Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA topoisomerase I (topo I) is the molecular target for the camptothecin group of anticancer drugs. These drugs are showing activity against a wide array of human tumors. Many data have indicated that the sensitivity of a tumor cell to the camptothecins is dependent on tumor topo I levels. Drug-sensitive cells have high levels of topo I. Unfortunately, there is still a relative lack of information on topo I levels in human malignancies. Because of this, we investigated topo I activity and immunoprotein levels in a variety of normal murine and human tissues, as well as tissues obtained from several carcinomas, lymphomas, and sarcomas. Flow cytometric analysis was also performed on the neoplastic specimens to determine the percentage of cycling cells. Topo I catalytic activity was detected in all normal tissues at a fairly constant level. The average topo I catalytic activity in normal mammalian tissues was 2.7 +/- 1.3 x 10(4) units/mg protein (range 1.1 to 5.0 x 10(4)). Topo I catalytic activity was much more variable in human malignancies and ranged from a low of 1.4 x 10(4) units/mg protein in a rhabdomyosarcoma to a high of 160 x 10(4) units/mg protein in a poorly differentiated ovarian carcinoma. Western blot analysis with either a mouse monoclonal antibody or scleroderma antibodies directed against topo I revealed that the elevated topo I catalytic activity levels in the malignant tissues are due to elevated amounts of topo I immunoprotein. It is possible that the high topo I levels that characterize several different types of human malignancies might indicate that these tumors would be sensitive to many of the new drugs that target topo I.
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PMID:Elevations of DNA topoisomerase I catalytic activity and immunoprotein in human malignancies. 870 83

Our objective was to evaluate in vitro and in vivo the effect of the combination of trabectedin (Yondelis, ET-743) and irinotecan (CPT-11) or its major metabolite SN-38 in a human rhabdomyosarcoma cell line. The schedule trabectedin (1 h) followed by irinotecan or SN-38 (24 h) and the opposite sequence (irinotecan or SN-38 24 h followed by trabectedin 1 h) were analyzed in a rhabdomyosarcoma cell line. In vivo studies were conducted with trabectedin and irinotecan at the doses of 0.2 and 20 mg/kg, respectively, simultaneously administered with a q4d x 3 schedule. In vitro studies indicated an overall additive effect [combination index (CI) relatively close to 1.0], with the former schedule slightly superior to the latter (at the IC50 effect levels: CI=0.89 versus 1.07). Neither transcription nor expression of DNA topoisomerase I was affected by trabectedin treatment. In vivo the therapeutic results of the combination were certainly more impressive: trabectedin and irinotecan combination caused a strong and long-lasting effect on tumor growth (tumor volume inhibition=89%, log10 cell kill=1.6), whereas each drug given as a single agent was only marginally active. The discrepancy between the in vitro and in vivo results suggests possible mechanisms involving host cells, other than tumor cells. The striking effects of the combination observed in vivo could be related to a combination of a direct cytotoxic and an anti-inflammatory indirect effect. The very marked and long-lasting effect of the trabectedin and irinotecan combination in vivo suggests a basis for a clinical evaluation in pediatric patients with rhabdomyosarcoma.
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PMID:Combination of trabectedin and irinotecan is highly effective in a human rhabdomyosarcoma xenograft. 1609 28

Soft-tissue sarcomas (STS) include a spectrum of histologically and clinically different tumors. Patients with these tumors are typically relatively young and the course of disease is characterized by early metastasis as well as limited response to chemotherapy. However, a few subtypes, such as small round-cell tumors and rhabdomyosarcoma (other than pleomorphic), are considered chemotherapy sensitive. In addition, reflecting successful translational research of recent years, gastrointestinal stromal tumor and dermatofibrosarcoma protuberans have become model diseases for targeted oncologic therapy. We summarize current treatment options for metastatic STS, including established first-line chemotherapy approaches, mainly with anthracyclines and/or ifosfamide and second-line treatment choices beyond anthracyclines. Until only a few years ago, treatment choices for metastatic STS were easy to review because of the very limited number of active compounds available. However, with the advent of novel therapeutic strategies such as the anti-angiogenic approach and a multitude of novel compounds available both outside and within clinical studies, it has potentially become more difficult to keep track of currently available treatment options for STS and their clinical safety and efficacy. In this practice-oriented article, we therefore review treatment goals in advanced STS and provide an overview of compounds with proven activity in this setting. Anthracyclines with or without ifosfamide are still considered standard of care for most STS subtypes, especially for high-grade tumors. There is no evidence-based recommendation regarding use of second-line treatment options. However, a number of established compounds, including dacarbazine/temozolomide, gemcitabine, taxanes, trofosfamide, DNA topoisomerase I inhibitors, DNA minor groove binders, and bendamustine have shown activity. Recently, trabectedin, a DNA minor groove binder initially isolated from a sea sponge, has proven effective and received European approval for use in treatment-refractory STS. In addition, novel compounds such as bevacizumab, multi-tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, imatinib, and the thrombospondin agonist ABT 510 represent attractive partners for the above-mentioned cytostatic agents, or may even be effective single agents in the clinically advanced setting. Novel combinations are being evaluated in clinical studies. In order to be successful, it may be necessary to combine not only different compounds but also different targets beyond the proliferation machinery of sarcoma cells such as tumor angiogenesis, the tumor stromal compartment, or tumor cell oncogene products.
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PMID:Potential combination chemotherapy approaches for advanced adult-type soft-tissue sarcoma. 1857 72