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)

CPT-11 and Topotecan are a new semisynthetic derivative of CPT, and have been shown to inhibit DNA topoisomerase I and to have a strong antitumor activity with low toxicity against murine tumor. On the other hard, the new antitumor compounds, NC-190 and IST-622 have been shown to inhibit DNA topoisomerase II, and the clinical study are currently under progress. A phase II study of CPT-11 demonstrated that CPT-11 was a very active agent which a acceptable toxicities against patient with advanced non-small cell lung cancer and small cell lung cancer.
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PMID:[DNA topoisomerase inhibitor]. 133 23

The topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts comprising four lines of adult colon adenocarcinoma, three colon tumors derived from adolescents, six childhood rhabdomyosarcomas from previously untreated patients as well as sublines selected in vivo for resistance to vincristine and melphalan, and three lines of childhood osteogenic sarcoma. Efficacy was determined at maximal tolerated dose levels using intermittent i.p. administration [every 4 days for 4 doses (q4dx4)] or daily p.o. or i.p. administration 5 days per week for up to 20 courses. On a q4dx4 schedule, the maximum tolerated dose (MTD) was 12.5 mg/kg per administration, which caused marked weight loss and lethality in approximately 5% of the tumor-bearing mice. This schedule caused significant growth inhibition (but no tumor regression) in advanced adult colon adenocarcinomas. The minimal treated/control (T/C) ratios were 0.49, 0.54, and 0.3 for three of the tumor lines and were achieved at 18-21 days after the initiation of treatment. In contrast, rhabdomyosarcomas were considerably more sensitive, with T/C ratios being < 0.1 for three lines, whereas topotecan was less active against two other rhabdomyosarcoma xenografts (minimal T/C ratios, 0.17 and 0.14). As inhibitors of topoisomerase I have been demonstrated to have activity in the replication phase of the cell cycle (S-phase-specific), prolonged administration schedules were examined. Mice received topotecan 5 days per week for 3 weeks either by i.p. injection or by oral gavage (p.o.). In selected experiments, p.o. administration was continued for up to 20 weeks. Oral administration for 3 weeks (2 mg/kg per dose) resulted in complete regression of all six lines of rhabdomyosarcoma, with two lines demonstrating no regrowth during the period of observation (> or = 84 days). Similar results were obtained after i.p. administration, suggesting significant schedule dependency for these tumors. For colon tumors, the daily administration schedule (i.p. or p.o.) demonstrated some advantage over the intermittent schedule, resulting in partial regressions and significant inhibition of the growth of several colon adenocarcinoma lines. In rhabdomyosarcoma Rh12 and VRC5 colon adenocarcinoma, both of which demonstrated intermediate sensitivity to topotecan, and in osteosarcoma OS33, protracted p.o. administration for 13-20 weeks (1.0-1.5 mg/kg per dose given daily x 5 days) caused complete regression without regrowth in Rh12 and OS33 tumors and partial regression of all VRC5 tumors. No toxicity was observed using this schedule of administration. Topotecan demonstrated significant activity against all three osteosarcoma xenografts examined, with optimal schedules causing complete regression in two lines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. 146 61

Genomic DNA was extracted from archival pathology specimens comprising 10 squamous and 14 adenocarcinomas, including 7 with Barrett's epithelium adjacent to tumor, and corresponding normal esophagus from the resection margin. The polymerase chain reaction was used to amplify selected exons of p53 which were analyzed for mutations using single-strand conformation polymorphism analysis. Mutations were localized to exon 8 for 1 adenocarcinoma and to exon 5 for 1 squamous tumor and 4 of 7 Barrett's specimens. Sequencing confirmed mutations at codons 273 (CGT----CAT; adenocarcinoma) and 176 (TGC----TTC; squamous) and in Barrett's epithelium at codons 152 (CCG----CTG), 155 (ACC----GCC) and 175 (CGC----CAC). Specimens of Barrett's epithelium from separate sites had identical p53 mutations suggesting a clonal origin. Cancers arising in mutant epithelium did not have mutations corresponding to those found in the Barrett's specimens suggesting that other events are required for tumorigenesis.
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PMID:p53 gene mutations in Barrett's epithelium and esophageal cancer. 186 73

