UMLS:C0029463 - FACTA Search

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Query: UMLS:C0029463 (osteosarcoma)
16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth inhibition assays indicated that the IC50 values for methotrexate (MTX) and 5-fluorodeoxyuridine (FdUrd) in HS-18, a liposarcoma cell line lacking retinoblastoma protein (pRB), and SaOS-2, an osteosarcoma cell line with a truncated and nonfunctional pRB, were 10- to 12-fold and 4- to 11-fold higher, respectively, than for the HT-1080 (fibrosarcoma) cell line, which has wild-type pRB. These Rb-/- cell lines exhibited a 2- to 4-fold increase in both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) enzyme activities as well as a 3- to 4-fold increase in mRNA levels for these enzymes compared to the HT-1080 (Rb+/+) cells. This increase in expression was not due to amplification of the DHFR and TS genes. Growth inhibition by MTX and FdUrd was increased and DHFR and TS activities and expression were correspondingly decreased in Rb transfectants of SaOS-2 cells. In contrast, there was no significant difference in growth inhibition among these cell lines for the nonantimetabolites VP-16, cisplatin, and doxorubicin. A gel mobility-shift assay showed that parental SaOS-2 cells had increased levels of free E2F compared to the Rb-reconstituted SaOS-2 cells. These results indicate that pRB defective cells may have decreased sensitivity to growth inhibition by target enzymes encoded by genes whose transcription is enhanced by E2F proteins and suggest mechanisms of interaction between cytotoxic agents and genes involved in cell cycle progression.
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PMID:Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines. 747

28 patients with telangiectatic osteogenic sarcoma of the extremities were treated between March 1983 and March 1990 with neoadjuvant chemotherapy according to two different protocols activated successively. With the first protocol, patients preoperatively received high dose methotrexate (HDMTX)-cisplatinum (CDP) and postoperatively, depending on the histological response, either HDMTX-CDP-doxorubicin (ADM) or ADM-"BCD". With the second protocol patients were preoperatively treated with HDMTX-CDP-ADM and postoperatively either with the same drugs or with the same drugs plus ifosfamide and VP-16. Preoperatively, CDP was delivered intraarterially. A good histological response (tumour necrosis > 90%) was observed in 25 patients (89%) and at a mean follow-up of 5 years (2-9 years) 23 patients (82%) remained continuously disease-free and 5 developed lung metastases. These results are better than those obtained in 272 contemporary cases of conventional osteosarcoma of the extremities treated with the same protocols (62% good histological responses and 61% continuously disease-free survival).
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PMID:Primary chemotherapy and delayed surgery for non-metastatic telangiectatic osteosarcoma of the extremities. Results in 28 patients. 808 Jun 76

The relationship between the serum concentration of methotrexate and the prognosis has been studied in 108 patients with osteosarcoma of the extremities treated from September 1986 to December 1989 at the Chemotherapy Department of Rizzoli Hospital. The protocol of neoadjuvant chemotherapy included high doses of methotrexate (HDMTX) adriamycin, cisplatinum, ifosfamide and VP-16. After a median follow-up of 40.4 months (range 24-62), 84 (77.7%) of the patients studied remained continuously disease-free (CDF) and 24 relapsed. Significantly higher mean serum MTX concentrations were observed in the patients who remained CDF (669.5 mumol/l) than in the patients who relapsed (571.9 mumol/l) (p < .004). The breaking point of prognostic significance for the serum MTX levels seems to be 700 mumol/l. In fact, according to the mean MTX concentrations, the patients with less than 700 mumol/l showed a significantly lower disease-free survival than the patients with higher mean MTX concentrations (68.12% vs 94.87% p < .0013). The distribution of prognostic variables between the two groups was the same in terms of site and histological type of tumor and alkaline phosphatase serum levels at diagnosis. In the group which had more than 700 mumol/l MTX, a higher percentage of good histological response after primary chemotherapy was observed. This is probably independent from the MTX because no significant preoperative MTX serum levels between good and partially responding patients were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum methotrexate (MTX) concentrations and prognosis in patients with osteosarcoma of the extremities treated with a multidrug neoadjuvant regimen. 851 97

