the response of human tumor cells to toxic concentrations of commonly used cancer chemotherapy agents. In both human lung adenocarcinoma cells (HTB-54) and human rhabdomyosarcoma cells (CCl-136), pulse exposures to the topoisomerase II inhibitors etoposide and nalidixic acid; to the antibiotic doxorubicin; to the microtubule inhibitors vincristine, vinblastine, and colchicine; to the DNA cross-linking agent cisplatinum; to hydroxyurea; and to the antimetabolites 1-beta-D-arabinofuranosylcytosine, 5-fluorouracil, 5-fluorodeoxyuridine, and methotrexate were associated with profound drug-induced DNA hypermethylation. Exposure of human T-lymphocytes (MOLT-4) to toxic pulse doses of 3'-azidodideoxythymidine was associated with similar drug-induced DNA hypermethylation. In every case, drug-induced DNA hypermethylation was observed only when the degree of DNA synthesis inhibition caused by the drug exceeded 90% and when drug levels or duration of exposure was sufficient to kill 90-100% of exposed cells. Drug-induced DNA hypermethylation was shown not to represent a tissue culture phenomenon, since it occurred in vivo during high-dose 1-beta-D-arabinofuranosylcytosine and hydroxyurea treatments in two leukemic patients. Drug-induced alterations in DNA methylation were frequently biphasic, with hypomethylation occurring at drug concentrations which produced mild DNA synthesis inhibition and which killed less than 50% of exposed cells. Exposure to the alkylating agents 1,3-bis(2-chloroethyl)-1-nitrosourea and cyclophosphamide and to the antimetabolites 5-azadeoxycytidine and 6-thioguanine was associated with DNA hypomethylation at all studied concentrations in HTB-54 cells. Drug-induced DNA hypermethylation could be blocked by preexposure to hypomethylating agents administered at nontoxic to mildly toxic concentrations. Drug-induced DNA hypermethylation may be capable of creating drug-resistant phenotypes by inactivating genes the products of which are required for drug cytotoxicity. Perhaps paradoxically, drug-induced DNA hypermethylation may also produce a second class of drug-resistant tumor cells, characterized by overexpression of particular gene products, by potentiating the process of gene amplification.
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PMID:Drug-induced DNA hypermethylation and drug resistance in human tumors. 279 Jul 94

High dose, multiple alkylating agent chemotherapy is being employed in conjunction with autologous marrow transplantation in the clinic. We have investigated the scheduling of several alkylating drugs in an effort to optimize their antitumor effects. In vitro modeling of "continuous" (up to 72 h) versus "bolus" (1 h) exposure in MCF-7 cells showed that for N,N',N"-triethylenethiophosphoramide (thiotEPA), cis-diamminedichloroplatinum(II) (CDDP), 4-hydroperoxycyclophosphamide, carboplatin, and L-phenylalanine mustard (L-PAM) "continuous" exposure yielded essentially the same killing kinetics as "bolus" exposure. For N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), however, even with fresh drug additions every 30 min, "bolus" exposure produced superior cytotoxicity. In vivo modeling of "continuous" (three i.p. injections over 9 h) versus "bolus" (single dose) administration of the alkylating agents cyclophosphamide, BCNU, thiotEPA, melphalan, CDDP, and carboplatin was conducted in mice bearing EMT6 tumors, and tumor cell killing as measured by tumor cell survival in vitro was compared with killing of bone marrow (CFU-GM) measured in culture as a representative sensitive normal tissue. With cyclophosphamide there was a considerable increase in the therapeutic index (killing of tumor cells/killing of CFU-GMs) when the same total dose of drug was administered in multiple injections versus a single injection. For BCNU and thiotEPA, smaller increases in therapeutic index were observed. With L-PAM and CDDP, some advantage to multiple versus single dose administration was observed, and for carboplatin a decrease in the therapeutic index was seen. In conclusion, for all six alkylating agents examined, the multiple dose schedule was at least as effective against the tumor as the single dose schedule at all dose levels.
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PMID:Influence of schedule on alkylating agent cytotoxicity in vitro and in vivo. 279 Aug 13

We describe the neuropathologic findings at autopsy in six patients who developed a progressive encephalopathy complicating the treatment of malignant gliomas with combined intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cerebral irradiation. Four brains were free of tumor and one contained a microscopic focus of residual glioma. In only one case was there evidence of tumor progression. A disseminated process characterized by miliary foci of necrosis with mineralizing axonopathy was present in all cases, restricted to the internal carotid distribution of the perfused hemisphere and involving primarily though not exclusively the white matter, which was diffusely and severely edematous. This was combined in 3 cases with a histologically dissimilar, massive necrotizing leukoencephalopathy indistinguishable from pure radionecrosis. Much of the toxicity of this therapy is mediated by vascular injury, but the disseminated necrotizing lesion probably reflects, at least in part, direct neural damage.
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PMID:Fatal necrotizing encephalopathy complicating treatment of malignant gliomas with intra-arterial BCNU and irradiation: a pathological study. 182 43

BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea, Carmustine] is a nitrosourea that crosslinks DNA and is useful in cancer chemotherapy. Tumor cells resistant to BCNU produce high levels of O6-alkylguanine-DNA-alkyltransferase (AT), a protein that removes the O6-guanine adduct formed by BCNU prior to crosslinking. By the transfection of a human cosmid library into the Chinese hamster ovary cell line AA8, several transgenic cell lines which express the AT gene have been constructed. These 'BR' cells were isolated on the basis of their resistance to G-418 and BCNU. Like human mer+ strains, BR cells (relative to the parental AA8 cells) are approximately 500 times more resistant to the cytotoxic effects of 80 microM BCNU. Treatment with exogenous O6-methylguanine (O6MG), which depletes cellular AT, abolishes their BCNU resistance. Also consistent with the mer+ phenotype, BR cells are resistant to the mutagenic and killing activity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Treatment with exogenous O6MG, while reversing the resistance to MNNG mutation, does not reverse the resistance to MNNG killing. Unexpectedly, BR cells also exhibit resistance to killing by dimethylsulfate (DMS). The BR cells are not, however, detectably resistant to UV light. These results suggest that AT activity in mammalian cells is closely linked to the activity of other DNA repair pathways.
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PMID:Transfectant CHO cells expressing O6-alkylguanine-DNA-alkyltransferase display increased resistance to DNA damage other than O6-guanine alkylation. 282 84

Rodent (9L and 9L-2) and human (SF-126 and SF-188) brain tumor cells were treated with methylating, ethylating, and chloroethylating nitrosoureas. 9L-2 and SF-188 cells were 10-fold and 5.4-fold more resistant to the cytotoxic effects of 1-(2-chloroethyl)-1-nitrosourea (CNU) than were 9L and SF-126 cells. SF-188 cells were 2.5- to 3-fold more resistant to N-methyl-N-nitrosourea (MNU) and streptozotocin (STZ) than SF-126 cells. 9L-2 cells were slightly more resistant to the cytotoxic effects of STZ and MNU than were 9L cells, but the rodent cells were 5- to 15-fold more resistant to these agents than the human cells. There were only small differences in cytotoxicity among the four cell lines after treatment with N-ethyl-N-nitrosourea (ENU). SF-188 and 9L-2 cells were 7- to 8-fold more resistant to the induction of sister chromatid exchange (SCEs) by CNU than were SF-126 and 9L cells. SF-126 cells were 80-fold more sensitive to the induction of SCEs by both STZ and MNU than were SF-188 cells. Only small differences in SCE induction were observed in 9L and 9L-2 cells treated with MNU and STZ. After ENU treatment, SF-126, 9L, and 9L-2 cells showed similar levels of SCEs; SF-188 cells were more resistant to the induction of SCEs by ENU. Pretreatment of 9L-2 cells with MNU resulted in a dose-dependent increase in cytotoxicity and SCE induction by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Treatment with 1 mM MNU completely reversed the cellular resistance of 9L-2 cells to BCNU but did not potentiate either cytotoxicity or SCE induction in 9L cells. These results suggest that O6-alkylguanine-DNA-alkyltransferase (O6-AT) plays an important role in determining the cytotoxicity of and the induction of SCEs by CNU in both rodent and human tumor cells. O6-AT may also influence the response of human cells to both the cytotoxic effects of and the induction of SCEs by MNU and STZ. In the rodent cells, however, biochemical mechanisms other than O6-AT appear to determine the cytotoxic response to these agents. O6-AT does not appear to influence the cytotoxicity of ENU in either human or rodent cells but may have a small effect on SCE induction in human cells.
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PMID:Cytotoxicity and induction of sister chromatid exchanges in human and rodent brain tumor cells treated with alkylating chemotherapeutic agents. 283 51

High-dose 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) infusion into the internal carotid artery following cranial irradiation in the treatment of glioblastoma multiforme is accompanied by evidence of leukoencephalopathy in a significant number of patients. In an attempt to avoid this problem, a phase I trial was performed using intracarotid BCNU infusion before irradiation. Twenty-eight patients with grade III/III astrocytoma (World Health Organization Classification, equivalent to Kernohan grade IV) received a 400-mg infusion of BCNU into the infraophthalmic carotid artery. The treatment was repeated every 4 weeks for a total of four cycles prior to cranial irradiation (5500 to 6000 cGy). The major toxic sequelae included nausea and vomiting (24%), decreased visual acuity (14%), transient cerebral ischemia (3.5%), and thrombocytopenia (3.5%). Fatal leukoencephalopathy occurred in two patients. The median survival time was 37 weeks for all evaluable patients and 56+ weeks for those completing the protocol. The tumor response to drug infusion as judged by computerized tomography (CT) was complete in 22% of patients and partial in 22%; 56% showed no CT tumor response. Pre-irradiation intracarotid artery BCNU benefits a very small group of patients with grade III/III astrocytoma. The associated severe leukoencephalopathy makes this mode of therapy unacceptable for a phase III trial.
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PMID:Pre-irradiation internal carotid artery BCNU in treatment of glioblastoma multiforme. 283 67

