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)

Osteosarcoma cells are involved in the remodeling of the extracellular matrix (ECM) that affects their growth, invasive and metastatic activities. The tumour ECM provided effective protection against chemotherapy agents in several previously studied malignancies. The current study examined the effects of doxorubicin on cells that were migrated into a 3-dimensional extracellular matrix gel (ECM-gel) in comparison with its effects on cells remaining in the monolayer compartment. A human osteosarcoma cell line (OSCORT) was treated with doxorubicin in monolayer culture for 4 or 24 hours, and then overlaid by ECM-gel for 24 hours. Tumour cells remaining in the monolayer were separated from the cells migrated into ECM-gel, and both of them were characterized. OSCORT cells migrated into ECM-gel showed elevated levels and activity of topoisomerase II, increased protein expression of beta1 integrin and matrix metalloproteinase-9 activity. Doxorubicin treatment for 4 hours resulted in increased cytotoxicity in the monolayer compartment relative to the cells migrated into ECM-gel, whereas 24-hour treatment at a low concentration (0.01 microg/ml) showed an antimigratory effect. Different antiproliferative and antimigratory effects of doxorubicin treatment schedules warrant short-term, high-dose treatment for targeting the tumour growth, and long-term, low-dose treatment for targeting the invasion of osteosarcoma.
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PMID:Antiproliferative and antimigratory effects of doxorubicin in human osteosarcoma cells exposed to extracellular matrix. 1586 12

Although TNF-related apoptosis-inducing ligand (TRAIL) usually induces cell death in tumor cells, there are some tumor cell types that are resistant to its apoptogenic effects. Some chemotherapeutic drugs, however, can sensitize resistant cancer cells to TRAIL by either upregulating surface TRAIL death receptor expression or by modulating intracellular signalling pathways emanating from TRAIL receptors. U2OS human osteosarcoma cells express TRAIL-R2 but are resistant to TRAIL-induced apoptosis. however, the genotoxic drugs, Doxorubicin and Cisplatin, are able to sensitize U2OS cells to TRAIL, without affecting their surface expression of either death or decoy TRAIL receptors. We demonstrate that Doxorubicin and Cisplatin downmodulate X-IAP, while not affecting FLIP levels in U2OS cells. Selective downmodulation of X-IAP protein synthesis by specific small interference RNA transfection induced a sensitization of U2OS cells to TRAIL comparable to that induced by pharmacological treatment with genotoxic drugs. TRAIL-R2 downmodulation by siRNAs completely abolished the TRAIL-induced apoptosis of genotoxin-treated U2OS cells. Our findings demonstrate that Doxorubicin and Cisplatin do not sensitize U2OS osteosarcoma cells to TRAIL by surface receptor modulation but rather by the removal of the intracellular signalling inhibition generated by X-IAP, suggesting a foreseeable relevant advantage to the therapy of these tumors by the combined regimen of genotoxin-based chemotherapy and TRAIL.
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PMID:Anticancer agents sensitize osteosarcoma cells to TNF-related apoptosis-inducing ligand downmodulating IAP family proteins. 1632 88

Chemotherapy is assumed to be immunosuppressive; yet to the authors' knowledge, the effects of common chemotherapy protocols on adaptive immune responses in dogs with cancer have not been fully evaluated. Therefore, a study was conducted to evaluate the effects of 2 common chemotherapy protocols on T- and B-cell numbers and humoral immune responses to de novo vaccination in dogs with cancer. Twenty-one dogs with cancer (12 with lymphoma, 9 with osteosarcoma) were enrolled in a prospective study to assess effects of doxorubicin versus multi-drug chemotherapy on adaptive immunity. Numbers of circulating T and B cells were assessed by flow cytometry, and antibody responses to de novo vaccination were assessed before, during, and after chemotherapy. The T- and B-cell numbers before treatment also were compared with those of healthy, age-matched, control dogs. Prior to treatment, dogs with cancer had significantly fewer (P < .05) CD4+ T cells and CD8+ T cells than did healthy dogs. Doxorubicin treatment did not cause a significant decrease in T- or B-cell numbers, whereas treatment with combination chemotherapy caused a significant and persistent decrease in B-cell numbers. Antibody titers after vaccination were not significantly different between control and chemotherapy-treated dogs. These findings suggest that chemotherapy may have less impact on T-cell numbers and ability to mount antibody responses in dogs with cancer than was previously anticipated, though dogs with lymphoma or osteosarcoma appear to be relatively T-cell deficient before initiation of chemotherapy.
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PMID:Effects of chemotherapy on immune responses in dogs with cancer. 1659 92