Ifosfamide, Carboplatin and Etoposide (ICE) therapy was used to treat 4 patients, 2 with refractory osteosarcoma, and one each with relapsed brain tumor and newly diagnosed brain tumor. ICE therapy was administered in doses of Ifosfamide 1,800 mg/m2 x 5, Carboplatin 400 mg/m2 x 2 and Etoposide 100 mg/m2 x 5. A total of 30 courses were administered. Two cases of osteosarcoma had a stable disease (range, 3-9 months) and 2 cases of brain tumor had a complete response by magnetic resonance imaging. Moderate or severe toxicity evaluated on a per course basis included: neutropenia 83%, thrombocytopenia 93%, fever 30%, hepatotoxicity 3%, and hemorrhagic cystitis 3%. The median time to hematologic recovery was 20 days. ICE therapy is highly effective for the treatment of refractory or recurrent solid tumors with acceptable toxicity.
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PMID:[Pilot study of relapsed osteosarcoma and brain tumor with ifosfamide, carboplatin and etoposide (ICE therapy)]. 949 32

This prospective study was designed to test the activity of an ifosfamide-etoposide (VP-16) regimen on poor-risk, nonmetastatic, osteogenic sarcoma. A total of 13 patients with nonmetastatic osteogenic sarcoma with a poor histologic response to primary high-dose methotrexate-doxorubicin (Adriamycin)-cisplatinum chemotherapy received a total of six 5-day courses of ifosfamide (1,800 mg/m2) and etoposide (100 mg/m2) at three weekly intervals. The protocol was well tolerated, with only one case of transient renal failure. At present, eight patients (62%) have been in sustained complete remission with no evidence of recurrent disease for a mean follow-up of 3.4 years (range, 1.5-7.0 years). One patient is alive with lung metastases, and four have died of progressive disease. This prospective, albeit small, study confirms the efficacy of an ifosfamide-VP-16-based regimen in poor-risk, extremity, nonmetastatic osteogenic sarcoma. The demonstrated activity should spark large trials of ifosfamide-containing regimens in osteogenic sarcoma.
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PMID:Postsurgical etoposide-ifosfamide regimen in poor-risk nonmetastatic osteogenic sarcoma. 949 63

An Italian-Scandinavian treatment and research protocol with high-dose chemotherapy and double peripheral blood stem cell (PBSC) transplantation has been designed in an attempt to improve overall results of children with metastatic osteosarcoma (OST). Six patients, aged 12-17 years, underwent PBSC mobilization with CY 4 g/m2 and VP-16 600 mg/m2 followed by G-CSF (n = 4 with recurrent disease) or ifosfamide 15 g/m2 plus G-CSF (n = 2 with synchronous metastases). The target dose of CD34+ cells for two transplant procedures was 8 x 10(6)/kg or more; conditioning regimen for both the grafts consisted of carboplatin 375 mg/m2/day for 4 days and VP16 450 mg/m2/day for 4 days. The first transplant was planned 2-4 weeks after the mobilization, the second transplant 4-6 weeks after the first graft. In three patients a single course of CY-VP16 mobilised a total number of CD34+ sufficient for two transplants; in the patient who did not obtain the target dose of CD34+ cells a bone marrow harvest was added. In the two other children high-dose ifosfamide failed to achieve the required CD34+ number: one patient underwent a single transplant procedure, one patient was successfully mobilized with doxorubicin 90 mg/m2 plus G-CSF. Patients underwent a median of two collections (range 2-4). Leukapheresis resulted in the collection of a median of 8.9 CD34+ cells/kg (range 1.3-14.8). The median time to granulocyte count recovery to more than 0.5 x 10(9)/l was 10 days (range 9-14 days) after the first graft and 11 days (range 10-12 days) after the second graft, respectively. Platelets recovered to 50 x 10(9)/l at a median of 11 (range 10-30 days) and 13 days (range 10-28) respectively after the first and the second graft. Conditioning regimen was well tolerated in all patients with mild extra haematological toxicity, also following the second transplant. Two patients grafted with metastases at diagnosis are alive and disease free 3 and 7 months from the transplant. One of the four patients transplanted for recurrent disease developed pulmonary metastases 2 months after the procedure; one patient is alive with significant reduction of tumor mass 1 month after the first transplant, one patient is alive without evidence of disease 9 months from the second transplant and one after a complete metastasectomy (tumor necrosis >90%) which followed the second transplant. With the limits of the small number of cases and the short follow-up, these preliminary results show that this approach may be promising for the treatment of patients with metastatic OST who currently are not cured by conventional-dose regimens.
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PMID:Feasibility of high-dose chemotherapy and autologous peripheral blood stem cell transplantation in children with high grade osteosarcoma. 998 88

