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)

In an effort to improve the additive anti-tumor efficacy of commonly used alkylating agents, the topoisomerase-II inhibitor etoposide was used in combination with either the mitochondrial poison and energy-depleting agent lonidamine or the hemorheologic agent and tumor-blood-flow-increasing agent pentoxifylline. In the FSaIIC murine fibrosarcoma system, these modulators were evaluated for modulation of whole-tumor cell killing vs. bone-marrow CFU-GM toxicity with the alkylating drugs CDDP, CTX, L-PAM or BCNU. Etoposide alone was essentially additive with the alkylating drugs for both tumor-cell and bone-marrow killing, except for BCNU, where a substantial increase in tumor-cell killing occurred (0.5 to 2.0 logs over the dose range of BCNU tested) without a significant increase in bone-marrow toxicity. Etoposide plus lonidamine was significantly more active than etoposide alone only with CTX and BCNU in tumor-cell vs. bone-marrow killing. Etoposide plus pentoxifylline was also most active with these two alkylating agents, where increases in tumor-cell killing of 0.5 to 1.0 log were observed. Hoechst-33342-defined tumor-cell sub-population studies revealed that etoposide significantly improved the killing of dim (putative hypoxic) cells by CDDP, but neither lonidamine nor pentoxifylline significantly improved killing of bright or dim cells together. With CTX, etoposide plus lonidamine or pentoxifylline substantially improved killing of dim cells over etoposide alone (each by about 0.8 logs). These data indicate that a therapeutic advantage may be achievable by combining etoposide with lonidamine or pentoxifylline for use with alkylating drugs.
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PMID:Etoposide with lonidamine or pentoxifylline as modulators of alkylating agent activity in vivo. 204 6

Tumor necrosis factor (TNF) has confirmed anti-tumor activity. When used in combination with interferon gamma (IFNG) or chemotherapeutic drugs targeted at DNA topoisomerase II, synergistic cytotoxicity has been observed. Investigations of the anti-tumor activity of recombinant mouse TNF in a mouse bladder tumor model (MBT-2) were performed. The cytotoxicity of TNF and low dose actinomycin-D (AMD) against MBT-2 in vitro was examined alone and following preincubation with IFNG. The activity of TNF/AMD in vivo utilizing an intravesical implantation mode (MBT-2) was also evaluated. TNF alone had no cytotoxic effect in vitro. TNF/AMD was cytotoxic for MBT-2 growth in vitro. Maximum cytotoxicity (86%) occurred at one microgram./ml. TNF/one microgram./ml. AMD with 50% cytotoxicity at .64 micrograms./ml. TNF/one/microgram./ml. AMD. A two hour preincubation with IFNG markedly increased the cytotoxicity of TNF/AMD whereas longer incubations did not enhance cytotoxic activity. TNF alone and in combination with AMD did not significantly reduce the percentage of intravesical tumor outgrowth in vivo compared to controls. This study demonstrated that TNF/AMD exhibits cytotoxicity for MBT-2 cells in vitro but is ineffective in reducing implantation of intravesical tumors in vivo. The in vitro data suggest brief exposure of MBT-2 cells to IFNG augments the subsequent anti-tumor activity of TNF/AMD.
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PMID:In vitro and in vivo anti-tumor activity of recombinant mouse tumor necrosis factor (TNF) in a mouse bladder tumor (MBT-2). 211 89

We investigated the cytotoxic effects of recombinant tumor necrosis factor (TNF) alone and in combination with interferon-gamma (IFN-gamma) and/or cytotoxic drugs on a variety of human tumor cell lines (U937, IGROV-1, HT29, LoVo, MCF7 and U20S), including cell lines with in vitro acquired resistance (LoVo/DX and MCF7/DX selected for resistance to doxorubicin (DX) and characterized by pleiotropic drug resistance; U20S selected for resistance to cisplatin (CDDP], using MTT assay. U937 and MCF7 were sensitive to the cytotoxic effect of TNF, whereas all the other cells were insensitive up to 1000 U/ml (the maximum tested dose). Surprisingly, TNF was cytotoxic (30-40% cytotoxicity) against two resistant lines (LoVo/DX and U20S/Pt) but not against the parent sensitive lines. Treatment with increasing doses of TNF after 6 h incubation with a subtoxic concentration of IFN-gamma produced a synergistic effect in four cell lines (U937, HT29, LoVo/DX and MCF7), whereas in the other five the cell killing of the combination was comparable with that achieved by TNF alone. The combination of subtoxic doses of TNF and increasing doses of drugs targeted at DNA topoisomerase II (i.e. DX, actinomycin D and VP16) produced an additive cytotoxic effect in all cell lines. The same results were obtained combining TNF and CDDP, except in U20S/Pt cells in which TNF synergistically increased CDDP cytotoxicity. The combination of TNF and IFN-gamma enhanced cytotoxicity about 20-fold for DX and 6-fold for CDDP, evaluated in terms of the modification index, against LoVo/DX and U20S/Pt cells respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of tumor necrosis factor on human tumor cell lines sensitive and resistant to cytotoxic drugs, and its interaction with chemotherapeutic agents. 213 Oct 48