The current combination treatment, chemotherapy and surgery, has significantly improved the cure rate and the survival rate of primary bone osteosarcoma. The 5-year survival rate has increased in the last 30 years from 10% to 70%. Even in patients with poor prognosis, such as those with metastases at diagnosis, the 5-year survival rate has reached 20-30% due to chemotherapy and the surgical removal of metastases and primary tumor. However, the most effective drugs are still the same as those employed over the last 20 years as front line neoadjuvant or adjuvant chemotherapy: Doxorubicin, Cisplatin, Methotrexate, Ifosfamide. No standard, second line therapy exists for those who relapse. At relapse, due to the lack of new non-cross-resistant drugs, surgery is still the main option when feasible. Other drugs have been employed in relapsed patients with poor results. This article reviews the state of the art of treatment for bone osteosarcoma in the pediatric age.
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PMID:Primary bone osteosarcoma in the pediatric age: state of the art. 1686 Sep 38

Doxorubicin (Doxo) is a widely used anticancer drug given for the treatment of leukemias, lymphomas, and solid tumors. Despite its potent antitumor effects, the cardiotoxicity of this drug limits its clinical use. The biochemical mechanisms of Doxo-induced cardiotoxicity remain unclear. Doxo has been shown to induce apoptosis in cardiomyocytes that seems to be responsible, at least in part, for Doxo cardiotoxicity. In this study, we investigated tumor necrosis factor-alpha (TNF-alpha) receptor-mediated signaling to better understand the causes of Doxo-induced cardiotoxicity. Here, we report that Doxo is a potent inducer of apoptosis in both H9c2 cardiomyocytes and U2OS osteosarcoma tumor cells, with significant differences in terms of kinetics and caspase activation between the two cell lines. Interestingly, Doxo-induced apoptosis is accompanied by relevant changes in TNF-alpha receptor levels in H9c2 cardiomyocytes but not in U2OS cells. Moreover, treatment with exogenous TNF-alpha strongly potentiates the apoptotic effect of Doxo in H9c2 cardiomyocytes but not in U2OS cells. Our findings show that the function of TNF receptors I and II is affected by Doxo to ultimately modulate apoptosis and cell survival in H9c2 cardiomyocytes, reinforcing the recent evidence of the relevant role of TNF-alpha receptor-mediated signaling in cardiotoxicity induced by anthracyclines.
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PMID:Change in TNF-alpha receptor expression is a relevant event in doxorubicin-induced H9c2 cardiomyocyte cell death. 1765 Oct 20

The overall survival of patients with osteosarcoma of the extremity with localized disease has greatly improved in recent decades and today about half of them are long-term survivors (i.e. more than 10 years). Owing to the increased number of long-term survivors, late side effects of combined chemotherapy are more evident and have been better studied. Doxorubicin-induced cardiac toxicity is still an important and ominous side effect even if the percentage of affected patients is low. In this study, we report the incidence of clinically symptomatic cardiac toxicity induced by doxorubicin, in our series of 755 patients with localized osteosarcoma of the extremity, who had been treated from 1983 to 2000 with different protocols at our institution. Thirteen (1.7%) patients developed a clinically symptomatic cardiac toxicity (New York Heart Association class II-IV). Six of them died. Of the seven still alive, three needed a heart transplant. The case report of these 13 patients is described in detail. A higher incidence of cardiac toxicity was noted in women patients (eight women=2.5% and five men=1.1%). Cumulative dose and dose intensity (cumulative dose/week of treatment) are the most important risk factors in developing doxorubicin-related cardiomyopathy.
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PMID:Long-term follow-up of patients with doxorubicin-induced cardiac toxicity after chemotherapy for osteosarcoma. 1776 6

