Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the concluding section of this review of cancer destruction by disruption of energy metabolism, the cellular mechanism for interfering with energy production is considered in terms of drug resistance arising independently of previous tumor injury. The occurrence of various degrees of damage to cancerous growths as a consequence of secondary shock is interpreted on the basis of elevated levels of stress hormones, including vasopressin, which have earlier been shown to interfere with energy metabolism in a murine sarcoma. Similarly, the indirect action of various antineoplastic procedures can be related to a role for the endocrine system, with particular reference to vasopressin and inappropriate anti-diuretic hormone secretion syndrome. Multiple drug resistance is also discussed, and the mode of action of the topoisomerase inhibitor doxorubicin is critically examined. The basis of selectivity of disruption of energy metabolism by substances such as hydralazine and L-isoproterenol is discussed from the viewpoint of altered activities of antioxidant enzymes in transformed cells, but these considerations alone are not thought to be sufficient to account for the highly specific nature of the antineoplastic action. Conversely, antioxidant enzymes, more especially those concerned with glutathione metabolism, probably play a major role in multiple drug resistance, although in this respect the case of autoxidative cellular injury awaits attention. Theoretical strategies for the intensification of tumor injury include the aim of prolonging the half-lives of lysophosphatides within damaged tissue. Whereas the clinical application of the principle of tumor destruction through selective disruption of energy metabolism is at present compromised for lack of information, the use of phenothiazines as antineoplastic agents is feasible, and awaits serious exploitation. The relative lack of incapacitating side-effects of phenothiazines should provide an attractive change for the clinical oncologist.
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PMID:Cancer destruction in vivo through disrupted energy metabolism. Part III. Spontaneous drug resistance, selectivity of antineoplastic action, and strategies for intensifying tumor injury. 146 33

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin- 7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) was evaluated for antitumor activity against a spectrum of tumor systems in culture and in mice. NSC 370147 was cytotoxic to a variety of mouse and human cell lines at nanomolar concentrations. The compound exhibited good in vivo antitumor activity against several murine tumors (P388 and L1210 leukemia, colon 11/A and 36, mammary 16/C, and M5076 sarcoma). Activity was largely independent of route of administration but favored a prolonged treatment schedule. NSC 370147 was as active against murine leukemia sublines resistant to Adriamycin, amsacrine, vincristine, melphalan, cisplatin, methotrexate, and CI-920 (a topoisomerase II inhibitor) as against the corresponding parental lines. Only the 1-beta-D-arabinofuranosylcytosine-resistant P388 subline exhibited any cross-resistance to NSC 370147. NSC 370147 has a spectrum of activity similar to that of vincristine and, unlike vincristine, is active against multidrug-resistant cell lines. Therefore, NSC 370147 is a candidate for clinical trial because of its favorable activity compared to vincristine, its effectiveness against multidrug-resistant cells, and its retention of activity for p.o. administration.
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PMID:Antitumor activity of ethyl 5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido [3,4-b]pyrazin-7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) against selected tumor systems in culture and in mice. 233 19

Oxygen is thought to be involved both directly and indirectly in the mechanisms of action of several anti-cancer agents. We studied the effects of various oxygen concentrations on the cytotoxicities of the following drugs: bleomycin (BLM), etoposide (VP-16), doxorubicin (DOX), and mitomycin C (MMC). Human sarcoma cells, MESSA, were exposed to drug for 1 h at one of several oxygen concentrations: less than 1%, 2.5%, 5%, 21%, and 95%. Cytotoxicity was assessed by cellular incorporation of 3H-thymidine into DNA 5 days after drug exposure. Control experiments varying oxygen concentration without drugs demonstrated toxicity only at the highest concentration (95%). Three different responses of drug sensitivity to varying oxygen tensions were observed. BLM, which has been shown to utilize oxygen as a substrate in generating free radicals and producing DNA scission, demonstrated a progressive increase in cytotoxicity over the entire range of increasing oxygen concentrations. This is consistent with the model of a BLM-cation-oxygen complex and catalytic reduction of oxygen. VP-16, which also produces DNA strand breakage but by interaction with topoisomerase II, exhibited a threshold response. VP-16 toxicity was ameliorated by anoxic conditions (less than 1% O2), but not by oxygen concentrations of 2.5%-95%. The reason for this protective effect of anoxia with VP-16 is not clear. In contrast, acute anoxia had no effect on the cytotoxicities of DOX and MMC. We conclude that acute hypoxia protects cells from both BLM and VP-16 but that the nature of that protection is different. VP-16 toxicity is blunted only by severe anoxia, whereas BLM exhibits a dose response effect over the entire range of oxygen concentrations.
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PMID:Differential protective effects of varying degrees of hypoxia on the cytotoxicities of etoposide and bleomycin. 243 23

