Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0393754 (HSA)
 2,996 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A soluble immune complex was used as a drug carrier targeted to Fc-receptor-positive cells. Two receptor-positive tumor cell lines, WEHI-3 and M5076, were exposed to methotrexate-human serum albumin conjugate (MTX-HSA) in the presence and absence of anti-HSA antiserum. Both cell types were killed by 30 nM MTX when the drug conjugate was given in the presence of antiserum but were totally unaffected in the absence of antiserum. Drug-free HSA given with antiserum had no effect. Both cell lines responded similarly despite their marked difference in phagocytotic activity. One of the two lines, M5076, is defective in MTX transport and hence resistant to free MTX. Since this line would not be affected by MTX released extracellularly from MTX-HSA, its susceptibility implies that MTX is released inside cells, after endocytosis of the complex, and that endocytosis circumvents the transport defect. Two cell lines lacking Fc receptors (CHO and L929) were not influenced by the drug complex. The pharmacologic effect is mediated by a specific ligand-receptor interaction, since Fc receptor-positive cells are protected by an excess of unconjugated HSA and by the addition of a small amount of staphylococcal protein A, which binds to the Fc portion of IgG. These data demonstrate that Fc receptors can be exploited for cellular drug delivery using a common antigen-antibody complex as a drug carrier.
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PMID:Selective killing of Fc-receptor-bearing tumor cells through endocytosis of a drug-carrying immune complex. 636 28

The active principles of a monoclonal antibody (791T/36)-human serum albumin-methotrexate (MoAb-HSA-MTX) conjugate have been investigated and identified. This drug-carrier conjugate has previously been shown to be selective for the target cell line, more potent than the 'free' drug, to be internalized into the lysosomes of the cell and to work by a lysosomotropic mechanism. Digestion of MTX-HSA by lysosomal enzymes showed three peaks by HPLC assay. Using authentic standards prepared by solid-phase peptide synthesis, these peaks were identified as 'free' MTX, MTX-Lys (alpha-epsilon) and MTX-Lys (gamma-epsilon). Optimization of the digestion conditions allowed for a maximum total release of MTX-containing material of 5% after 48 h. Of this released material, only 10% was in the form of 'free' MTX. It was shown that increasing the ratio of drug to carrier improved the efficiency of release of drug, and these results were complemented by in vitro cytotoxicity assays. Such a low level of drug release associated with a conjugate which has been shown to be superior, in terms of cytotoxicity, to 'free' drug against the target cell line was an unexpected finding. The consequences of these results are discussed.
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PMID:Studies on the mechanism of action of an MTX-HSA-MoAb conjugate. 769 11

Methotrexate-albumin conjugate (MTX-HSA) is a novel human albumin-based prodrug conjugate of methotrexate (MTX). A low MTX loading rate provided optimal tumor targeting and therapeutic efficacy during preclinical testing. The objectives of this first Phase I study of MTX-HSA were to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in a weekly regimen. Seventeen cancer patients who were no longer amenable to standard treatment were enrolled and were evaluable for DLT. Up to eight injections were performed in weekly intervals. Dose escalation was as follows: 20, 40, 50, and then 60 mg/m2 MTX-HSA (based on the amount of MTX bound to albumin). Additional MTX-HSA courses were feasible in case of tumor response. DLT (mainly stomatitis, Common Toxicity Criteria grade 3) occurred, beginning at the 50 mg/m2 dose level after repeated administrations; in one case, thrombocytopenia was dose-limiting. Two events of DLT occurred at the 60 mg/m2 dose level within the first two administrations. Mild anemia, transaminitis, and one case of skin toxicity were found. No significant leukopenia, nausea, renal toxicity, or other toxicities were observed. MTX-HSA was well tolerated. Drug accumulation occurred on the weekly schedule. The half-life of the drug was estimated to be up to 3 weeks. Tumor responses were seen in three patients: (a) a partial response was seen in one patient with renal cell carcinoma (response duration, 30 months, ongoing); (b) a minor response was seen in one patient with pleural mesothelioma (response duration, 31 months, ongoing); and (c) a minor response was seen in one patient with renal cell carcinoma (response duration, 14 months until progression). Poststudy treatment was administered at 2-4-week intervals. No signs of toxicity or drug accumulation were seen. Altered pharmacological properties of MTX-HSA such as plasma half-life, tumor targeting, or intracellular metabolism might have contributed to these responses. The MTD for weekly administration was 4 x 50 mg/m2 MTX-HSA during short-term treatment. A regimen with MTX-HSA injections of 50 mg/m2 every 2 weeks was recommended for a further clinical Phase I study.
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PMID:Phase I trial of methotrexate-albumin in a weekly intravenous bolus regimen in cancer patients. Phase I Study Group of the Association for Medical Oncology of the German Cancer Society. 1021 9