The article presents the influence of silicon carbide upon an organism, on the basis of the publications which, according to Chemical Abstracts, appeared on this subject from 1944 until 1987. The insolubility of silicon carbide, in the liquids of an organism and its indigestibility are indicated. A connection is presented between the size and shape of micrograins and the probability of tumor formation in rats; and the difference between silicon carbide and other dusts in the absorption of x-rays, inhibition of the TTC-dehydrogenase activity, collagenisation of lesions, carcinogenicity are also presented. The problem of interpretation of radiological images of lungs in people exposed to the influence of carborundum dust is dealt with. The biological inertness of silicon carbide is questioned.
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PMID:Pathogenic and carcinogenic properties of silicon carbide. 248 17

The authors consider some difficulties in the roentgenological interpretation of the filling defect in the biliary tracts revealed by a direct contrast study using the TTC or ERCG methods. The greatest difficulties are observed in the presence of the parietal defect that can be determined by an undisplaceable concrement, a small polypoid cancer of the duct and metastases to the lymph nodes, the lesser omentum along the common bile and hepatic ducts. To differentiate between these diseases one should bear in mind a degree of outlining the filling defect with a contrast medium, the presence of a constricted area below the defect, local tenderness, and bile infectiousness. The authors also consider a problem of how to interpret the symptom of a "snake mouth" or a "concave lens" which (depending on its cause) can be either transient (in a large concrement) or stable (in an exophytic tumor, completely occluding the duct).
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PMID:[Difficulties in the differential x-ray diagnosis of choledocholithiasis]. 274 24

The efficacy of protracted schedules of therapy of the topoisomerase I inhibitors 9-dimethyl-aminomethyl-10-hydroxycamptothecin (topotecan) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (irinotecan; CPT-11) were evaluated against a panel of 21 human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas, representing an intrinsically chemorefractory malignancy, six lines derived from childhood rhabdomyosarcoma (three embryonal, three alveolar) representing a chemoresponsive histiotype, sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine and melphalan, and three pediatric brain tumors. All tumors were grown at the subcutaneous site. Topotecan was administered by oral gavage 5 days per week for 12 consecutive weeks. The maximum tolerated dose (MTD) was 1.5 mg/kg per dose. Irinotecan was given by i.v. administration daily for 5 days each week for 2 weeks [(d x 5)2](one cycle of therapy), repeated every 21 days. The MTD for three cycles was 10 mg/kg per dose. Treatment was started against advanced tumors. Topotecan caused a high frequency of objective regressions in one of eight colon tumor lines, whereas irinotecan caused complete regressions (CR) of all tumors in three colon lines and a high frequency of CRs in three additional lines. Both drugs demonstrated similar activity against rhabdomyosarcoma xenografts. Topotecan caused CR of all tumors in four of six lines, and irinotecan in five of six lines evaluated. Both agents retained full activity against tumors selected for primary resistance to vincristine, but only irinotecan retained activity against a tumor selected for primary resistance to melphalan. Both agents demonstrated good activity against brain tumor xenografts with irinotecan causing CR in two of three lines and topotecan inducing CR in one of three lines. Results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either equi-effective or more efficacious than more intense shorter schedules of administration reported previously.
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PMID:Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. 763 81

We have assessed the antiproliferative effects of a 24-hr exposure to the topoisomerase I inhibitors, topotecan and camptothecin, on two colon and one ovarian human tumor cell lines, cultured as subconfluent and as multilayered postconfluent cultures. Chemosensitivity was measured by the sulforhodamine B assay. In general, postconfluent cultures were less sensitive to these agents, yielding GI50S (drug concentrations inhibiting growth by 50%) from 1.2 to more than 6000 times higher than those of subconfluent cultures. Both compounds displayed similar effects on subconfluent cells, inducing complete growth inhibition at concentrations ranging from 0.03 to 0.5 microM. Topotecan, however, was more potent than camptothecin in two out of the three cell lines tested as multilayered postconfluent cultures. Topoisomerase I mRNA expression on postconfluent cultures was 50% lower than on subconfluent cultures in the three cell lines studied. However, we did not detect any reproducible differences in topoisomerase I protein expression and in relaxation activity of supercoiled DNA between the two types of cultures. From accumulation experiments it appeared that the peak concentration of the lactone form of topotecan as well as the area under the concentration-time curve (AUC) were 2-fold higher in the monolayer than in the multilayer cultures. Therefore, the differences in the activity of topoisomerase I inhibitors under our experimental conditions were likely due to a decreased rate of proliferation of postconfluent cells, associated with a reduction in drug uptake.
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PMID:Antiproliferative activity of the topoisomerase I inhibitors topotecan and camptothecin, on sub- and postconfluent tumor cell cultures. 794 8

