Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

Vindesine (VDS) was coupled directly to a monoclonal antibody (791T/36) raised against a human osteogenic sarcoma cell line, and methotrexate (MTX) was coupled to 791T/36 via an intervening human serum albumin (HSA) bridge. Both the VDS-791T/36 and MTX-HSA-791T/36 conjugates were cytotoxic in vitro specifically for tumour target cells expressing the 791T/36-defined antigen, while the free drug in each case was indiscriminately toxic to all target cells. The VDS-791T/36 conjugate retarded growth of osteogenic sarcoma xenografts in immunodeprived mice when administered in multiple doses. Free 791T/36 did not significantly affect tumour growth. VDS was tumour inhibitory, but was toxic to the mice at a total dose of 20 micrograms per kg body weight, while VDS-791T/36 conjugate was not toxic at total doses incorporating VDS at up to 45 mg per kg. It is suggested that this is due to selectivity conferred upon the conjugate by the antibody moiety, and that such conjugates may offer considerable potential as anti-cancer agents.
...
PMID:Experience in the preparation and experimental use of immunocytostatics. 659 15

The preparation and properties of a drug-carrier-antibody preparation are reported. The antifolate chemotherapeutic agent methotrexate was covalently coupled to human serum albumin as a carrier. The carrier-drug preparation was then chemically linked to a monoclonal antibody, raised originally against a human osteogenic sarcoma cell line, 791T, in a manner permitting retention of antibody-binding activity. The cytotoxic properties of the conjugate were tested in vitro in comparison with carrier-methotrexate and free methotrexate against a panel of tumour cell lines containing both antigenically cross-reactive cell lines and cell lines having low antigenic cross-reactivity with the monoclonal antibody. The cytotoxicity tests demonstrated that coupling of methotrexate to carrier caused a loss of some drug activity but that coupling of the antibody to the carrier-drug preparation permitted full expression of drug cytotoxicity against antibody-reactive cell lines. It was further demonstrated that the conjugate was selective in its action and was preferentially cytotoxic towards antibody-reactive cell types. The cytotoxicity against antibody-reactive cell lines was shown by competitive inhibition by free antibody to be entirely dependent on antibody binding. A clonogenic assay showed that the conjugate was capable of killing greater than 99% of 791T target cells. These results indicate that a drug-carrier antibody conjugate can be synthesized which has all the in vitro properties theoretically necessary for a successful antibody-targeted cytotoxic agent.
...
PMID:Preparation and properties of a drug-carrier-antibody conjugate showing selective antibody-directed cytotoxicity in vitro. 685 82

The immunoconjugate XMMCO-791/RTA consists of ricin A chain bound to a murine monoclonal antibody MoAb 791T. This monoclonal antibody (MoAb) binds to a glycoprotein of 72 kD, which is expressed on human colorectal carcinoma, ovarian carcinoma, and osteogenic sarcoma. XMMCO-791/RTA was tested in a Phase I trial with proposed dose escalation steps of 0.02, 0.04, 0.15, and 0.2 mg/kg per day. Twelve patients with metastatic colorectal carcinoma were treated at 0.02, 0.03, and 0.04 mg/kg per day dose levels administered over 1 hour on days 1-5. Study-related toxicities were hypotension (6 patients); greater than 10% weight gain (6 patients); peripheral edema (9 patients); fever (4 patients); confusion (3 patients); diarrhea (3 patients); proteinuria, as identified by dipstick (3 patients), greater than 0.6 mg/dl decrease in serum albumin (11 patients); greater than 25% decrease in oncotic pressure (10 patients), and a decrease in ionized calcium (8 patients). Six patients received a second course of treatment. HAMA levels developed in 9 patients and titers increased with number of courses administered. Decreased overall toxicity, in comparison to the first course, was noted, but one patient had an allergic-type response (hypotension, crushing chest pain, diaphoresis) after the test dose of the second course (HAMA level > 10,000 IgG). Life-threatening toxicity in the form of fluid shift, resulting in noncardiac pulmonary edema and third-spacing occurred after course 1 in 1 of 3 patients at the 0.04 mg/kg per day level. No further dose escalation was attempted and no antitumor activity was seen.
...
PMID:Phase I study of monoclonal antibody-ricin A chain immunoconjugate Xomazyme-791 in patients with metastatic colon cancer. 762 72