The purpose of these studies was to determine whether interferon-alpha (IFN-alpha) could enhance the sensitivity of human osteosarcoma cells to the cytotoxic actions of etoposide (VP-16). Cytostasis was determined using a [3H]thymidine incorporation assay, whereas cytotoxicity was quantified by a colony-formation assay. Low concentrations (0.1-5 U/ml) of IFN-alpha enhanced the cytostatic activity of VP-16 against MG-63, SAOS-2, and TE-85 osteosarcoma cells. The cytostatic activity of 1 microM VP-16 rose from 11% to 64%, 9% to 31%, and 10% to 71%, respectively, in the three cell lines when IFN-alpha was present. Survival fraction was also decreased when the osteosarcoma cells were treated with VP-16 + IFN-alpha as compared to either agent alone. The interaction between these two agents was determined to be synergistic rather than additive by interaction index analysis. Similar effects on cytostasis and cytotoxicity were observed when IFN-alpha was combined with Adriamycin but not cisplatin, actinomycin D, vinblastine, or amsacrine. VP-16 uptake was enhanced 12-fold in the presence of IFN-alpha, but this did not appear to translate into an increase in topoisomerase-II (topo-II)-DNA complex formation as quantified by the sodium dodecyl sulfate-KCl precipitation assay. We also could not detect alterations in topo-II expression, topo-II protein production, or cell cycle kinetics that have been shown to correlate with increased VP-16 cell sensitivity. Therefore, at this time the mechanism of enhanced cell sensitivity to the combination treatment remains unclear.
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PMID:Interferon-alpha enhances the sensitivity of human osteosarcoma cells to etoposide. 1043 62

Apo2L/TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines that induces death of cancer cells but not normal cells. Its potent apoptotic activity is mediated through its cell surface death domain-containing receptors, DR4 and DR5. Apo2L/TRAIL interacts also with 3 "decoy" receptors that do not induce apoptosis, DcR1, DcR2, which lack functional death domains, and osteoprotegerin (OPG). The aim of our study was to investigate the cytotoxic activity of Apo2L/TRAIL on established osteogenic sarcoma cell lines (BTK-143, HOS, MG-63, SJSA-1, G-292 and SAOS2) and in primary cultures of normal human bone (NHB) cells. When used alone, Apo2L/TRAIL at 100 ng/ml for 24 hr induced greater than 80% cell death in only 1 (BTK-143) of the 6 osteogenic sarcoma cell lines. In contrast, Apo2L/TRAIL-resistant cells were susceptible to Apo2L/TRAIL-mediated apoptosis in the presence of the anticancer drugs, Doxorubicin (DOX), Cisplatin (CDDP) and Etoposide (ETP) but not Methotrexate (MTX) or Cyclophosphamide (CPM). Importantly, neither Apo2L/TRAIL alone nor in combination with any of these drugs affected primary normal human bone cells under equivalent conditions. Apo2L/TRAIL-induced apoptosis, and its augmentation by chemotherapy in the resistant cell lines was mediated through caspase-8 and caspase-3 activation. Furthermore, Apo2L/TRAIL-induced apoptosis and its augmentation by chemotherapy was effectively inhibited by caspase-8 zIETD-fmk and caspase-3 zDEVD-fmk protease inhibitors and by the pan-caspase inhibitor zVAD-fmk. The pattern of basal Apo2L/TRAIL receptor mRNA expression, or expression of the intracellular caspase inhibitor FLICE-inhibitory protein, FLIP, could not be readily correlated with resistance or sensitivity to Apo2L/TRAIL-induced apoptosis. However, the augmentation of Apo2L/TRAIL effects by chemotherapy was associated with drug-induced up-regulation of death receptors DR4 and DR5 mRNA and protein. No obvious correlation was seen between the expression of OPG mRNA or protein and susceptibility of cells to Apo2L/TRAIL-induced apoptosis. Stable over-expression of a dominant negative form of the Fas-associated death domain protein (FADD) in the Apo2L/TRAIL-sensitive BTK-143 cells completely inhibited Apo2L/TRAIL-induced cell death. Our results indicate that chemotherapy and Apo2L/TRAIL act synergistically to kill cancer cells but not normal bone-derived osteoblast-like cells, which has implications for future therapy of osteosarcoma.
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PMID:Chemotherapeutic agents sensitize osteogenic sarcoma cells, but not normal human bone cells, to Apo2L/TRAIL-induced apoptosis. 1199 38