The time course of expression of topoisomerase I, topoisomerase II, and simian virus 40 (SV40) large tumor (T) antigen was determined in whole-cell extracts of uninfected versus SV40-infected TC7 cells. After a minor increase, the level of topoisomerase I remained fairly constant throughout the time course in both uninfected and SV40-infected cells. In contrast, the level of topoisomerase II increased markedly in SV40-infected cells but not in uninfected cells following the appearance of SV40 T antigen.
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PMID:Differential increase in topoisomerase II in simian virus 40-infected cells. 215 53

Streptozotocin (STZ) is a monofunctional nitrosourea employed in the treatment of patients with islet cell tumors. To analyze the role of DNA repair mechanisms in causing resistance to STZ, we evaluated the cytotoxicity by this agent in three human tumor lines that differ with respect to their abilities to repair N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) damaged virus (the Mer phenotype). HT-29, A2182, and BE human tumor lines are high, intermediate and low, respectively, with regard to features that define the Mer phenotype. Our results demonstrated that the order of resistance to STZ is HT-29 greater than A2182 greater than BE. The degree of inhibition of DNA synthesis by STZ was in the following order: BE greater than A2182 greater than HT-29. O6-Alkyltransferase activity was increased markedly in HT-29 cells compared to A2182 cells which, in turn, had significantly increased levels compared to the BE line. Other potential factors such as 3-methyladenine DNA glycosylase activity, the induction by STZ of single-stranded DNA breaks, and the kinetics of repair of these breaks do not clearly underlie differences in cytotoxicity among the three tumor lines. However, increased topoisomerase II activity, as well as enhanced sensitivity to agents that interact with topoisomerase II, was present in A2182 cells compared to BE cells. These findings demonstrate that while O6-alkyltransferase contributes to resistance to STZ in some Mer+ tumor lines, other mechanisms may also contribute to resistance to this agent.
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PMID:Mechanisms underlying resistance to streptozotocin in Mer+ and Mer- human tumor lines. 215 17

A combination of tumor necrosis factor (TNF) and the topoisomerase I inhibitor, camptothecin, or the topoisomerase II inhibitors, teniposide and amsacrine, produced dose-dependent synergistic cytotoxicity against the murine L929 fibrosarcoma cells. Similar synergy was not observed with a combination of TNF and bleomycin. To define the role of TNF in the augmentation of tumor cell killing by topoisomerase I or II inhibitors, the effect of TNF on the production of enzyme-linked DNA strand breaks induced in cells by topoisomerase inhibitors was investigated. L929 cells incubated for 1 h with the topoisomerase inhibitors contained protein-linked strand breaks. In contrast, TNF alone did not induce DNA strand breakage. However, when cells were incubated simultaneously with TNF and camptothecin, amsacrine, Adriamycin, actinomycin D, teniposide, or etoposide, increased numbers of strand breaks were produced. Preincubation of the cells with TNF for 30 min or 3 h before the addition of camptothecin or etoposide resulted in no more strand breaks than that observed in cells incubated with the drugs alone. TNF treatment of L929 cells produced a rapid and transient increase in specific activity of extractable topoisomerases I and II. These increases were maximum at 2-5 min of TNF treatment and by 30 min the activities of extractable enzymes were equal to or less than those detected in extracts from untreated cell controls. The transient nature of the increase in extractable topoisomerase activity may explain the kinetics and significance of the order of addition of TNF and inhibitors for maximal synergistic activity. These data are consistent also with a role for topoisomerase-linked DNA lesions in the TNF-mediated potentiation of killing of L929 cells by topoisomerase inhibitors.
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PMID:Potentiation of topoisomerase inhibitor-induced DNA strand breakage and cytotoxicity by tumor necrosis factor: enhancement of topoisomerase activity as a mechanism of potentiation. 215 96