Several fused tri- and tetracyclic quinolines (I and II) with [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino or [3-(N,N-dimethylamino)propyl]amino side chains were prepared, and their DNA intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. Some compounds having both intercalative ability and KB cytotoxicity were found to be inactive in vivo. However, a positive correlation was seen between the ability to induce topoisomerase II dependent DNA cleavage and antitumor activity in vivo. The indeno- (13a), benzofuro- (21a), and benzothieno- (22a) quinoline derivatives exhibited potent antitumor activities in vitro and in vivo, comparable to those of m-AMSA. They also intercalate DNA and induce topoisomerase II dependent DNA cleavage. Extended screening of 13a showed it to be active against solid tumors such as M5076 sarcoma, B16 melanoma, and colon 38 carcinoma.
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PMID:Synthesis and antitumor activity of fused tetracyclic quinoline derivatives. 1. 254 58

The activities of topoisomerases I and II were assayed in subcellular extracts obtained from nontumorigenic BALB/c 3T3 A31 and normal rat kidney (NRK) cell lines and from the same cells transformed by benzo[a]pyrene (BP-A31), Moloney (M-MSV-A31) and Kirsten (K-A31) sarcoma viruses, and simian virus 40 (SV-NRK). The enzymatic activity of topoisomerase I was monitored by the relaxation of negatively supercoiled pBR322 DNA and by the formation of covalent complexes between 32P-labeled DNA and topoisomerase I. Topoisomerase II activity was determined by decatenation of kinetoplast DNA (k-DNA). It was found that nuclear and cytoplasmic type I topoisomerase specific activities were higher in every transformed cell line than in the normal counterparts. These differences cannot be attributed to an inhibitory factor present in A31 cells. When chromatin was treated at increasing ionic strengths, the 0.4 M NaCl extract showed the highest topoisomerase I specific activity. Moreover, in this fraction the transformed cells exhibited the most significant increment in the enzymatic activity as compared with nontransformed cultures. Spontaneously transformed A31 cells showed topoisomerase I activity similar to that of extracts of cells transformed by benzo[a]pyrene. Topoisomerase II specific activity was also increased in SV-NRK cells, as judged by the assay for decatenation of k-DNA to yield minicircle DNA.
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PMID:Increment of DNA topoisomerases in chemically and virally transformed cells. 283 Oct 71

The effects of verapamil on the cytotoxicity and accumulation of multiple drugs were studied in a model of pleiotropic resistance generated by doxorubicin (DOX) selection of the human sarcoma cell line MES-SA. The in vitro sensitivity of the DOX-resistant variant (named Dx5), which is 50- to 100-fold resistant to DOX compared to MES-SA, was enhanced approximately 7-fold by verapamil (3 micrograms/ml). In addition, the cytotoxicity of several agents to which the Dx5 line displays cross-resistance, i.e., daunorubicin, dactinomycin, mitoxantrone, and etoposide, was also enhanced 2- to 14-fold by verapamil. These agents share the properties of DNA intercalation and/or interaction with topoisomerase II. In contrast, verapamil did not alter the sensitivity of Dx5 to several other agents to which cross-resistance had been demonstrated, i.e., vincristine, vinblastine, colchicine, mitomycin C, and melphalan; nor did verapamil enhance the cytotoxicity of DOX or other agents against the DOX-sensitive parent, MES-SA. The sensitizing effect of verapamil did not correlate well with its effects on intracellular drug accumulation. [14C]DPX accumulation was increased by 30-40% in Dx5 but not in MES-SA cells in the presence of verapamil. [3H]Vinblastine accumulation was increased by 24-72% in both MES-SA and Dx5 cells in the presence of verapamil, although cytotoxicity of the Vinca alkaloids was not affected. In this human sarcoma model of DOX-selected pleiotropic resistance, verapamil partially reversed the resistance to DOX, as well as four of the nine drugs for which cross-resistance had been demonstrated in Dx5. The potentiation by verapamil of the cytotoxicity of some but not all of these antitumor agents suggests that factors other than altered drug transport may be responsible. The pattern of sensitization, restricted to agents which produce DNA strand scission by interaction with topoisomerase II, suggests that verapamil may be acting to promote the formation or inhibit the repair of such DNA strand breaks.
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PMID:Verapamil-mediated sensitization of doxorubicin-selected pleiotropic resistance in human sarcoma cells: selectivity for drugs which produce DNA scission. 375 87

