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At least 127 records · Page 7Linked to original sources
PubMed2004

Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas.

PURPOSE: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas. EXPERIMENTAL DESIGN: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m(2) twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment. RESULTS: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months. CONCLUSIONS: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.

Adult↗
PubMed1981

Effect of interferon administration on pulmonary osteogenic sarcomas in an experimental murine model.

The iv inoculation of a suspension of osteogenic sarcoma cells induced metastatic tumor nodules in the lungs of C57BL/6 mice. The administration of 50,000-100,000 U of interferon daily for 7 days strikingly reduced the tumor mass in the lung and the number of tumor nodules present in histopathologic sections when the interferon treatment was initiated immediately after tumor cell inoculation. In some animals the development of any detectable metastatic lesion was completely prevented. Extending the therapy form 7 days to 21 days failed to improve the protective effect. Interferon therapy delayed until 7 days after tumor cell inoculation had no effect. These findings indicate the effectiveness of exogenous interferon in this murine osteogenic sarcoma model when interferon treatment is initiated within 1 hour of tumor cell inoculation, but not when it is delayed until tumor nodules are established in the lungs.

Animals↗
PubMed2006

A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma.

PURPOSE: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. EXPERIMENTAL DESIGN: Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. RESULTS: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. CONCLUSIONS: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.

Adult↗
PubMed2003

Experimental approaches to treatment of soft tissue sarcoma.

The experimental approaches described in this article represent potential new approaches for targeted therapy. Thus far, none of the preclinical data have demonstrated a cure for sarcomas; however, the antitumor effects of many of these new agents seem to be enhanced when the agents are combined with chemotherapeutic agents. The combination of novel therapeutics with conventional chemotherapy may be the most effective strategy in terms of maximization of tumor killing and minimization of toxicity and the risk of drug resistance. Not only are new drugs being developed for treatment of sarcomas but new ways of delivering drugs are also being investigated. The angiogenic, or metronomic, schedule of drug delivery may be preferable to conventional schedules in achieving optimal tumor inhibition. In addition, isolated limb perfusion is a unique approach to delivery of drugs, such as TNF and melphalan, for sarcomas and melanomas [137, 138]. The advantages of this method of drug delivery include the ability to administer therapeutic agents in high concentrations to a specific region of the body without systemic toxicity. Further advances in the understanding of the biology of sarcomas along with novel approaches to delivery of drugs are crucial to the development of new and effective therapies.

Angiogenesis Inhibitors↗
PubMed1987

Role of insulin in development of cancer cachexia in nongrowing sarcoma-bearing mice: special reference to muscle wasting.

This study evaluated whether altered insulin metabolism is a key factor behind weight loss during sarcoma growth in nongrowing mice (C57BL/6J). Fasted sarcoma-bearing mice had decreased blood glucose concentrations but unchanged levels of insulin, compared with those in pair-weighed and freely fed controls. During refeeding, insulin levels were inappropriately low for the degree of glycemia in sarcoma-bearing mice compared with those of pair-weighed and freely fed controls. Injections ip of glucose to tumor-bearing animals resulted in insulin levels comparable to postabsorptive values in healthy control animals, indicating that hypoinsulinemia in freely eating tumor-bearing animals was due to a reduced glycemic sensitivity for pancreatic insulin release. Insulin supplementation at doses [4 IU/100 g (body wt)] that increase body fat in normal animals could not protect the tumor-bearing host from progressive loss of body fat or lean tissues. Exogenous insulin in excess of endogenous insulin production did not stimulate tumor growth. Nitrogen and RNA-DNA content were significantly decreased in the quadriceps muscle of tumor-bearing mice. This reduction was independent of altered insulin levels and could not be prevented by exogenous insulin. The depressed capacity of protein synthesis in extensor digitorum longus (EDL) muscle could be entirely attributed to the state of malnutrition in tumor-bearing animals. The sensitivity and responsiveness of protein synthesis in EDL muscles to insulin were normal in tumor-bearing mice, regardless of whether exogenous insulin exerted its effect in vivo or in vitro. This study confirms insulin resistance for glucose metabolism in an experimental sarcoma animal model. Such changes are concluded to be secondary to anorexia and necessary to counteract hypoglycemia. In non-growing sarcoma-bearing mice, malnutrition and anorexia account entirely for depressed muscle protein synthesis, which is not explained by insulin resistance at the translational level. Insulin metabolism is not a key factor behind progression of wasting in sarcoma-bearing mice, but anorexia is.