Our previous in vitro studies demonstrated marked synergy with alkylating agents when novobiocin was present during and after alkylating agent exposure. To determine whether this effect is observed in vivo, novobiocin was administered daily for 3 days prior to alkylating agent treatment, during alkylating agent treatment, and for 2 days after completion of alkylating agent treatment. When combined with cis-diamminedichloroplatinum(II), 1,3-bis(2-chloroethyl)-1-nitrosourea, or cyclophosphamide, there was significant enhancement of the growth delay of the FSaIIC fibrosarcoma implanted s.c. in C3H mice when compared with alkylating agents alone. In a second assay using ex vivo studies of tumor cells exposed in vivo, single doses of 100 mg/kg of novobiocin followed by cis-diamminedichloroplatinum(II) resulted in a 3- to 4-fold increase in tumor cell killing by cis-diamminedichloroplatinum(II). At a dose of 100 mg/kg of 1,3-bis(2-chloroethyl)-1-nitrosourea there was about a 7-fold increase in tumor cell kill upon addition of novobiocin. Cyclophosphamide showed a dose response effect with novobiocin, reaching 13-fold at a dose of 300 mg/kg of cyclophosphamide. In all cases bone marrow elements were affected less than were neoplastic cells, suggesting that the combination of novobiocin and alkylating agents may be a clinically useful strategy.
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PMID:Effect of novobiocin on the antitumor activity and tumor cell and bone marrow survivals of three alkylating agents. 291 Apr 81

L1210 leukemia cells were treated in vitro with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and reovirus to determine their interactive effects on rejection of these tumor cells by mice. The cells were treated with BCNU at concentrations of 0, 3, or 10 microM, incubated for 48 h, then treated with reovirus at a multiplicity of infection of 0, 10, 30, or 100 for 2, 6, or 12 h. The survival of mice injected with cells treated with any amount of reovirus, regardless of BCNU treatment, was greater than that of mice injected with untreated cells. Exposure of the cells to reovirus for 6 or 12 h increased the survival of mice injected with these cells as compared with that of mice injected with cells exposed to reovirus for 2 h. Of the survivors, 76% were resistant to subsequent challenge with untreated L1210 cells. These results suggest that activities associated with reovirus replication may cause modifications of L1210 cells that enable them to induce an immune response, thus facilitating their rejection. A lack of correlation between differences in DNA synthesis (measured by 3H-thymidine uptake) by treated cells and the ability of those cells to kill recipient mice indicates that rejection of cells treated with reovirus or BCNU is not due to a decrease in their ability to proliferate or, presumably, to generate lethal tumors. The survival of mice injected with treated L1210 cell preparations containing as few as 2.9% reovirus-infected cells was enhanced to the same degree as that of mice injected with those containing as many as 14.6% infected cells, indicating that modification of only a minor component of the tumor cell population is sufficient to alter the ability of the cells to generate a lethal tumor.
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PMID:Rejection of reovirus-treated L1210 leukemia cells by mice. 294 8

The biological half-lives and decay rate constants under the conditions of a human brain tumor clonogenic cell assay were determined for six clinically used anticancer agents. The agents studied were: 1,3-bis(2-chloroethyl)-1-nitrosourea; 3-(2-chloroethyl-3-nitrosoureido-2-deoxy-D-glucopyranose; cis-diaminedichloroplatinum(II); 2,5-diaziridinyl-3,6-bis-(carboethoxyamino)-1,4-benzoquinone; 4-demethylepipodophylotoxin-D-thylidene glucoside; and 9-hydroxy-2-N-methylellipticine. In vitro decay of all six drugs was found to be according to first order kinetics. The half-lives of two drugs, namely, 1,3-bis(2-chloroethyl-1-nitrosourea and 3-(2-chloroethyl-3-nitrosoureido-2-deoxy-D-glucopyranose under the human tumor clonogenic cell assay (HTCA) conditions were found to be similar to their terminal in vivo half-lives in humans. For the other drugs, however, there was a very large difference between their in vitro and in vivo pharmacokinetics. In the case of 2,5-diaziridinyl-3,6-bis(carboethoxyamine)-1,4-benzoquinone, we observed about an 80-fold difference between its in vitro half-life of 40.76 h and its in vivo terminal half-life of 0.52 h. We describe the principles upon which these data can be used to design clinically more relevant in vitro drug exposure protocols in HTCAs. Since, generally, tumor cells are exposed to drugs in the HTCA either continuously or for a specified duration, e.g., 1 or 2 h, we computed the initial in vitro drug concentrations to which tumor cells should be exposed such that the resulting in vitro (c X t) after a 2-h or a continuous exposure will be within clinically achievable levels. The application of these in vivo and in vitro pharmacokinetic principles will provide for more physiological testing of patient tumor cell sensitivity to anticancer drugs in the HTCA, and is likely to result in lower rates of false positive responses in clinical trials using clonogenic cell assays.
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PMID:Application of in vivo and in vitro pharmacokinetics for physiologically relevant drug exposure in a human tumor clonogenic cell assay. 295 33


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