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)

Cancer chemotherapy has developed rapidly over the last twenty years. The majority of patients with cancer die from metastatic disease, so the major therapeutic advance now must be better systemic therapy. From its early beginning in the 1940's with oestrogen therapy for prostatic cancer, nitrogen mustards in the lymphomas, and folic acid antagonists in childhood leukaemia, there are now between thirty and forty active anti-cancer agents in clinical use. The main clinical pharmacological points of the major agents are briefly reviewed, together with their main dose-limiting toxic effects and their activity as single agents. Clinical chemotherapy has developed by the introduction of newer agents from the drug screening programmes and a better understanding of the scheduling to avoid serious toxicity. Although drug-resistance is still a major problem, by combining different active agents there has been a dramatic improvement in survival of patients with selected tumours. More recently, treatment of patients early, before they have gross clinical recurrence, has already shown some benefit in pre-menopausal patients with carcinoma of the breast and in patients with osteosarcoma. The limitations of clinical measurements in monitoring therapy are clear, and a major improvement could well be realised if therapy could be monitored on the basis of quantitative markers. The clinical impact of cancer chemotherapy has already been dramatic in drug-sensitive tumours, but these only contribute a small proportion of the total. Some of the common tumours fall into the group that are relatively drug sensitive where the lives of patients can be prolonged, but there is still a significant fraction of tumours which are insensitive to existing drugs and which will probably require the development of newer agents before chemotherapy can make any impact on the survival of patients with these tumours.
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PMID:The current role of cancer chemotherapy. 36 Nov 39

The biologic activity in terms of survival of normal hematopoietic stem, osteosarcoma, and L1210 leukemia cells was determined for the following compounds:cyclophosphamide, its derivatives isophosphamide and trophosphamide, its possible metabolites nor-nitrogen mustard, hydroxylamine mustard, 4-ketocyclophosphamide, and and acrolein, and two substitutes for its primary active metabolite 4-hydroxycyclosphamide anhydro-dimer (4-hydroxy-CP-anhydro-dimer) and 4-hydroperoxycyclophosphamide (4-hydroperoxy-CP). On a molar basis none of the compounds shows a better therapeutic ratio between osteosarcoma and bone marrow stem cells than the parent compound. The therapeutic ratio between L1210 leukemia and normal cells is slightly better for 4-hydroperoxy-CP only. It may be concluded that the conversion of 4-hydroxy-CP-anhydro-dimer and 4-hydroperoxy-CP to the primary active metabolite 4-hydroxycyclophosphamide differs quantitatively. Moreover, it appears that by the use of these precursors a better therapeutic ratio might be obtained for some malignancies but not for others.
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PMID:Biologic activity of two derivatives and six possible metabolites of cyclophosphamide (NSC-26271). 106 68

Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g/m2 ifosfamide daily x 5, given i.v. over 15 min, followed by 400 mg/m2 i.v. mesna at 15 min and 4 and 6 h after ifosfamide. Responses were noted in patients with osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma and other soft-tissue sarcomas, rhabdoid tumor, neuroblastoma, Wilms' tumor, primitive neuroectodermal tumor, retinoblastoma, germ-cell tumors, and B-cell lymphoma. Toxicity included mild to moderate nausea and vomiting, transient, reversible myelosuppression, transient elevations of serum blood urea nitrogen (BUN) and creatinine and liver enzymes, infections, and self-limiting neurotoxicity characterized by changes in mental status, motor dysfunction, cranial nerve palsy, cerebellar dysfunction, and seizures. Neurotoxic symptoms were generally seen in patients who had previously received cisplatin. Ifosfamide is an important alkylating agent that should be combined with other agents in phase II and III trials. Alternate dose schedules should also be investigated.
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PMID:Ifosfamide in pediatric malignant solid tumors. 250 57