The cytotoxic effect of the chemotherapeutic drug etoposide (VP-16) is thought to result from its ability to induce DNA damage and thereby to trigger apoptosis. Internucleosomal DNA fragmentation occurs late during apoptosis in many cell types. However, whereas human osteosarcoma cells undergo internucleosomal DNA fragmentation during staurosporine-induced apoptosis, they fail to do so in response to VP-16. Recently, we showed that these cells also do not express the poly(ADP-ribosyl)ation-regulated Ca(2+)- and Mg(2+)-dependent endonuclease DNAS1L3. The possibility that this deficiency underlies the failure of these cells to undergo internucleosomal DNA fragmentation in response to VP-16 was investigated. The proteolytic processing and consequent activation of procaspase-3, cleavage of the inhibitory subunit of DNA fragmentation factor, and the degradation of DNA into 50-kb fragments occurred similarly in osteosarcoma cells exposed to either staurosporine or VP-16. However, the additional processing of the 50-kb DNA fragments to oligonucleosomal fragments was not apparent in the VP-16-treated cells. Ectopic expression of DNAS1L3 conferred on osteosarcoma cells the ability to undergo VP-16-induced internucleosomal DNA fragmentation. Furthermore, expression of DNAS1L3 markedly potentiated the cytotoxic effect of VP-16 in these cells. Both DNAS1L3-mediated and staurosporine-induced internucleosomal DNA fragmentation were Ca(2+) dependent, but only the DNAS1L3-mediated DNA cleavage was blocked by expression of a caspase-3-resistant mutant of poly(ADP-ribose) polymerase-1. The present work results suggest a direct relation between the activity of a chemotherapeutic drug (VP-16) and a specific endonuclease (DNAS1L3). They also indicate that internucleosomal DNA fragmentation plays an active role in apoptosis and that the failure of cancer cells to undergo such DNA degradation may contribute to the development of resistance to chemotherapeutic drugs.
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PMID:The Poly(ADP-ribose) polymerase-1-regulated endonuclease DNAS1L3 is required for etoposide-induced internucleosomal DNA fragmentation and increases etoposide cytotoxicity in transfected osteosarcoma cells. 1215 52

Interferonalpha (IFNalpha) induces cell cycle arrest and triggers apoptosis and chemosensitivity. But the mechanism of IFNalpha in regulating chemosensitivity has not been fully understood. To study whether IFNalpha affected chemosensitivity of osteosarcoma cells, we treated p53-wild U2OS cells and p53-mutant MG63 cells with IFNalpha and etoposide, alone or in combination, and then examined growth inhibition, cell cycle arrest and apoptosis. IFNalpha enhanced etoposide-induced growth inhibition and apoptosis in p53-wild U2OS cells but not p53-mutant MG63 cells in a dose- and time-dependent manner. Etoposide-induced G2/M phase arrest was also enhanced by IFNalpha. The enhanced apoptosis was associated with the accumulation of transcriptionally active p53 accompanied with increased Bax and Mdm2, as well as decreased Bcl-2. IFNalpha also activated caspases-3, -8 and -9 protein kinases and PARP cleavage in response to etoposide in U2OS cells. Moreover, the combination-induced cytotoxicity and PARP cleavage were significantly reduced by caspase pan inhibitor and p53 siRNA. Thus we conclude that IFNalpha enhances etoposide-induced apoptosis in human osteosarcoma U2OS cells by a p53-dependent and caspase-activation pathway. The proper combination of IFNalpha and conventional chemotherapeutic agents may be a rational strategy for the treatment of human osteosarcoma with functional p53.
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PMID:Interferonalpha enhances etoposide-induced apoptosis in human osteosarcoma U2OS cells by a p53-dependent pathway. 1819 51

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