Animals↗
PubMed1997

Synergism of tumor necrosis factor-alpha and melphalan in systemic and regional administration: animal study.

Tumor necrosis factor (TNF) is a highly cytotoxic cytokine. However, due to its severe side effects, the only clinical situation allowing its administration in humans is isolated limb perfusion (ILP). Early studies have shown that TNF alone is of limited efficacy even at high doses via ILP, and that a chemotherapeutic agent needs to be added. The most commonly used drug in this setting is melphalan which is considered to be synergistic with TNF. However, since melphalan has not been commonly used in sarcoma, we believed that confirmation of its synergistic effect with TNF in an experimental sarcoma model could prove valuable for future drug choice. B16F10 melanoma and CT26 colon carcinoma cells were injected subcutaneously (s.c.) into mice, while GF fibrosarcoma cells were injected s.c. into the hindleg of Wistar rats. The animals were then divided into four treatment groups: TNF alone, melphalan alone, TNF and melphalan, and 0.9% NaCl controls. Mice were treated with intraperitoneal injections and rats by ILP. TNF dosage was 20 microgram for mice and 200 microgram for rats. Melphalan was given at 5-10 mg/kg for both mice and rats. Results showed synergism of TNF and melphalan in both modes of therapy. In the systemic administration groups (mice carrying B16F10 and CT26 tumors), tumors increased in size in all but the combined TNF-melphalan group. In the regional delivery groups (rats carrying GF sarcoma cells treated via ILP), there was a 16% decrease in tumor volume in rats treated with TNF alone, a 29% decrease in rats treated with melphalan, and a 75% decrease in the combined TNF-melphalan group. In conclusion, TNF and melphalan proved to be highly synergistic in both systemic and regional delivery. This fact makes melphalan an adequate choice for TNF perfusion in advanced limb malignancies.

Animals↗
PubMed2004

Vascular endothelial growth factor expression is up-regulated by EWS-ETS oncoproteins and Sp1 and may represent an independent predictor of survival in Ewing's sarcoma.

PURPOSE: Tumor markers ideally allow monitoring and prediction of disease progression. In Ewing's sarcoma, a devastating childhood cancer, only a few reliable prognostic markers have been identified. To this end, we analyzed the expression of four tumor-promoting proteins, cyclin D1, HER2/Neu, Mdm2, and vascular endothelial growth factor (VEGF), in Ewing's sarcoma. EXPERIMENTAL DESIGN AND RESULTS: Thirty-one tissue samples from patients with Ewing's sarcoma were stained with antibodies against cyclin D1, HER2/Neu, Mdm2, or VEGF. Whereas no significant expression of HER2/Neu and Mdm2 was detected, positive cyclin D1 and VEGF staining was observed in 42% and 55% of all tumors, respectively. Importantly, VEGF expression was found to be an independent negative predictor of survival in Ewing's sarcoma patients, whereas cyclin D1 expression did not correlate with survival in these patients. Consistently, the Ewing's sarcoma-specific EWS-ETS oncoproteins were capable of activating both the cyclin D1 and VEGF promoters in transient transfections of tissue culture cells. Furthermore, this activation was enhanced by coexpression of the Sp1 transcription factor. Using a mammalian two-hybrid system, some evidence was obtained that this may involve a physical interaction between EWS-ETS and Sp1 proteins. CONCLUSIONS: Our data reveal that VEGF may serve as a prognostic marker in Ewing's sarcoma patients and provide a molecular mechanism by which VEGF and cyclin D1 expression is up-regulated in approximately half of all Ewing's sarcomas.

Antigens, Protozoan↗
PubMed2004

[(11)C]methionine positron emission tomography and survival in patients with bone and soft tissue sarcomas treated by carbon ion radiotherapy.