The short-term metabolic fate of labeled nitrogen derived from [13N]ammonia or from L-[amide-13N]glutamine was determined in murine tumors known to be resistant (Ridgeway Osteogenic Sarcoma (ROS] or sensitive (Sarcoma-180 (S-180)) to glutaminase therapy. At 5 min after intraperitoneal injection of [13N]ammonia or of L-[amide-13N]glutamine, only about 0.7% of the label recovered in both tumors was in protein and nucleic acid. After [13N]ammonia administration, most of the label (over 80%) was in a metabolized form; a large portion of this metabolized label (50-57%) was in the urea fraction with a smaller amount in glutamine (37-42%). The major short-term fate of label derived from L-[amide-13N]glutamine was incorporation into components of the urea cycle with smaller amounts in the acidic metabolites and in acidic amino acids. No labeled urea was found during in vitro studies in which S-180 tumor slices were incubated with [13N]ammonia, suggesting that the [13N]urea formed in the tumor in the in vivo experiments was not due to de novo synthesis through carbamyl phosphate in the tumor. Both tumors exhibited very low glutamine synthetase activity. Following glutaminase treatment, glutamine synthetase and gamma-glutamyltransferase activities, while remaining low, increased in the resistant tumor but not in the sensitive tumor; this increase may be related to the insensitivity of the ROS tumor toward glutaminase treatment.
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PMID:[13N]Ammonia and L-[amide-13N]glutamine metabolism in glutaminase-sensitive and glutaminase-resistant murine tumors. 286 80

We studied the effect of total parenteral nutrition on recovery from myelosuppression in patients receiving intensive chemotherapy. Twenty-seven patients (ages 11 to 33 years) with locally recurrent or metastatic Ewing's sarcoma, rhabdomyosarcoma, or osteosarcoma were randomly selected to receive either conventional oral nutrition or total parenteral nutrition concurrently with intensive chemotherapy. The control group (15 patients) received significantly fewer calories (range 380 to 880/m2 per day, median 685 versus range 1,020 to 2,100 median 1,650) and less nitrogen (0-3.7 g/m2 per day, median 1.5 versus range 5.3 to 12.4, median 8.9) than the group receiving total parenteral nutrition (12 patients). Assessment of recovery from myelosuppression was based on the length of time the absolute granulocyte count was below 500/mm3, the length of time the platelet count was below 40,000/mm3, the number of days the platelet count was below 20,000/mm3, and the number of blood transfusions required. There was no statistical difference in any of the parameters evaluated between the group that received total parenteral nutrition and the control group (p less than 0.05); granulocyte and platelet recovery and the difference in transfusion requirements favored the control group with marginal statistical significance (p = 0.05). The frequency of clinical infections was similar in the patients receiving total parenteral nutrition (five of 12) and in those receiving conventional oral nutrition (five of 15). Thus, although total parenteral nutrition could be safely administered in this severely myelosuppressed population, no benefit could be defined in recovery from bone marrow suppression or frequency of clinical infections.
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PMID:The effect of total parenteral nutrition on chemotherapy-induced myelosuppression. A randomized study. 640 92

In 2 horses with rapidly growing, locally destructive tumors of the premaxilla, there was major disruption and displacement of some incisor teeth, with radiographic evidence of disruption of the premaxilla at the base of the tumors. In horse 1, most of the tumor was removed by incising it at its base, and the tumor bed was treated cryosurgically with 3 freeze-thaw cycles, using liquid nitrogen. The area healed by 2nd intention. The tumor was found to be a benign fibroblastic tumor, possibly a fibroma. After 4 years, there has been no recurrence. Horse 2 was euthanatized on the basis of a tentative biopsy diagnosis of osteogenic sarcoma. Postmortem studies supported a diagnosis of fibrosarcoma without metastasis.
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PMID:Fibroblastic tumor of the premaxilla in two horses. 657 8

