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The Journal of Biological Chemistry Apr 2006Motexafin gadolinium (MGd) is a chemotherapeutic drug that selectively targets tumor cells and mediates redox reactions generating reactive oxygen species. Thioredoxin...
Motexafin gadolinium (MGd) is a chemotherapeutic drug that selectively targets tumor cells and mediates redox reactions generating reactive oxygen species. Thioredoxin (Trx), NADPH, and thioredoxin reductase (TrxR) of the cytosol/nucleus or mitochondria are major thiol-dependent reductases with many functions in cell growth, defense against oxidative stress, and apoptosis. Mammalian TrxRs are selenocysteine-containing flavoenzymes; MGd was an NADPH-oxidizing substrate for human or rat TrxR1 with a Km value of 8.65 microM (kcat/Km of 4.86 x 10(4) M(-1) s(-1)). The reaction involved redox cycling of MGd by oxygen producing superoxide and hydrogen peroxide. MGd acted as a non-competitive inhibitor (IC50 of 6 microM) for rat TrxR. In contrast, direct reaction between MGd and reduced human Trx was negligible. The corresponding reaction with reduced Escherichia coli Trx was also negligible, but MGd was a better substrate (kcat/Km of 2.23 x 10(5) M(-1) s(-1)) for TrxR from E. coli and a strong inhibitor of Trx-dependent protein disulfide reduction. Ribonucleotide reductase (RNR), a 1:1 complex of the non-identical R1- and R2-subunits, catalyzes the essential de novo synthesis of deoxyribonucleotides for DNA synthesis using electrons from Trx and TrxR. MGd inhibited recombinant mouse RNR activity with either 3 microM reduced human Trx (IC50 2 microM) or 4 mM dithiothreitol (IC50 6 microM) as electron donors. Our results demonstrate MGd-induced enzymatic generation of reactive oxygen species by TrxR plus a powerful inhibition of RNR. This may explain the effects of the drug on cancer cells, which often overproduce TrxR and have induced RNR for replication and repair.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cytosol; Disulfides; Dose-Response Relationship, Drug; Edetic Acid; Electrons; Escherichia coli; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Insulin; Kinetics; Metalloporphyrins; Models, Chemical; NADP; Oxidation-Reduction; Oxidative Stress; Oxygen; Protein Binding; Rats; Reactive Oxygen Species; Ribonucleotide Reductases; Spectrophotometry; Thioredoxin-Disulfide Reductase; Thioredoxins; Time Factors
PubMed: 16481328
DOI: 10.1074/jbc.M511373200 -
Neuro-oncology Oct 2008The purpose of this study was to determine the dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, and intratumor and brain distribution of motexafin...
The purpose of this study was to determine the dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, and intratumor and brain distribution of motexafin gadolinium (MGd) with involved field radiation therapy in children with newly diagnosed intrinsic pontine gliomas. MGd was administered as a 5-min intravenous bolus 2-5 h prior to standard radiation. The starting dose was 1.7 mg/kg. After first establishing that 5 doses/week for 6 weeks was tolerable, the dose of MGd was escalated until dose-limiting toxicity was reached. Radiation therapy was administered to 54 Gy in 30 once-daily fractions. Forty-four children received MGd at doses of 1.7 to 9.2 mg/kg daily prior to radiation therapy for 6 weeks. The maximum tolerated dose was 4.4 mg/kg. The primary dose-limiting toxicities were grade 3 and 4 hypertension and elevations in serum transaminases. Median elimination half-life and clearance values were 6.6 h and 25.4 ml/kg/h, respectively. The estimated median survival was 313 days (95% confidence interval, 248-389 days). The maximum tolerated dose of MGd and the recommended phase II dose was 4.4 mg/kg when administered as a daily intravenous bolus in conjunction with 6 weeks of involved field radiation therapy for pediatric intrinsic pontine gliomas.
Topics: Adolescent; Adult; Area Under Curve; Brain Stem Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Female; Glioma; Half-Life; Humans; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Metalloporphyrins; Pons; Radiation-Sensitizing Agents; Radiotherapy
PubMed: 18715950
DOI: 10.1215/15228517-2008-043 -
Annals of Translational Medicine Mar 2020Studies have increasingly shown that carbamoyl phosphate synthetase 1 () plays a vital role in the occurrence and development of human malignant disease. Unfortunately,...
