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)

A dose-intensive regimen of cyclophosphamide (140 mg/kg over 2 days), doxorubicin (Adriamycin, 75 mg/m2 over 3 days), and vincristine (1 mg/m2 on days 1, 2, and 3 and 1.5 mg/m2 on day 9) was tested in 18 children and adolescents with poor-prognosis recurrent or refractory solid tumors. Nine were affected by neuroblastoma, 3 by Ewing's tumors, 2 by rhabdomyosarcoma, 2 by synovial sarcoma, 1 by hepatocellular carcinoma, and 1 by osteogenic sarcoma. All enrolled patients were heavily pretreated, including 2 patients after bone marrow transplantation. Forty courses were applied (median, 2). The overall response rate was 33% (2 complete remissions and 4 partial remissions). Responses were obtained in children with neuroblastoma, Ewing's tumors, and hepatocellular carcinoma. Myelosuppression [World Health Organization (WHO) grade IV after all courses] and cardiac toxicity (3 WHO grade I, 5 WHO grade III, and 3 WHO grade IV) were the main side effects. Nephrotoxicity and hepatoxicity were not observed. With further therapy consisting of surgery, radiotherapy, and high-dose chemotherapy [cisplatin, carboplatin/etoposide (VP16), or ifosfamide/VP16 with or without autologous stem cell reinfusion after conditioning with melphalan/VP16/carboplatin], 3 complete remissions and 5 very good partial remissions were obtained. Ten of 18 patients are alive after a median follow-up of 16 months.
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PMID:High-dose cyclophosphamide, adriamycin, and vincristine (HD-CAV) in children with recurrent solid tumor. 785 84

Adjuvant chemotherapy is currently employed in the treatment of patients with osteosarcoma, but the drug regimens, although effective in improving disease-free survival, are unsuccessful in 20-40% of patients and very toxic. It would be useful to know whether tumor cells are sensitive to a given drug prior to its use. To this end, we developed a method of assessing Adriamycin (doxorubicin) binding to tumor nuclei as a possible means of detecting sensitivity to the drug. Adriamycin-sensitive murine osteosarcoma cells were used to develop the assay. The in vitro conditions (drug concentration, duration of incubation, and temperature) were optimized with use of the murine osteosarcoma cells in culture. After the cells had been incubated with Adriamycin, cell viability was determined and Adriamycin fluorescence intensity was measured with a cytofluorometer. The optimal parameters for Adriamycin binding were found to be a 30-minute incubation in a 10 micrograms/ml concentration of Adriamycin at 37 degrees C; the frequency of cells that emitted Adriamycin fluorescence from the nucleus compared with the total number of living cells reached 100% under these conditions. In a murine leukemia cell line with known sensitivity to Adriamycin, the cells emitted red fluorescence from the nucleus and cytoplasm, whereas in a resistant line the cells emitted Adriamycin fluorescence from only the cytoplasm. We demonstrated that it is possible to differentiate nuclear from cytoplasmic concentration of Adriamycin in a tumor cell with use of a fluorescent microscope and that resistant cell lines can be distinguished from sensitive cell lines by this method.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An assay to measure adriamycin binding in osteosarcoma cells. 793 78

Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a biological agent in phase I and II trials for osteosarcoma and melanoma. Its mechanism of action has been linked to its ability to activate monocyte tumoricidal function and to stimulate monocyte production of tumor necrosis factor (TNF) and interleukins(IL)-1, -6, and -8. Our ultimate goal is to combine L-MTP-PE with chemotherapy. The purpose of this study was to determine whether doxorubicin (Adriamycin) interfered with the ability of L-MTP-PE to activate monocyte cytokine production. Human monocytes were cultured with or without 5-500 ng/ml of Adriamycin for 3 h and washed before being exposed to 2 micrograms/ml L-MTP-PE for 16 h. Cultured supernatants were collected and assayed for TNF, IL-1, IL-6, and IL-8. The messenger RNA expression of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, and IL-8 was quantified with northern blot analysis. Adriamycin did not suppress the up-regulation of any of these cytokines. We concluded that combination therapy with L-MTP-PE and Adriamycin is feasible and that this combination warrants further investigation in a clinical setting.
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PMID:Effect of Adriamycin on liposomal muramyl tripeptide's ability to up-regulate monocyte cytokine expression. 824 65