The oncogene c-Jun has been found to be up-regulated in a variety of cancers, including osteosarcoma. Doxorubicin is a frontline chemotherapeutic against osteosarcoma, but is limited by toxicity. DNAzymes are oligonucleotides capable of specific catalysis of target mRNA. A biocompatible c-Jun DNAzyme nanoparticle formulated from chitosan regressed the growth and metastasis of pre-established tumors, especially in combination with doxorubicin. In vitro data confirmed that c-Jun knockdown chemosensitized these cells to doxorubicin treatment. c-Jun down-regulation-mediated tumor inhibition also led to concomitant decreased osteolysis. Clinically, knockdown of c-Jun with chitosan nanobiotechnology may proffer an improved treatment outcome for osteosarcoma.
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PMID:c-Jun knockdown sensitizes osteosarcoma to doxorubicin. 1864 1

Doxorubicin is a genotoxic chemotherapy agent used in treatment of a wide variety of cancers. Significant clinical side effects, including cardiac toxicity and myelosuppression, severely limit the therapeutic index of this commonly used agent and methods which improve doxorubicin efficacy could benefit many patients. Because doxorubicin cytotoxicity is cell cycle specific, the cell cycle is a rational target to enhance its efficacy. We examined the direct, cyclin-dependent kinase inhibitor roscovitine as a means of enhancing doxorubicin cytotoxicity. This study showed synergistic cytotoxicity between doxorubicin and roscovitine in three sarcoma cell lines: SW-982 (synovial sarcoma), U2OS-LC3-GFP (osteosarcoma), and SK-LMS-1 (uterine leiomyosarcoma), but not the fibroblast cell line WI38. The combined treatment of doxorubicin and roscovitine was associated with a prolonged G(2)-M cell cycle arrest in the three sarcoma cell lines. Using three different methods for detecting apoptosis, our results revealed that apoptotic cell death did not account for the synergistic cytotoxicity between doxorubicin and roscovitine. However, morphologic changes observed by light microscopy and increased cytoplasmic LC3-GFP puncta in U20S-LC3-GFP cells after the combined treatment suggested the induction of autophagy. Induction of autophagy was also shown in SW-982 and SK-LMS-1 cells treated with both doxorubicin and roscovitine by acridine orange staining. These results suggest a novel role of autophagy in the enhanced cytotoxicity by cell cycle inhibition after genotoxic injury in tumor cells. Further investigation of this enhanced cytotoxicity as a treatment strategy for sarcomas is warranted.
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PMID:Autophagy: a novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model. 1882 54

The current management of primary osteosarcoma (OS) and its secondary metastasis is limited by the lack of an efficient drug delivery system. Here we report an in situ gelling chitosan/dipotassium orthophosphate hydrogel system designed to directly deliver the frontline chemotherapeutic agent (Doxorubicin) in a sustained time period to tumor sites. A significant reduction of both primary and secondary OS in a clinically relevant orthotopic model was measured when doxorubicin was administered with the hydrogel. This hydrogel delivery system also reduced cardiac and dermal toxicity of Doxorubicin in mice. The results obtained from this study demonstrate the potential application of a biodegradable hydrogel technology as an anti-cancer drug delivery system for successful chemotherapy.
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PMID:A chitosan-dipotassium orthophosphate hydrogel for the delivery of Doxorubicin in the treatment of osteosarcoma. 1934 93

Metastatic bone disease is often associated with bone pain, pathologic fractures, and nerve compression syndromes. Effective therapies to inhibit the progression of bone metastases would have important clinical benefits. Therefore, we developed a novel calcium phosphate-binding liposome for a bone-targeting drug delivery system. We synthesized a novel amphipathic molecule bearing a bisphosphonate (BP) head group to recognize and bind to hydroxyapatite (HA). We demonstrated that the liposomes having BP moieties show high affinity for HA. Doxorubicin-loaded liposomes adsorbed on the surface of HA significantly reduce the number of viable human osteosarcoma MG63 cells. This shows that the liposomes can be excellent carriers for anticancer drugs because they specifically target bone tissue. This calcium phosphate-binding liposome system could be used with many drugs for bone-related diseases such as osteoporosis, rheumatoid arthritis, and multiple myeloma.
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PMID:Synthesis of calcium phosphate-binding liposome for drug delivery. 1952 21


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