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)

PA-III rat prostate adenocarcinoma cells are capable of inducing osteoblastic reaction after inoculation onto rat skeleton. In this study PA-III cells and osteoblast-derived rat osteosarcoma cells (UMR 106 cells) were employed to characterize the cellular interactions in the PA-III cell-induced bone tumors, in vitro. Insulin-like growth factor-I (IGF-I) and conditioned media (CM) of UMR 106 cells stimlated tritiated-thymidine incorporation into the DNA of PA-III cells growing in serum-free media. This effect was inhibited by monoclonal anti-hIGF-I antibody. In addition PA-III cell CM contained proteinolytic activity for the IGF-binding proteins of UMR 106 cell CM (IGFBP-1 and -2). This proteinase activity hydrolyzed also benzyloxycarbonyl-lysine thiobenzyl ester (BLT) and its action on IGFBPs and BLT was inhibited by benzamidine and aprotinin. Proteinase activity of PA-III cell CM when bound covalently to tritiated-dilsopropylfluoro-phosphate (DFP) and then analyzed on SDS-PAGE gel electrophoresis, revealed the presence of radioactivity linked with a 35 kDa protein band. This proteinase was eluted in the void volume of the G-50 sephadex column and was retained on and eluted from p-benzamidine affinity column. The 35 kDa proteinase was retained on and was eluted from cartridges of the C18 silica by 80% acetonitrile over 0.1% trifuroacetic acid. This partially purified material hydrolyzed BLT substrate and IGFBPs of UMR 106 cell CM and its effect was inhibited by benzamidine and aprotinin. These data indicate that PA-III cell CM contains a 35 kDa proteinase capable of digesting the IGFBPs and thus increases the bioavailability of osteoblast-derived IGFs. This mechanism may participate in the pathophysiology of the PA-III cell-induced bone tumor and its subsequent osteoblastic reaction.
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PMID:Proteinolytic activity against IGF-binding proteins involved in the paracrine interactions between prostate adenocarcinoma cells and osteoblasts. 137 96

Boron analogues of carbamoylcholine and thiocholine and esters of these analogues were prepared. These compounds were fairly stable toward hydrolysis and demonstrated moderate anti-inflammatory and hypolipidemic activities in mice. The hypolipidemic activity of the compounds at a dose of 8 mg/kg/day was equivalent in reducing lipid levels in serum to those of clofibrate at 150 mg/kg/day and lovastatin at 8 mg/kg/day. The compounds demonstrated significant cytotoxic activity against the growth of murine and human tumor cells; all were active against the growth of human HeLa-S3 uterine suspended cells, and some were active against murine L1210 lymphoid leukemia, human Tmolt3 leukemia cells, colorectal adenocarcinoma, KB nasopharynx, osteosarcoma, and glioma. These studies demonstrated that antimetabolite analogues of acetylcholine exhibit the same types of pharmacological activity as other boron-substituted betaine and amino acids. Furthermore, a strong positive correlation exists between hypolipidemic activity and cytotoxicity for these new choline derivatives, as has previously been demonstrated for other boron-containing amino acids, amides, esters, and peptides.
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PMID:Synthesis, cytotoxicity, hypolipidemic and anti-inflammatory activities of amine-boranes and esters of boron analogues of choline and thiocholine. 140 80

Reverse transcription-polymerase chain reactions and RNA protection experiments were used to examine alternative splicing of the six exons 3B-5, 12, and 13 affecting the COL1 and NC2 domains of type XIII collagen in seven human tissues and four cell lines. Distinct differences in the proportions of the variant mRNAs were found. With respect to the COL1 domain, all studied samples contained mRNAs corresponding to the shortest COL1 variants of 57 and 66 residues, with the former variant being prominent in most samples. Most of the samples also contained notable amounts of mRNAs that corresponded to the longest COL1 variants, mainly those of 104 and 95 residues. Particularly the extent of inclusion of exon 12 and 13 sequences, encoding most of the NC2 domain, varied according to the type of tissue or cell analyzed. Bone, cartilage, and colon adenocarcinoma samples contained little or none of the mRNAs corresponding to the long NC2 variants, whereas in fibroblast, lung, muscle, and osteosarcoma cells, those mRNAs were the major variants. The relative proportions of the various combinations of exons 3B-5, 12, and 13 were evaluated in four of the RNA samples. Interestingly, each of these samples appeared to contain only one to three major combinations of the six exons, representing about 40% to nearly 100% of all variants.
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PMID:Patterns of expression of the six alternatively spliced exons affecting the structures of the COL1 and NC2 domains of the alpha 1(XIII) collagen chain in human tissues and cell lines. 144 10

The topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts comprising four lines of adult colon adenocarcinoma, three colon tumors derived from adolescents, six childhood rhabdomyosarcomas from previously untreated patients as well as sublines selected in vivo for resistance to vincristine and melphalan, and three lines of childhood osteogenic sarcoma. Efficacy was determined at maximal tolerated dose levels using intermittent i.p. administration [every 4 days for 4 doses (q4dx4)] or daily p.o. or i.p. administration 5 days per week for up to 20 courses. On a q4dx4 schedule, the maximum tolerated dose (MTD) was 12.5 mg/kg per administration, which caused marked weight loss and lethality in approximately 5% of the tumor-bearing mice. This schedule caused significant growth inhibition (but no tumor regression) in advanced adult colon adenocarcinomas. The minimal treated/control (T/C) ratios were 0.49, 0.54, and 0.3 for three of the tumor lines and were achieved at 18-21 days after the initiation of treatment. In contrast, rhabdomyosarcomas were considerably more sensitive, with T/C ratios being < 0.1 for three lines, whereas topotecan was less active against two other rhabdomyosarcoma xenografts (minimal T/C ratios, 0.17 and 0.14). As inhibitors of topoisomerase I have been demonstrated to have activity in the replication phase of the cell cycle (S-phase-specific), prolonged administration schedules were examined. Mice received topotecan 5 days per week for 3 weeks either by i.p. injection or by oral gavage (p.o.). In selected experiments, p.o. administration was continued for up to 20 weeks. Oral administration for 3 weeks (2 mg/kg per dose) resulted in complete regression of all six lines of rhabdomyosarcoma, with two lines demonstrating no regrowth during the period of observation (> or = 84 days). Similar results were obtained after i.p. administration, suggesting significant schedule dependency for these tumors. For colon tumors, the daily administration schedule (i.p. or p.o.) demonstrated some advantage over the intermittent schedule, resulting in partial regressions and significant inhibition of the growth of several colon adenocarcinoma lines. In rhabdomyosarcoma Rh12 and VRC5 colon adenocarcinoma, both of which demonstrated intermediate sensitivity to topotecan, and in osteosarcoma OS33, protracted p.o. administration for 13-20 weeks (1.0-1.5 mg/kg per dose given daily x 5 days) caused complete regression without regrowth in Rh12 and OS33 tumors and partial regression of all VRC5 tumors. No toxicity was observed using this schedule of administration. Topotecan demonstrated significant activity against all three osteosarcoma xenografts examined, with optimal schedules causing complete regression in two lines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. 146 61

N2-Isobutyryl-2'-deoxyguanosine-N7-cyanoborane derivatives were observed to be potent antineoplastic agents and to be active against a number of human tissue culture tumor cells, e.g. Tmolt3 leukemia, HeLa-S3 uterine carcinoma. Selective agents were active against colon adenocarcinoma, osteosarcoma and glioma growth. These agents preferentially inhibited both DNA and RNA synthesis of L1210 cells. De novo synthesis of purines was significantly inhibited at the regulatory sites of PRPP amido transferase and IMP dehydrogenase. Other sites of inhibition were thymidylate synthetase, OMP decarboxylase and thymidine kinases. The agents also significantly reduced deoxyribonucleotide levels and caused DNA strand scission.
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PMID:The synthesis and anti-neoplastic activity of N2-isobutyryl-2'-deoxyguanosine-N7-cyanoborane derivatives. 149 12

The sugar boronated thymidine nucleoside, 5' -0-[(triphenylphosphine-boryl) carbonyl]-3'-0-acetyl thymidine 1, and the boron-modified nucleoside phosphotriester, 5'-(diethylphosphite- cyanoborane)-3'-acetylthymidine 2, were successfully synthesized. Both compounds demonstrated differential activity when tested against eight cell lines, with significant cytotoxic activity against the growth of human Tmolt3 leukemia, colon adenocarcinoma, HeLa S3 uterine carcinoma, and osteosarcoma cells. In in vivo studies these agents were found to be active against the growth of Ehrlich ascites carcinoma at 8 mg/kg/day I.P. and to be marginally active against the growth of L1210 and Lewis lung cancers in mice. The mode of action of these thymidine derivatives in Tmolt3 cells was the inhibition of DNA and protein synthesis. Compound 2 was highly effective in inhibiting DNA polymerase alpha and m-RNA, r-RNA and t-RNA polymerase activities. Both compounds inhibited ribonucleoside reductase activity. The de novo purine pathway appeared to be the major site of inhibition of the agents, with IMP dehydrogenase, PRPP amido transferase, and dihydrofolate reductase activities being significantly inhibited. In the pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase activities were inhibited by 1. As expected, d[NTP] levels were significantly reduced by treatment with the agents. DNA strand scission was evident after incubating Tmolt3 cells for 24 hr with the agents.
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PMID:Antineoplastic activity of boron-containing thymidine nucleosides in Tmolt3 leukemic cells. 150 1