The potential usefulness of alpha-particle radioimmunotherapy in the treatment of osteosarcoma was studied in vitro by using the monoclonal antibody TP-3 and cells of three human osteosarcoma cell lines (OHS, SAOS and KPDX) differing in antigen expression. Cell survival curves were established after treatment with (a) 211At-TP-3 of different specific activities, (b) 211At-labeled bovine serum albumin (BSA), (c) free 211At and (d) external-beam X rays. The three osteosarcoma cell lines showed similar survival curves, whether treated with external-beam X rays, 211At-BSA or free 211At. The D0's were lower for free 211At than for 211At-BSA. The survival curves for 211At-TP-3 treatment, on the other hand, differed significantly among the cell lines, suggesting that sensitivity to 211At-TP-3 treatment was governed by cellular properties other than sensitivity to external-beam X rays. The cellular property most important for sensitivity to 211At-TP-3 treatment was the antigen expression. Cell inactivation after 211At-TP-3 treatment increased substantially with increasing specific activity of the 211At-TP-3. At high specific activities, the cytotoxic effect of 211At-TP-3 was significantly higher than that of 211At-BSA. In conclusion, 211At-TP-3 has the potential to give clinically favorable therapeutic ratios in the treatment of osteosarcoma.
...
PMID:Inactivation of human osteosarcoma cells in vitro by 211At-TP-3 monoclonal antibody: comparison with astatine-211-labeled bovine serum albumin, free astatine-211 and external-beam X rays. 805 93

Microcolonies were obtained by culturing cells of two human osteosarcoma lines (OHS and KPDX) and one human melanoma line (WIX-c) for either 24 or 72 h. The microcolonies were treated with either alpha-particle radiation emitted by the 211At-labelled monoclonal antibody (MAb) TP-3 or external beam X-rays. Survival of microcolonies was assayed by colony formation. Therapeutic gain factor (TGF) values were calculated for two survival levels, 50% and 20% microcolony regeneration (i.e. at least one cell in 50% or 20% of the colonies survived the treatments). The TGF values were affected by the specific activity of the 211At-MAb conjugate, the antigen expression of the cells and the size and growth pattern of the microcolonies. Treatment with 211At-TP-3 gave TGF values that varied from 1.3 +/- 0.4 to 4.5 +/- 0.7 (mean +/- s.e.). The antigen-rich OHS cell line had on average 1.6 times higher TGF than the antigen-poor KPDX cell line. The TGF increased significantly with colony size for the densely packed colonies of the KPDX cell line but not for the OHS cell line, which had colonies with cells growing in a more scattered pattern. Control experiments with the two non-specific 211At forms, free 211At and 211At-labelled bovine serum albumin, gave TGF values from 0.6 +/- 0.1 to 1.0 +/- 0.3. This study suggests that in vivo evaluation of 211At-MAbs using relevant tumour models is desirable.
...
PMID:Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody. 819 60

Derivatives of 2'-deoxyuridine and of the anticancer agent 5-fluoro-2'-deoxyuridine (FdUR) were linked indirectly via a human serum albumin carrier (HSA) to the murine antiosteosarcoma monoclonal antibody 791T/36. Starting from the 2'-deoxyuridines 1a and 1b, the new nucleosides containing 5'-succinamic acid 7 and 5'-maleamic acid 8 spacers were synthesized from the key intermediate 5'-aminonucleoside 4, and the ribofuronamidobenzoic acid 13 from ribofuranuronic acid 10. These nucleosides were linked via their spacer functionality to HSA. High molar substitution ratios (MSR: moles of drug/mole of HSA) of 25-40 for these derivative-HSA conjugates were achieved. All derivatives were less cytotoxic than the parent drug against both antigen positive osteogenic sarcoma 791T and antigen negative bladder carcinoma T24 cell lines; no IC50 was achieved with any derivative against 791T cells. The fluorodeoxyuridine-HSA conjugates were then further linked via a stable thioether bond to the mouse monoclonal antibody 791T/36. The optimum fluorinated 5'-succinamic acid immunoconjugate exhibited an IC50 of 1 microM against 791T and T24 cells, slightly better than that of fluorodeoxyuridine. The unconjugated derivative 7 was much less cytotoxic than immunoconjugate, with an IC50 of 62 microM on T24 cells, and failed to reach 50% inhibition of 791T cell growth at 290 microM concentration. Derivative 7-HSA conjugate was 10-fold less cytotoxic than the immunoconjugate against both cell lines. Immunoconjugates synthesized with the other 5-fluoro derivatives were unable to effect 50% inhibition of growth of cell lines. Nonfluorinated derivatives and their HSA conjugates and immunoconjugates exhibited no cytotoxicity.
...
PMID:Synthesis of 2'-deoxyuridine and 5-fluoro-2'-deoxyuridine derivatives and evaluation in antibody targeting studies. 849 26