BACKGROUND
Studies have increasingly shown that carbamoyl phosphate synthetase 1 () plays a vital role in the occurrence and development of human malignant disease. Unfortunately, the detailed function of in the development and prognosis of lung cancer, especially lung adenocarcinoma (LADC), is still not fully understood. In this research, we performed a comprehensive bioinformatics analysis with respect to the function of in human LADC.
METHODS
Several biological databases including UALCAN, GEPIA and Oncomine were used to analyze the expression of in LADC. Meanwhile, TCGA and GEO databases were utilized to analyze relevant clinical data. In addition, databases including Methsurv, etc., were used to analyze methylation levels in LADC.
RESULTS
The Oncomine platform, UALCAN and gene expression profiling interactive analysis (GEPIA) were used and revealed that the expression levels of were significantly increased in LADC tissues. Furthermore, we analyzed the methylation level of in LADC and found that cases with high levels of showed hypomethylated . The clinical data from the Wanderer database, which is linked to The Cancer Genome Atlas (TCGA) database, demonstrated that the expression and methylation values of were both significantly related to the clinical characteristics and prognosis of LADC. Through analysis of the dataset from the Gene Expression Omnibus (GEO) database, we found that the expression level of was markedly downregulated in human A549 lung cancer cells treated with the chemotherapeutic drug motexafin gadolinium (MGd) in a time-dependent manner.
CONCLUSIONS
Our work indicated that is upregulated in LADC samples and that might be used as a potential biomarker for the diagnostic and prognostic evaluation of LADC. Determining the detailed biological function of in LADC tissues will provide promising and insightful information for our further study.
PubMed: 32355785
DOI: 10.21037/atm.2020.02.146 -
International Journal of Nanomedicine 2007Despite recent advances in technology, targeting, and chemotherapy, brain metastasis from non-small cell lung cancer (NSCLC) remains a significant problem. The vast... (Review)
Review
Despite recent advances in technology, targeting, and chemotherapy, brain metastasis from non-small cell lung cancer (NSCLC) remains a significant problem. The vast majority of patients with this diagnosis undergo whole brain radiation therapy (WBRT). However, outcomes are still quite poor with median survivals measured in only months. In an effort to enhance outcomes from external beam radiation treatments, radiosensitizers have been investigated. Motexafin gadolinium (MGd) (Xcytrin, Sunnyvale, CA, USA) is a novel radiation sensitizer with a unique mechanism of action that may increase the therapeutic index of WBRT for patients with brain metastases, particularly in those with NSCLC histologies. Here we review the rationale for the use of this drug as well as its current and future role as a radiation enhancer in the management of NSCLC brain metastasis.
Topics: Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Carriers; Drug Delivery Systems; Humans; Injections, Intralesional; Lung Neoplasms; Metalloporphyrins; Nanomedicine; Nanostructures; Photosensitizing Agents; Treatment Outcome
PubMed: 17722515
DOI: 10.2147/nano.2007.2.1.79 -
Journal of Neuro-oncology Jan 2009Photodynamic therapy (PDT) has been investigated as a postoperative treatment in patients with high grade gliomas. The purpose of this in vitro investigation was to...
Photodynamic therapy (PDT) has been investigated as a postoperative treatment in patients with high grade gliomas. The purpose of this in vitro investigation was to determine whether motexafin gadolinium (MGd), a known radiation sensitizer, could potentiate the effects of 5-aminolevulinic acid (ALA)-PDT. Human glioma (ACBT) spheroids (250 microm diameter) were incubated in 5-aminolevulinic acid (ALA) with and without MGd and irradiated with 635 nm light for a total light fluence of 6, 12, or 18 J cm(-2) delivered at a fluence rate of 5 mW cm(-2). Spheroid growth was monitored for a period of 4 weeks following each treatment. In another set of experiments, 400-500 microm diameter ACBT spheroids were implanted into a gel collagen matrix and subjected to ALA-PDT (fluence: 3 or 6 J cm(-2)), MGd, or a combination of ALA-PDT and MGd. The migration distance of surviving glioma cells in each treatment group was recorded over a 5-day period. The results showed that MGd interacted with PDT in a synergistic manner resulting in greater cytotoxicity than that achievable with either treatment modality alone. The degree of synergism was shown to increase with increasing light fluence. At the highest light fluence investigated (18 J cm(-2)), the percentage of spheroids demonstrating growth 4 weeks following exposure to MGd, ALA-PDT, or MGd + ALA-PDT was 100%, 75%, and 15%, respectively. The results of cell migration studies revealed that the combination of PDT and MGd produced a significant inhibitory effect on glioma cell migration: the addition of MGd resulted in an approximately three times reduction in migration distance compared with PDT alone. Overall, the results suggest that MGd can potentiate both the cytotoxic and migration inhibitory effects of ALA-PDT and hence, this combined therapeutic approach has the potential to extend treatment volumes in patients with malignant gliomas.