The cytotoxic activity and cross-resistance pattern of the novel topoisomerase I inhibitor topotecan (Topo) were investigated in ten cell lines, representing different mechanisms of cytotoxic drug resistance, and in 218 fresh human tumour samples using the fluorometric microculture cytotoxicity assay (FMCA). Resistance to Topo in the cell lines was associated with expression of the multidrug resistance-associated protein (MRP), whereas the cell lines with P-glycoprotein (P-gp), topoisomerase II and glutathione-associated resistance did not show decreased sensitivity to the drug. Topo was more active in haematological than in solid tumour samples, but substantial activity was observed in carcinomas of the ovary and breast, sarcoma and childhood solid tumours. Cross-resistance to standard drugs representing different mechanisms of action was generally low in patient cells. The effect of Topo was better after longer exposure, but this time-dependent effect was largely abolished when adjustment for in vitro exposure was made. Topo showed activity both in proliferative and non-proliferative cell systems. The results indicate that Topo is insensitive to major mechanisms of resistance except for MRP. Proliferation does not seem to be necessary for the effect of Topo, and no superiority for protracted dosing schedules was observed. The results also suggest that, for example, leukaemias, lymphomas, sarcomas and childhood solid tumours may be suitable targets for future phase II trials.
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PMID:Cytotoxic activity of topotecan in human tumour cell lines and primary cultures of human tumour cells from patients. 923 21

The antineoplastic action and development of drug resistance are reviewed for chemotherapeutic agents used in the treatment of sarcoma, including alkylating agents (cyclophosphamide, ifosphamide, dacarbazine), platinum compounds (cisplatin, carboplatin), the anthracycline compound doxorubicin, the topoisomerase II inhibitor etoposide, and the taxanes (paclitaxel, taxotere). Drug resistance mechanisms discussed include changes in intracellular glutathione and metallothione levels, increased aldehyde dehydrogenase levels, enhanced DNA repair and protection from apoptosis (for alkylating agents); increased 0-6 alkyltranferase levels (for dacarbazine); multidrug resistance 1- and multidrug resistance associated protein-mediated drug export from cells (anthracyclines, taxanes); and structural alteration of microtubules (taxanes).
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PMID:Drug resistance in the treatment of sarcomas. 934 25

The polyanionic species suramin is a potential anti-cancer agent of narrow therapeutic index. Among other pharmacological characteristics, suramin is an inhibitor of angiogenesis. We have targeted its angiostatic properties as part of a program to discover less toxic analogs. From screening a series of commercially available compounds, structurally related to suramin and containing a sulfonic acid substituted naphthylamine moiety, we discovered a new lead, Eriochrome Black T (EBT). EBT is a novel inhibitor of angiogenesis, more potent and less toxic than suramin in the chick chorioallantoic membrane assay. EBT was more active than suramin in inhibiting endothelial cell proliferation in primary culture and in inhibiting proliferation of three tumor cell lines, A431, L1210 and M5076 (IC50 10-100 microM). Cell cycle studies on the A431 line showed that both EBT and suramin caused an accumulation of cells in the S phase, EBT being 10-fold more potent. We suggest that this cell cycle perturbation is linked to inhibition of topoisomerase II catalytic activity. EBT was found to be a moderate but significant inhibitor of matrix metalloproteinases (10 microM range), more efficient than suramin. In a s.c. M5076 sarcoma model in mice, EBT had similar efficacy to suramin both by the i.p. or s.c. route and was moreover better tolerated. Combined pharmacological results show that EBT compared favorably with suramin in all assays, and that in ovo and in vivo, EBT is an analog of suramin with diminished toxicity.
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PMID:Eriochrome Black T, structurally related to suramin, inhibits angiogenesis and tumor growth in vivo. 939 18

CPT-11, a semi-synthetic derivative of camptothecin, was investigated for its activity in panels of 15 human ovarian-cancer lines and 10 human soft-tissue sarcoma lines grown s.c. in nude mice. Various factors were analyzed that may be of influence on the extent of tumor-growth inhibition induced by CPT-11. At equitoxic doses, CPT-11 was more effective in the daily x5 schedule than the weekly x2 schedule, although a 2-fold higher dose was administered in the weekly x2 schedule. Since i.p. and i.v. injections were similarly effective, the selected treatment schedule was 20 mg/kg i.p. daily x5, starting when tumors measured approximately 150 mm3. Growth inhibition of > or = 75% was obtained in 8/15 human ovarian-cancer lines and in 6/10 human soft-tissue sarcoma lines. A weak correlation was found between topoisomerase-I mRNA in xenograft tissues and sensitivity to CPT-11. Relative topoisomerase-I expression was highest in MRI-H-207 and WLS-160 xenografts, in which CPT-11 was able to induce cures of all tumors. The high efficacy in the 2 panels of human tumor lines suggests over-prediction of its potential clinical activity in these tumor types. The difference in efficacy of CPT-11 between species may be related to the metabolism of the drug, since CPT-11 is converted more efficiently into SN-38 in mice. In addition, mice may be less sensitive to SN-38-induced side-effects. On the basis of the preclinical data, frequent administration of lower doses of CPT-11 should be considered in order to increase response rates in the clinic.
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PMID:Anti-tumor activity of CPT-11 in experimental human ovarian cancer and human soft-tissue sarcoma. 939 72


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