Hyaluronidase has gained increasing interest as an adjuvant in local and systemic cancer therapy, despite the incomplete knowledge of its physiological function. To this end, direct intratumoral injection of bovine testicular hyaluronidase (500, 1600 or 7500 U in 50 microl phosphate-buffered saline (PBS)) was performed in orthotopic (o.t.) osteosarcoma xenografts grown in the hind leg of nude mice. Control tumours received 50 microl PBS alone or supplemented with 10% bovine serum albumin (BSA). Central tumour interstitial fluid pressure (IFP) and mean arterial blood pressure (MABP) were measured using the wick-in-needle technique and after cannulation of the carotid artery, respectively. IFP was 32 +/- 8 mmHg (n = 44, mean +/- SD) in untreated tumours and there was a significant correlation between tumour IFP and volume (P < 0.01). The hyaluronidase injection reduced IFP to 63-84% after 1 h compared with controls (P < 0.05) and in a non-linear concentration-dependent manner. MABP was not affected significantly. In conclusion, an intratumoral hyaluronidase injection might reduce IFP temporally in solid osteosarcoma xenografts.
...
PMID:Hyaluronidase reduces the interstitial fluid pressure in solid tumours in a non-linear concentration-dependent manner. 983 21

Elevated interstitial fluid pressure (IFP) in solid tumors may reduce the effect of systemically administered anticancer drugs. Modulation of the tumor extracellular matrix might reduce the elevated IFP. To study the influence of the microenvironment, the IFP was measured in human osteosarcoma xenografts grown both subcutaneously and orthotopically. The IFP response was recorded in xenografts grown at both sites after direct intratumoral injection of bovine testicular hyaluronidase (500 or 1600 units in 50 microliters saline). Control tumors received 50 microliters saline alone or 10% bovine serum albumin in saline. IFP was measured centrally in the tumors using the wick-in-needle technique, and mean arterial blood pressure was monitored after carotid cannulation. Tumor tissue sections were stained with hyaluronectin and analyzed for hyaluronan content using confocal laser scanning fluorescence microscopy. The baseline IFP was significantly higher in orthotopic (30 +/- 9 mmHg, n = 30) compared with subcutaneous tumors (17 +/- 6 mmHg, n = 11) of comparable sizes (p < 0.001). Injection of hyaluronidase reduced the IFP in both tumor models to 61-81% compared with controls 1 h after injection (p < 0.05), without affecting the mean arterial blood pressure significantly. The hyaluronan staining intensity increased in subcutaneous tumor sections, but remained unchanged in orthotopic tumor sections 1 h after injection of 1600 units of hyaluronidase. The IFP was restored within 48 h after hyaluronidase injection. Interestingly, IFP increased with tumor volume in orthotopic tumors, but not in subcutaneous tumors. In conclusion, intratumoral hyaluronidase injection reduces the IFP transiently in solid osteosarcoma xenografts. Furthermore, this study emphasizes that physiological parameters might differ significantly between human osteosarcoma xenografts grown subcutaneously versus orthotopically in nude mice.
...
PMID:Interstitial fluid pressure in human osteosarcoma xenografts: significance of implantation site and the response to intratumoral injection of hyaluronidase. 1113 54