The aim of this study was to investigate the cytotoxic activity of the third-generation nitrogen-containing bisphosphonate zoledronic acid (ZOL) as a single agent, and in combination with clinically relevant anticancer drugs, in a panel of human osteogenic sarcoma cell lines (HOS, BTK-143, MG-63, SJSA-1, G-292, and SAOS2). We found that ZOL, when used alone, reduced cell number in a dose- and time-dependent manner, due either to cell cycle arrest in S-phase or to the induction of apoptosis. In the sensitive HOS, BTK-143, and G-292 cell lines, genomic DNA fragmentation and morphological changes characteristic of apoptosis were evident, and cells became nonadherent. Induction of apoptosis in osteosarcoma cells by ZOL was associated with caspase activation. However, coaddition of the broad-spectrum caspase inhibitors, z-VAD-fmk, Boc-D-fmk, or the caspase-3-specific inhibitor z-DEVD fmk, failed to protect these cells from ZOL-induced apoptosis. Our data support a ZOL-specific induction of cell apoptosis that involves cell detachment (anoikis), and in which caspase activation occurs secondarily to, and is redundant as a mediator of cell death. The addition of geranylgeraniol, an intermediate of the mevalonate pathway, suppressed the ZOL-induced apoptosis, suggesting that the cytotoxic effects of ZOL in osteosarcoma cells were mediated by the mevalonate pathway. While treatment of osteosarcoma cells with the chemotherapeutic agents doxorubicin or etoposide decreased cell viability, combination of these agents with ZOL did not significantly augment apoptosis in any of the cell lines tested. These observations suggest that ZOL has direct effects on the proliferation and survival of osteosarcoma cells in vitro, which has implications for future therapy of osteosarcoma.
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PMID:Induction of cell death of human osteogenic sarcoma cells by zoledronic acid resembles anoikis. 1449 55

The purpose of this study was to evaluate the clinical safety of pamidronate when administered at a mean dosage of 1.0 mg/kg IV q28d in 33 tumor-bearing dogs. Biochemical tests of renal function were evaluated before each successive pamidronate treatment. Of 33 dogs treated with pamidronate, 1 dog had clinically relevant increases in serum creatinine and blood urea nitrogen concentrations. The biologic activity of IV pamidronate was assessed prospectively in 10 dogs with appendicular osteosarcoma and was assessed on reductions in urine N-telopeptide excretion (P = .042) and enhanced bone mineral density of the primary tumor measured with dual-energy x-ray absorptiometry (P = .024). Additionally, in these 10 dogs, pamidronate's therapeutic activity was supported by subjective improvement in pain control in 4 of the 10 dogs treated. IV pamidronate appears clinically safe in tumor-bearing dogs and may possess modest biologic activity for managing neoplastic complications associated with pathologic bone resorption.
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PMID:Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement. 1571 51

1 Bisphosphonates are inhibitors of tumor cell growth as well as of bone resorption by inducing cell apoptosis. However, little is known regarding the mechanisms by which the drug induces cell apoptosis. The aim of the present study was to determine the effect of alendronate, one of the nitrogen-containing bisphosphonates on the phoshoinositide 3-kinase (PI3K)-Akt-NFkappaB pathway, the major cell survival pathway. 2 The PI3K-Akt-NFkappaB pathway was activated in the osteosarcoma cell line MG-63 treated with tumor necrosis factor-alpha or insulin. Saos-2 was also used in some experiments. This was assessed by the production of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)), increased PI3K activity, phosphorylation of Akt at serine 473 and threonine 308, increase in activity of the inhibitor of nuclear factor kappaB (IkappaB) kinase (IKK) and finally phosphorylation of IkappaB and its subsequent degradation. 3 Pretreatment with alendronate at 100 microM for 24 h prior to the stimulation with tumor necrosis factor-alpha or insulin partially inhibited the IkappaB phosphorylation and degradation. These events were more clearly observed in the presence of inhibitors of proteasomes, which are responsible for the degradation of IkappaB. The drug also partially inhibited the activity of IKK, but almost fully inhibited the phosphorylation of Akt and the production of PtdIns(3,4,5)P(3). 4 The inhibitory effect of alendronate on IkappaB phosphorylation and degradation was not attenuated by the exogenous addition of geranylgeraniol to replenish the cytosolic isoprenyl lipid substrate. 5 The present findings demonstrate that alendronate inhibited the PI3K-Akt-NFkappaB cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate.
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PMID:The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFkappaB pathway in osteosarcoma cells. 1610 May 24

Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N = 9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy.
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PMID:Anticancer effects of zoledronic acid against human osteosarcoma cells. 1660 11


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