PURPOSE: The development of the novel carbon ion radiotherapy (CIRT) in the treatment of refractory cancers has resulted in the need for a way to accurately evaluate patient prognosis. We evaluated whether L-[methyl-(11)C]-methionine (MET) uptake and its change after CIRT were the early survival predictors in patients with unresectable bone and soft tissue sarcomas. EXPERIMENTAL DESIGN: MET positron emission tomography was prospectively performed in 62 patients with unresectable bone and soft tissue sarcomas before and within 1 month after CIRT. Tumor MET uptake was measured with the semiquantitative tumor:nontumor ratio (T/N ratio). The MET uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analysis. RESULTS: The overall median survival time was 20 months. Patients with a baseline T/N ratio of 6 (2-year survival rate: 69.4% versus 32.3%; P = 0.01). Patients with a post-CIRT ratio of 4.4 (2-year survival rate: 63.7% versus 41.3%; P = 0.01). A significant higher survival rate was observed in patients with post-therapeutic MET uptake change of >30% than patients in lower change group (2-year survival rate: 74.6% versus 41.6%; P = 0.049). The multivariate analysis showed that both baseline and post-CIRT T/N ratio were statistically significant independent predictors of patient survival. Tumors with larger T/N ratio had a significantly poorer prognosis. CONCLUSIONS: MET uptake as measured by either baseline or post-CIRT T/N ratio was an independent predictor of survival in patients with bone and soft tissue sarcomas treated by carbon ion radiotherapy, whereas post-therapeutic MET uptake change might have potential value for the same purpose.

Adolescent↗
PubMed2002

Effectiveness of Ecteinascidin-743 against drug-sensitive and -resistant bone tumor cells.

PURPOSE: The identification of new drugs is strongly needed for bone tumors.Ecteinascidin-743 (ET-743), a highly promising antitumor agent isolated from the marine tunicate Ecteinascidia turbinata, is currently under Phase II clinical investigation in Europe and the United States for treatment of soft tissue sarcoma. In this study, we analyzed the preclinical effectiveness of this drug in osteosarcoma and Ewing's sarcoma. EXPERIMENTAL DESIGN: The effects of ET-743 were evaluated against a panel of human osteosarcoma and Ewing's sarcoma cell lines characterized by different drug responsiveness and compared with the effects of standard anticancer agents. In addition, combination treatments with ET-743 and the other standard chemotherapy agents for sarcoma were analyzed to highlight the best drug-to-drug interaction RESULTS: A potent activity of ET-743 was clearly observed against both drug-sensitive and drug-resistant (multidrug-resistant, methotrexate- and cisplatin-resistant) bone tumor cells at concentrations that are easily achievable in patients (pM to nM range). Ewing's sarcoma cells appeared to be particularly sensitive to the effects of this drug. The analysis of the effects of ET-743 on cell cycle, apoptosis, and differentiation indicated that both osteosarcoma and Ewing's sarcoma cells had a slower progression through the different phases of the cell cycle after treatment with ET-743. However, the drug was able to induce a massive apoptosis in Ewing's sarcoma but not in osteosarcoma cells. In the latter neoplasm, ET-743 showed a differential effect, as indicated by the significant increase in the expression and activity of alkaline phosphatase, a marker of osteoblastic differentiation. Concurrent exposure of cells to ET-743 and other chemotherapeutic agents resulted in greater than additive interactions when doxorubicin and cisplatin were used, whereas subadditive effects were observed with methotrexate, vincristine, and actinomycin D. CONCLUSIONS: Overall, these results encourage the inclusion of this drug in the treatment of patients with bone tumors, although a careful design of new regimens is required to identify the best therapeutic conditions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

A comparison of efficacy of photoradiation therapy and other conventional treatment modalities on experimental MS-2 sarcoma.

The therapeutic efficacy of photoradiation therapy (PRT) following hematoporphyrin derivative (HpD) administration was compared in the experimental MS-2 tumour model to that of conventional treatment methods for local control of neoplastic diseases. The therapeutic effects of PRT and surgical removal of primary tumour were comparable in these experiments. However, optimal effects were critically dependent on the stage of tumour development. In addition, the therapeutic advantage of PRT over radiotherapy suggest an interesting role of a new approach in tumours resistant to this conventional treatment.

Animals↗