Methotrexate covalently bound to human serum albumin in a 1:1 molar ratio (MTX-HSA) is a new macromolecular drug which is currently being studied in phase I clinical trials by the German Association for Medical Oncology (AIO) Phase I/II study group. Previous studies have shown that MTX-HSA differs favorably from unbound MTX in terms of plasma half-life time, tumor accumulation of albumin and uptake mechanisms into cancer cells. To achieve optimal drug efficacy, repeated treatment cycles were necessary. To evaluate the anti-tumor activity of MTX-HSA and MTX in pre-clinical in vivo models, we selected 7 solid human tumor xenografts growing s.c. in nude mice and administered drug either i.p. or i.v. weekly for 3 weeks. The maximal tolerated dose (MTD) of MTX-HSA in nude mice was 12.5 mg/kg given i.p. on days 1, 8 and 15, whereas the MTD for free MTX was 100 mg/kg given i.v. MTX-HSA was significantly more active (p > 0.01) than MTX in 3 models. In the soft tissue sarcoma SXF 1301, MTX-HSA effected complete remission/cure after a single injection, whereas free MTX resulted in short-lasting, partial tumor regression. In the prostate-cancer model PRXF PC3M, MTX-HSA produced growth inhibition of 92.8% of control or an optimal test/control (T/C) of 7.2% compared to a T/C of 20.8% for MTX (p = 0.05). In the osteosarcoma model SXF 1410, optimal T/C values were 10.2% and 14.5%, respectively (p = 0.025). In lung cancers LXFE 409 and LXFL 529, bladder cancer BXF 1258 and breast cancer MAXF 449, both compounds were inactive. The improved therapeutic effects seen in 3 xenograft models under MTX-HSA treatment are promising and might be due to specific accumulation of the compound in solid tumors owing to their enhanced permeability and retention effect. Thus, clinical development of MTX-HSA will continue and sarcomas as well as prostate cancers will be included as potential target tumors for upcoming clinical phase II trials.
...
PMID:Pre-clinical evaluation of a methotrexate-albumin conjugate (MTX-HSA) in human tumor xenografts in vivo. 1134 May 78

In chronically uncompensated diabetes mellitus, an increase has been observed in the content of advanced glycation endproduct (AGE)-modified proteins in various tissues, including bone. This increase can lead to a local imbalance in the secretion of cytokines and growth factors, and has been implicated in the pathophysiology of the longterm complications of diabetes. We have previously shown that the proliferation and differentiation of UMR106 rat osteosarcoma and MC3T3E1 mouse calvaria-derived cell lines are regulated by AGE-modified proteins, possibly through the recognition of these AGEs by specific membrane-associated receptors. In the present study, we investigated the effects of AGE-proteins on the secretion of insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBPs) by both osteoblast-like cell lines. In the case of MC3T3E1 cells, this was studied throughout their successive stages of development: proliferation, differentiation and mineralisation. For every condition, cells were incubated 24 hours with increasing concentrations of either bovine serum albumin (BSA) or AGE-BSA. IGF-I in conditioned media was separated from IGFBPs by acid gel filtration-centrifugation, and measured by radioimmunoassay. IGFBPs in conditioned media were analysed by a semi-quantitative western ligand blot. In UMR106 cells, low doses of AGE-BSA significantly decreased the secretion of both IGF-I (56% of control) and a 24 kDa IGFBP (80% of control). Results for MC3T3E1 cells, which predominantly secrete 29 kDa IGFBPs, were dependent on the stage of development. In proliferating preosteoblastic cells, AGE-BSA decreased the secretion of IGF-I (34%-37% of control) while increasing the secretion of IGFBP (124%-127% of control). On the other hand, secretion of these components of the IGF system by mature (differentiated) cells was unaffected by the presence of AGE-BSA. When these cells finally attained mineralisation, incubation with AGE-modified BSA provoked an increase both in IGFBP (131%-169% of control) and in IGF-I secretion (119%-123% of control). The presented evidence suggests that the modulation of growth and development by AGE-modified proteins, previously described for both cell lines, could be the result of an autocrine-paracrine mechanism involving the IGF-IGFBP system.
...
PMID:Effect of advanced glycation endproducts on the secretion of insulin-like growth factor-I and its binding proteins: role in osteoblast development. 1182 31


<< Previous 1 2 3 4 5 Next >>

---