The enzymes involved in the regulation of the three-dimensional structure of DNA, topoisomerase I and II, are important for the handling of DNA during vital cellular processes such as translation, transcription and mitosis. The enzymes are currently being studied intensively, they are being biochemically characterized and their mechanism of action is now better understood. Empirically discovered antitumor drugs appear to interfere with these enzymes, especially topoisomerase II. The DNA-topoisomerase II complex, which is an intermediate in the normal enzyme pathway, is stabilized by the drug and forms a 'cleavable complex', which appears to be cytotoxic. The drugs involved are, e.g. anthracyclines, epipodophyllotoxins and acridines. The central role of this enzyme offers the cell an opportunity for the development of resistance by down-regulation of this enzyme or the production of resistant mutants, provided the adaptation does not hamper other vital cell functions. Knowledge of the working mechanism and the cellular regulation of the topoisomerases might lead to the selection of most effective drugs and treatment schedules, and to circumvention of drug resistance.
Med Oncol Tumor Pharmacother 1990
PMID:Topoisomerases, new targets in cancer chemotherapy. 216 32

Adriamycin is commonly used as a chemotherapeutic agent and is known to intercalate into the major groove of DNA and inhibit DNA and RNA synthesis. Results presented in this communication suggest that adriamycin affects topoisomerase cleavage of DNA. The resultant change in negative superhelicity (decrease) is responsible for the decrease in transcription. This process is not dependent on the continued presence of adriamycin. The reaction between topoisomerases, DNA and adriamycin is dose-dependent. The results help to explain the relatively enhanced cytotoxicity of this drug to tumor cells.
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PMID:Inhibition of transcription by adriamycin is a consequence of the loss of negative superhelicity in DNA mediated by topoisomerase II. 216 Oct 74

NC-190, a benzophenazine derivative (N-beta-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxy-benzo[a]phenazine-6-carboxamide), was effective against multidrug-resistant human and mouse tumor cells in vitro and in vivo. When vincristine (VCR)-resistant P388 leukemia-bearing mice were treated with an optimal dose of NC-190, four of six mice were cured, whereas treatment of mice with VCR resulted in only a marginal increase in life span. The compound also showed chemotherapeutic effect against Adriamycin-resistant P388 leukemia-bearing mice and was effective against various multidrug-resistant human and murine tumor cells in vitro. Its cytotoxicity to multidrug-resistant K562 cells was not enhanced by the addition of verapamil. The accumulation of NC-190 in multidrug-resistant K562 cells was slightly lower than that observed in sensitive K562 cells; the compound did not efficiently inhibit the binding of VCR to the plasma membrane of resistant cells, indicating that NC-190 has little affinity for P-glycoprotein. NC-190 inhibited the activity of DNA topoisomerase II. These observations suggest that NC-190 (1) is not transported out of resistant cells by P-glycoprotein and (2) inhibits DNA topoisomerase II activity in the cells, resulting in its likely effectiveness against various multidrug-resistant tumor cells.
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PMID:A benzophenazine derivative, N-beta-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxy-benzo[a]phenazine-6-carboxamide, as a new antitumor agent against multidrug-resistant and sensitive tumors. 216 Dec 96

We have previously shown that blockade of the Na+,K(+)-pump by the cardiac glycoside ouabain produces doxorubicin resistance and decreases topoisomerase II-mediated DNA strand breakage in hamster cells. To determine if this were a general phenomenon, the effect of pump blockade on doxorubicin resistance was assessed in three human tumor cell lines: A549 lung and HT29 colon adenocarcinomas and U1 melanoma. When cells were exposed to 1 microM ouabain prior to and during incubation with doxorubicin, cytotoxicity was markedly reduced. Ouabain had no effect on either the influx or the efflux of doxorubicin. However, all cell lines showed a ouabain-induced decrease in doxorubicin-induced topoisomerase-mediated DNA strand breakage (SSB). These data suggest that blockade of the Na+,K+ pump decreases doxorubicin cytotoxicity in human tumor cells by inhibiting topoisomerase-mediated SSB. Furthermore, they indicate that altered ionic gradients are a potential cause of resistance to drugs that use topoisomerase II as a target.
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PMID:The influence of Na+,K(+)-pump blockade on doxorubicin-mediated cytotoxicity and DNA strand breakage in human tumor cells. 216 43


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