Twenty-nine patients with high-grade nonmetastatic osteogenic sarcoma of the extremities were treated with adjuvant chemotherapy following definitive surgery. Chemotherapy consisted of systemic intravenous Adriamycin and cisplatin in a sequential fashion given for six courses. Nineteen out of 29 patients are alive and continuously disease free over a follow-up period ranging from 9+ to 30+ months. The relapse-free survival was 72%, and overall survival for the entire group was 69%. Median survival is not reached yet. Six out of 29 patients relapsed, of which 1 patient is alive for 6+ months after relapse. Three patients died of chemotherapy toxicity. The results were superior to historical controls treated with surgery alone. The need for more aggressive treatment approaches is discussed.
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PMID:Adjuvant chemotherapy for osteogenic sarcoma of the extremity with sequential adriamycin and cisplatin. 844 Dec 77

P-glycoprotein is an adenosine triphosphate-dependent drug-efflux pump that extrudes drugs from cells and causes drug-resistance. P-glycoprotein is believed to mediate drug-resistance in a wide variety of tumors. In this study, we developed two P-glycoprotein-positive, murine osteosarcoma cell lines that were resistant to Adriamycin (doxorubicin) (MOS/ADR1 and MOS/ADR2). We created the cell lines by short-term pulse exposures of the parent cell line to Adriamycin followed by single-cell cloning. The MOS/ADR1 and MOS/ADR2 cells were sevenfold and eighteenfold more resistant to Adriamycin than the cells from the parent line. Expression of P-glycoprotein, as examined with an immunofluorescence method, was detected in most of the MOS/ADR1 and MOS/ADR2 cells but not in the parent cells. After the cells had been incubated with Adriamycin for one hour, there was less accumulation of the drug in the resistant cell lines than in the parent cell line. The reduced accumulation was due to the increased efflux of Adriamycin. The Adriamycin-resistant cell lines demonstrated greater alkaline phosphatase activity than the parent cell line and produced more differentiated osteoblastic sarcomas in mice. Dose survival studies with use of a tetrazolium colorimetric assay showed that the MOS/ADR1 cells were cross-resistant to vincristine, vinblastine, etoposide, bleomycin, mitomycin C, and actinomycin D but not to dacarbazine, cisplatin, carboplatin, cytosine arabinoside, carmustine, cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil. Although the MOS/ADR2 cells exhibited a similar spectrum of cross-resistance, they were more resistant than the MOS/ADR1 cells. We also tested the effect of three different resistance-modifying agents on the reversal of resistance to Adriamycin. We found that verapamil and trifluoperazine substantially reversed resistance to Adriamycin in the P-glycoprotein positive cell lines, whereas cyclosporin A was relatively ineffective. Because these cell lines retain the histological and biochemical features of bone-producing sarcomas and display the multidrug-resistant phenotype, they may be useful models for additional investigations of drug resistance in osteosarcoma.
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PMID:Experimental models for the study of drug resistance in osteosarcoma: P-glycoprotein-positive, murine osteosarcoma cell lines. 861 43

Intra-arterial (IA) and intravenous (IV) cisplatinum (CDP) were studied in a multiagent regimen of neoadjuvant chemotherapy for osteosarcoma of the extremities. Preoperatively two cycles of high-dose methotrexate (HDMTX) were administered, followed 5 days later by CDP and Adriamycin (ADM). MTX and ADM were administered IV, and CDP was delivered IA or IV. Postoperatively, good responders received 3 more cycles of the same drugs, while poor responders had a longer chemotherapy including ifosfamide. The rate of good histological response to chemotherapy was significantly higher in patients treated intraarterially (78% vs 46%: P < .004), while no significant differences in terms of disease-free survival were observed between patients who received CDP IA and patients who received CDP IV (55% vs 51%). In the IA group, however, there was only one local recurrence vs 5 in the IV group. The IA infusion of CDP is more active on the primary tumor than the IV infusion.
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PMID:Intra-arterial versus intravenous cisplatinum (in addition to systemic Adriamycin and high dose methotrexate) in the neoadjuvant treatment of osteosarcoma of the extremities. results of a randomized study. 883 14

