Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ICRF-159 is active in several animal tumor model systems and human adult malignancies. In this phase II study, ICRF-159 was given on a weekly schedule, 3000 mg/m2/day, orally in three divided doses at 6-hour intervals to 78 children with a variety of malignant neoplasms. Fifty-three patients were evaluable for tumor response. Toxicity was primarily hematopoietic and gastrointestinal. There were no responses in any of the eight patients with osteogenic sarcoma, four with lymphoma, five with Ewing's sarcoma, ten with neuroblastoma, or six with rhabdomyosarcoma. There was a transient partial response in one of four children with Wilms' tumor. Further trials with this drug using this schedule are not indicated for the common childhood solid tumors.
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PMID:ICRF-159 (razoxane) in the treatment of pediatric solid tumors: a Southwest Oncology Group study. 47 12

The cytostatic and antimetastatic activities of 1,2-di(3,5-dioxopiperazin-1-yl) propane (ICRF-159, razoxane) were studied in a transplantable, slowly growing osteosarcoma in Sprague-Dawley rats. This tumor model is characterized by osteoid formation and spontaneous metastasization to lungs, kidneys and lymph nodes. Razoxane given intraperitoneally (i.p.) from 2 days before to 14 days after tumor transplantation (30 mg/kg or 10 mg/kg per day) resulted in a dose-dependent prolongation of median survival time (83 or 48 days respectively, versus 38 days for the control group), but showed no influence on the growth of the primary tumor. Early treatment with razoxane (30 mg/kg i.p. from day -2 to +14) showed a greater inhibition of pulmonary metastases than later treatment (30 mg/kg i.p. from day +14 to +28 after transplantation). Whereas 59.9 per cent of the total sectional area of the lungs in the control animals was covered by osteosarcoma metastases, only 3.4 per cent and 26.1 per cent respectively was affected in the early and late razoxane treatment groups. Toxic side-effects of these treatment schedules were reversible diffuse alopecia, but no retardation of body weight gain.
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PMID:Antimetastatic effects of razoxane in a rat osteosarcoma model. 347 Jan 64

Patients with objectively measurable soft tissue sarcomas, osteosarcomas, chondrosarcomas, and mesotheliomas were treated with dibromodulcitol (DBD) (180 mg/m2 p.o. days 1-10 q4 wks.). ICRF-159 (300 mg/m2 p.o. tid days 1-3 q4 wks), or maytansine (MAYT) (1.5 mg/m2 I.V. q3 wks.). Forty-five evaluable patients received DBD, 47 MAYT, and 37 ICRF-159. Only patients who had had their histopathologic diagnoses confirmed by a pathology reference panel were included in the final analysis. Two patients had objective partial responses: a patient with osteosarcoma who responded to DBD and a patient with fibrosarcoma who had a partial response of brief duration to ICRF-159. Approximately 70% of the patients treated with each drug were of ECOG performance status 0 or 1, and over half had moderate or worse toxicity. It seems unlikely that these drugs have significant therapeutic activity for common mesenchymal malignancies.
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PMID:Phase II evaluation of dibromodulcitol, ICRF-159, and maytansine for sarcomas. 695 36

DNA topoisomerase II is an essential nuclear enzyme for proliferation of eukaryotic cells and plays important roles in many aspects of DNA processes. In this report, we have demonstrated that the catalytic activity of topoisomerase IIalpha, as measured by decatenation of kinetoplast DNA and by relaxation of negatively supercoiled DNA, was stimulated approximately 2-3-fold by the tumor suppressor p53 protein. In order to determine the mechanism by which p53 activates the enzyme, the effects of p53 on the topoisomerase IIalpha-mediated DNA cleavage/religation equilibrium were assessed using the prototypical topoisomerase II poison, etoposide. p53 had no effect on the ability of the enzyme to make double-stranded DNA break and religate linear DNA, indicating that the stimulation of the enzyme catalytic activity by p53 was not due to alteration in the formation of covalent cleavable complexes formed between topoisomerase IIalpha and DNA. The effects of p53 on the catalytic inhibition of topoisomerase IIalpha were examined using a specific catalytic inhibitor, ICRF-193, which blocks the ATP hydrolysis step of the enzyme catalytic cycle. Clearly manifested in decatenation and relaxation assays, p53 reduced the catalytic inhibition of topoisomerase IIalpha by ICRF-193. ATP hydrolysis assays revealed that the ATPase activity of topoisomerase IIalpha was specifically enhanced by p53. Immunoprecipitation experiments revealed that p53 physically interacts with topoisomerase IIalpha to form molecular complexes without a double-stranded DNA intermediary in vitro. To investigate whether p53 stimulates the catalytic activity of topoisomerase II in vivo, we expressed wild-type and mutant p53 in Saos-2 osteosarcoma cells lacking functional p53. Wild-type, but not mutant, p53 stimulated topoisomerase II activity in nuclear extract from these transfected cells. Our data propose a new role for p53 to modulate the catalytic activity of topoisomerase IIalpha. Taken together, we suggest that the p53-mediated response of the cell cycle to DNA damage may involve activation of topoisomerase IIalpha.
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PMID:The p53 tumor suppressor stimulates the catalytic activity of human topoisomerase IIalpha by enhancing the rate of ATP hydrolysis. 1076 86

We present a new approach to the handling and interrogating of large flow cytometry data where cell status and function can be described, at the population level, by global descriptors such as distribution mean or co-efficient of variation experimental data. Here we link the "real" data to initialise a computer simulation of the cell cycle that mimics the evolution of individual cells within a larger population and simulates the associated changes in fluorescence intensity of functional reporters. The model is based on stochastic formulations of cell cycle progression and cell division and uses evolutionary algorithms, allied to further experimental data sets, to optimise the system variables. At the population level, the in-silico cells provide the same statistical distributions of fluorescence as their real counterparts; in addition the model maintains information at the single cell level. The cell model is demonstrated in the analysis of cell cycle perturbation in human osteosarcoma tumour cells, using the topoisomerase II inhibitor, ICRF-193. The simulation gives a continuous temporal description of the pharmacodynamics between discrete experimental analysis points with a 24 hour interval; providing quantitative assessment of inter-mitotic time variation, drug interaction time constants and sub-population fractions within normal and polyploid cell cycles. Repeated simulations indicate a model accuracy of +/-5%. The development of a simulated cell model, initialized and calibrated by reference to experimental data, provides an analysis tool in which biological knowledge can be obtained directly via interrogation of the in-silico cell population. It is envisaged that this approach to the study of cell biology by simulating a virtual cell population pertinent to the data available can be applied to "generic" cell-based outputs including experimental data from imaging platforms.
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PMID:Flow-based cytometric analysis of cell cycle via simulated cell populations. 2041 43