A series of tricyclohexyl- and triphenylphosphine boranes, carboxyboranes and cyanoboranes were synthesized. These compounds have potent hypolipidemic effects, antineoplastic and antiinflammatory activities in rodents. Furthermore, they demonstrated potent cyctotoxicity against standard human tissue culture lines. The compounds which afforded the best hypolipidemic activity, i.e. greater than 40% reduction of serum cholesterol and triglyceride levels, were diphenyl-(4-methylphenyl)-phosphine borane and triphenylphosphine carboxyborane. Other derivatives demonstrated more potent antineoplastic activity against the Ehrlich ascites carcinoma growth including triphenylphosphine cyanoborane, 2-amino-4-methyl-pyridine cyanoborane and 2-amino-pyridine cyanoborane. Most of the derivatives showed good activity against murine L1210 lymphoid leukemia, Tmolt3 human leukemia, uterine HeLaS cells, and human glioma cell growth. Select compounds were active against colon adenocarcinoma, KB nasopharynx, lung bronchogenic and osteosarcoma cell growth. Tricyclohexyl- and triphenylphosphine boranes and the carboxy derivatives of the latter borane demonstrated good antiinflammatory activity.
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PMID:Relationship of hypolipidemic and antineoplastic activities of tricyclohexyl- and triphenylphosphine boranes, carboxyboranes, cyanoboranes, and related derivatives. 152 68

Naturally occurring sesquiterpene lactones and their semisynthetic derivatives, such as the O = C-C = CH-bearing helenalin and its esters, have been shown to demonstrate potent cytotoxicity against the growth of murine L1210 lymphoid leukemia and human Tmolt3 leukemia, colon adenocarcinoma, HeLaS3, lung bronchogenic, KB, osteosarcoma, and glioma cells. The modes of action of helenalin in L1210 cells are the inhibition of DNA, RNA, and protein syntheses. This study confirms that thiol bearing enzymes of nucleic acid metabolism were significantly inhibited, e.g. DNA polymerase alpha, IMP hydrogenase, and ribonucleoside reductase. The addition of GSH to the reaction medium demonstrated total recovery of L1210 ribonucleoside reductase activity. Helenalin reduced cellular GSH levels in L1210 cells. Helenalin also reduced all four pool levels of d(NTP)s which would account for part of the observed inhibition of DNA synthesis. Reductions in the ribonucleotide pool levels were also generally evident after drug treatment. Thus, the sesquiterpene lactones appear to have more than one mode of action in L1210 cells. All of the modes of actions of helenalin are feasible mechanisms to lower nucleic acid synthesis and cause cell death of the L1210 leukemia cells.
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PMID:The cytotoxicity of helenalin, its mono and difunctional esters, and related sesquiterpene lactones in murine and human tumor cells. 152 2

2,3-Dihydrophthalazine-1,4-dione derivatives demonstrated potent cytotoxicity against the growth of murine leukemia cells and human single cell suspension, i.e. Tmolt3 leukemia and HeLa-S3, as well as colon adenocarcinoma and KB nasopharynx. However, only select compounds demonstrated activity against bronchogenic lung, osteosarcoma and glioma growth. 2,3-Dihydrophthalazine-1,4-dione was active in vivo against L1210 leukemia, Lewis lung and Ehrlich ascites carcinoma growth. In L1210 cells the agents inhibited both DNA and RNA synthesis, and a few of the compounds were capable of inhibiting protein synthesis at 3 times their ED50 values. When 2,3-dihydrophthalazine-1,4-dione and N-butyl-2,3-dihydrophthalazine-1,4-dione were examined for their mode of action in the L1210 lymphoid leukemia cells, the sites of inhibition by the agents appear to be the de novo purine pathway at the enzymes IMP dehydrogenase and PRPP amido transferase. IMP dehydrogenase activity was inhibited at least 45% by 45 min at 100 microM concentration of drugs whereas the remaining enzymes that were affected by the drugs were not inhibited as early. Secondary sites were dihydrofolate reductase and thymidylate synthetase. The d(NTP) levels were also reduced specifically dATP and dCTP levels.
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PMID:The anti-neoplastic activity of 2,3-dihydrophthalazine-1,4-dione and N-butyl-2,3-dihydrophthalazine-1,4-dione in human and murine tumor cells. 162 17

Taxotere (RP 56976; NSC 628503; N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol) is a new microtubule stabilizing agent. It is obtained by semisynthesis from a noncytotoxic precursor extracted from the needles of the tree, Taxus baccata L. Taxotere was evaluated for antitumor activity against a variety of transplantable tumors of mice. Taxotere had no marked schedule dependency and was found active by the i.v. and the i.p. routes. Upon i.v. administration, 9 of 11 tumor models tested responded to Taxotere. B16 melanoma was found highly sensitive to Taxotere, with a tumor growth inhibition of 0% and a 3.0 log10 tumor cell kill at the maximum tolerated dose. In the same trial, taxol produced only a 1.1 log10 tumor cell kill at the maximum tolerated dose. Taxotere cured early stage pancreatic ductal adenocarcinoma 03 (6 of 6 cures) and colon adenocarcinoma 38 (7 of 7 cures). It also effected greater than 80% complete regressions of advanced stage disease with both tumors. Taxotere was active against early and advanced stage colon adenocarcinoma 51, with 2.3 and 1.7 log10 cell kill, respectively. Four other tumors responded to a lesser extent: Lewis lung (5.5% tumor growth inhibition), Glasgow osteogenic sarcoma (27.2% tumor growth inhibition), L1210 and P388 leukemias (70 and 54% increase in life span, respectively). Because of its good preclinical activity and its unique mechanism of action, Taxotere has entered Phase I clinical trials.
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PMID:Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. 168 23


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