The authors investigated the influence of methotrexate (MTX) serum concentration on (histologically evaluated) tumor necrosis, induced by a primary multiagent chemotherapy, including MTX, for osteosarcoma. MTX serum peaks in 151 patients, preoperatively treated with MTX (8-12g/m2), cisplatin (120mg/m2) and Adriamycin (60mg/m2), were analyzed. Significantly (p < 0.01) higher serum MTX mean peaks were observed in patients with complete tumor necrosis (MTX 773.8 mumol/l) compared to patients with 90-99% tumor necrosis (639.8 mumol/l), 50-89% tumor necrosis (649.1 mumol/l) or less than 50% tumor necrosis (610 mumol/l). Complete tumor necrosis was observed in 9% of patients with MTX peaks of less than 600 mumol/l, in 27% of patients with serum MTX peaks between 600 and 699 mumol/l and in 37% of those with MTX peaks ranging from 700 to 799 mumol/l. Higher MTX peaks (800-899, 900-999, > 1000 mumol/l) were not associated with a further increase of cases with complete tumor necrosis. 40% of patients with an MTX peak greater than 700 mumol/l had complete tumor necrosis, compared to 15.5% of patients who did not reach this value (p < 0.002). At a multivariant analysis including age, sex, tumor site and volume, pretreatment serum alkaline phosphatase and lactic dehydrogenase levels, MTX peaks of 700 mumol/l and, less significantly, the histologic type (telangiectatic osteosarcoma), were independent factors influencing tumor necrosis. The authors conclude that MTX serum peaks significantly influence chemotherapy-induced tumor necrosis in osteosarcoma. In a primary treatment consisting of cisplatin, Adriamycin and MTX, complete tumor necrosis can be obtained in 40% of patients with MTX peak concentrations > or = 700 mumol/l.
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PMID:Methotrexate serum concentration and histological response to multiagent primary chemotherapy for osteosarcoma of the limbs. 898 Nov 89

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

Bone only metastasis in patients with estrogen receptor (ER) positive breast cancer reported to have favorable response to chemotherapy, favorable prognosis, and an "indolent" course. Therefore, we assessed the ability of MG-63 osteoblast-like human osteosarcoma cells (MG-63 cells) and MG-63 conditioned media (CM) to influence adriamycin-cytotoxicity of ER-positive MCF-7 human breast cancer cells. Estradiol (E2; 100 nM) increased the distribution at S and G2/M phases in the cell cycle and stimulated the growth of MCF-7 cells. Adriamycin (100 nM) inhibited the growth and arrested the MCF-7 cells supplemented with or without 100 nM of estradiol [(-E2) and (+E2) MCF-7 cultures] at G2/M phase in the cell cycle. In addition, adriamycin (100 nM) increased the distribution at G1/G0 phase in the cell cycle of (+E2) MCF-7 cultures. Adriamycin (100 nM and 10 microM) did not induce apoptosis of MCF-7 cells as assessed by flow cytometry and analysis of DNA fragmentation on simple agarose gel. Exogenous insulin-like growth factor I (IGF I) stimulated while transforming growth factor beta 1 (TGF beta 1) and MG-63 CM inhibited the growth of MCF-7 cells. Furthermore, MG-63 CM and TGF beta 1 enhanced while exogenous IGF I reversed adriamycin (100 nM)-cytostasis of MCF-7 cells. These data suggested that osteoblastic CM contained growth factors, such as TGF beta 1 capable of enhancing adriamycin-cytostasis, in vitro. Conceivably, these osteoblast-derived "enhancers" of chemotherapy-cytostasis can explain the favorable prognosis and "indolent" course of ER-positive breast cancer patients with bone only metastasis.
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PMID:Osteoblast-derived growth factors enhance adriamycin-cytostasis of MCF-7 human breast cancer cells. 989 70

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


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