The activity of dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts derived from ependymomas (D528 EP, D612 EP), childhood high-grade gliomas (D-456 MG, D-212 MG), adult high-grade gliomas (D-245 MG, D-54 MG), and medulloblastomas (D425 Med) growing s.c. and i.c. (intracranially) in athymic nude mice. Topotecan was given at a dose of 1.9 mg/kg by i.p. injection in 0.9% saline using a volume of 90 ml/m2 on days 1-5 and 8-12, which represents the dose lethal to 10% of treated animals. Topotecan was active in the therapy of all s.c. xenografts tested, with growth delays ranging from 6.3 days in D-54 MG to 55.7 days in D528 EP. Topotecan produced statistically significant tumor regressions in D425 Med, D-456 MG, D-245 MG, D528 EP, and D612 EP. No tumor regression was seen in any control animal. Statistically significant increases in median survival were seen in the two i.c. xenografts--D-456 MG (28.6% increase) and D-54 MG (39% increase)--treated with topotecan. These studies suggest that topotecan may be an important new addition to the therapy of central nervous system tumors.
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PMID:Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts. 819 69

Topoisomerase I and topoisomerase II allow a metabolically active cell to mobilize its supercoiled chromosomal DNA and undergo replication, transcription, recombination, and repair. Several topoisomerase inhibitors have recently been shown to be active in preclinical systems. Topotecan (SK&F 104,864), a water-soluble camptothecin analog, is an inhibitor of topoisomerase I. Novobiocin is an inhibitor of topoisomerase II. Lonidamine depletes cellular adenosine 5'-triphosphate (ATP) and may impede energy-dependent DNA repair, MCF-7 human breast-cancer cells were treated in vitro with topotecan, novobiocin, and lonidamine alone, in paired combinations, and in combination with CDDP and melphalan. The three enzyme inhibitors alone and in combination did not increase tumor cell sensitivity to CDDP. However, the combinations of topotecan/novobiocin and lonidamine/novobiocin did enhance the cytotoxicity of melphalan. Mice bearing the FSaII fibrosarcoma were treated in vivo with topotecan, novobiocin, and lonidamine alone, in paired combinations, and in combination with CDDP, melphalan, BCNU, and cyclophosphamide. The combination of topotecan/novobiocin had the greatest impact on tumor cell sensitivity to each cytotoxic agent tested in both tumor cell-survival and tumor growth-delay assays. This sensitization was greatest at the highest concentrations of the cytotoxic agent tested. Combinations of topoisomerase I and topoisomerase II inhibitors may be useful as modulators of antitumor alkylating agents.
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PMID:Modulation of antitumor alkylating agents by novobiocin, topotecan, and lonidamine. 825 94

The cytotoxicity of the topoisomerase I inhibitors, camptothecin and topotecan, toward exponentially growing EMT-6 murine mammary carcinoma cells under various conditions of oxygenation, pH and temperature was assessed. Under normal pH (pH 7.40) conditions both camptothecin and topotecan were more cytotoxic toward normally oxygenated cells. Both agents were more cytotoxic under acidic pH (pH 6.45) and the differential in cytotoxicity due to the cellular oxygenation level disappeared. Neither camptothecin nor topotecan was enhanced in cytotoxicity by hyperthermia (42 degrees C or 43 degrees C, 60 min) during drug exposure. Both camptothecin and topotecan killed increasing numbers of FSaIIC tumor cells with increasing dose of the drugs in vivo in a log/linear manner. Local hyperthermia (43 degrees C, 30 min) increased the tumor cell killing of the drugs but decreased the toxicity of these agents to the bone marrow granulocyte/macrophage-colony-forming units. Topotecan was a more effective modulator of cisplatin than was camptothecin, as determined by FSaIIC tumor cell survival assay and by FSaIIC tumor growth delay. Although both camptothecin and topotecan were effective additions to a treatment regimen including cisplatin and daily fractionated radiation (5 x 3Gy), neither of these topoisomerase I inhibitors increased the tumor growth delay produced by the trimodality regimen of cisplatin/hyperthermia/radiation.
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PMID:Addition of a topoisomerase I inhibitor to trimodality therapy [cis-diamminedichloroplatinum(II)/heat/radiation] in a murine tumor. 839 65


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