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.
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PMID:Pre-clinical evaluation of a methotrexate-albumin conjugate (MTX-HSA) in human tumor xenografts in vivo. 1134 May 78

Active targeting could increase the efficacy of anticancer drugs. Methotrexate-human serum albumin (MTX-HSA) conjugates, functionalized by luteinizing hormone-releasing hormone (LHRH) as targeting moieties, with the aim of specifically targeting the cancer cells, were prepared. Owing to the high expression of LHRH receptors in many cancer cells as compared to normal cells, LHRH was used as the targeting ligand in this study. LHRH was conjugated to MTX-HSA nanoparticles via a cross-linker. Three types of LHRH targeted nanoparticles with a mean particle size between 120-138 nm were prepared. The cytotoxicity of LHRH targeted and non-targeted nanoparticles were determined on the LHRH positive and negative cell lines. The internalization of the targeted and non-targeted nanoparticles in LHRH receptor positive and negative cells was investigated using flow cytometry analysis and fluorescence microscopy. The cytotoxicity of the LHRH targeted nanoparticles on the LHRH receptor positive cells were significantly more than non-targeted nanoparticles. LHRH targeted nanoparticles were also internalized by LHRH receptor positive cells significantly more than non-targeted nanoparticles. There were no significant differences between the uptake of targeted and non-targeted nanoparticles to the LHRH receptor negative cells. The active targeting procedure using LHRH targeted MTX-HSA nanoparticles could increase the anti-tumoral activity of MTX.
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PMID:Enhanced anti-tumoral activity of methotrexate-human serum albumin conjugated nanoparticles by targeting with Luteinizing Hormone-Releasing Hormone (LHRH) peptide. 2184 98

The use of targeted drug delivery systems is a growing trend in cancer treatment to decrease the adverse effect of anti-cancer drugs. In this study, we sought to conjugate methotrexate-human serum albumin nanoparticles (MTX-HSA NPs) with luteinizing-hormone releasing hormone (LHRH). The LHRH was intended to target LHRH receptors overexpressed on the several types of tumors. The expression of LHRH receptors on the 4T1 breast cancer cells was confirmed by FITC conjugated LHRH receptor antibody using fluorescence microscopy. Female Balb/c mice bearing 4T1 breast cancer tumor were treated with a single i.v. injection of free MTX, non-targeted MTX-HSA NPs and LHRH targeted MTX-HSA NPs. LHRH targeted MTX-HSA nanoparticles showed stronger anti-tumor activity in vivo. By 7 days after treatment, average tumor volume in the LHRH targeted MTX-HSA NPs treated group decreased to 8.67% of the initial tumor volume when the number of attached LHRH molecules on MTX-HSA NPs was the highest, while the average tumor volume in non-targeted MTX-HSA NPs treated mice grew rapidly and reached 250.7% of the initial tumor volume 7 days after the treatment. LHRH targeted MTX-HSA NPs could significantly extend the survival time of tumor bearing mice compared with the non-targeted MTX-HSA NPs and free MTX formulations.
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PMID:The in vivo antitumor activity of LHRH targeted methotrexate-human serum albumin nanoparticles in 4T1 tumor-bearing Balb/c mice. 2253 53

Targeted drug delivery systems could reduce the systemic toxicity of anticancer drugs following cancer chemotherapy. In this study we developed methotrexate-human serum albumin conjugated nanoparticles (MTX-HSA NPs) which were surface decorated using trastuzumab (TMAB) molecules. The size of TMAB-MTX-HSA NPs was between 123 and 346 nm according to the amount of TMAB molecules conjugated on their surfaces. The cytotoxicity of TMAB-MTX-HSA NPs on HER2 positive cells after 24h was significantly higher than that for non-targeted MTX-HSA NPs and also free MTX. However when the number of attached TMAB molecules was very high, the cytotoxicity of TMAB-MTX-HSA NPs was similar to the cytotoxicity of non-targeted MTX-HSA NPs approximately. There were no significant differences between cytotoxicity of TMAB-MTX-HSA NPs and MTX-HSA NPs for HER2 negative cells after 24h. The results of flow cytometry analysis showed that the binding activity of TMAB molecules remained approximately unchanged after conjugation, if the number of the attached TMAB molecules on the surface of MTX-HSA NPs was not very high. Moreover, TMAB-MTX-HSA NPs showed higher uptake to HER2 positive cells compared to non-targeted MTX-HSA NPs when the optimized amount of TMAB was conjugated on the surface of NPs. In conclusion, conjugation of TMAB molecules on the MTX conjugated HSA nanoparticles is an appropriate method for active tumor targeting of MTX.
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PMID:Trastuzumab decorated methotrexate-human serum albumin conjugated nanoparticles for targeted delivery to HER2 positive tumor cells. 2277 47