Topics: Aminolevulinic Acid; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Radiation; Drug Synergism; Ethidium; Glioma; Humans; Metalloporphyrins; Neoplasm Invasiveness; Photochemotherapy; Spheroids, Cellular; Time Factors
PubMed: 18777009
DOI: 10.1007/s11060-008-9692-4 -
Cancers Sep 2022Background: Residual viable tumor cells after ablation at the tumor periphery serve as the source for tumor recurrence, leading to treatment failure. Purpose: To develop...
Background: Residual viable tumor cells after ablation at the tumor periphery serve as the source for tumor recurrence, leading to treatment failure. Purpose: To develop a novel three-dimensional (3D) multi-modal perfusion-thermal electrode system completely eradicating medium-to-large malignancies. Materials and Methods: This study included five steps: (i) design of the new system; (ii) production of the new system; (iii) ex vivo evaluation of its perfusion-thermal functions; (iv) mathematic modeling and computer simulation to confirm the optimal temperature profiles during the thermal ablation process, and; (v) in vivo technical validation using five living rabbits with orthotopic liver tumors. Results: In ex vivo experiments, gross pathology and optical imaging demonstrated the successful spherical distribution/deposition of motexafin gadolinium administered through the new electrode, with a temperature gradient from the electrode core at 80 °C to its periphery at 42 °C. An excellent repeatable correlation of temperature profiles at varying spots, from the center to periphery of the liver tumor, was found between the mathematic simulation and actual animal tumor models (Pearson coefficient ≥0.977). For in vivo validation, indocyanine green (ICG) was directly delivered into the peritumoral zones during simultaneous generation of central tumoral lethal radiofrequency (RF) heat (>60 °C) and peritumoral sublethal RF hyperthermia (<60 °C). Both optical imaging and fluorescent microscopy confirmed successful peritumoral ICG distribution/deposition with increased heat shock protein 70 expression. Conclusion: This new 3D, perfusion-thermal electrode system provided the evidence on the potential to enable simultaneous delivery of therapeutic agents and RF hyperthermia into the difficult-to-treat peritumoral zones, creating a new strategy to address the critical limitation, i.e., the high incidence of residual and recurrent tumor following thermal ablation of unresectable medium-to-large and irregular tumors.
PubMed: 36230690
DOI: 10.3390/cancers14194768 -
Angewandte Chemie (International Ed. in... Oct 2016Water-soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to...
Water-soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co-incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of Pt(IV) to Pt(II) promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt(IV) species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present "activation by reduction" approach may allow for the cancer-selective enhancement in the cytotoxicity of Pt(IV) prodrugs.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Electrochemical Techniques; Humans; Metalloporphyrins; Oxidation-Reduction; Platinum; Prodrugs
PubMed: 27377046
DOI: 10.1002/anie.201604236 -
3.0-T MR imaging of intracoronary local delivery of motexafin gadolinium into coronary artery walls.Radiology Aug 2013To develop a technique with clinical 3.0-T magnetic resonance (MR) imaging to delineate local contrast agent distribution in coronary artery walls for potential...
PURPOSE
To develop a technique with clinical 3.0-T magnetic resonance (MR) imaging to delineate local contrast agent distribution in coronary artery walls for potential molecular MR imaging-guided local gene or drug therapy of atherosclerotic coronary artery disease.
MATERIALS AND METHODS
This animal protocol was approved by the institutional animal care and use committee and was in compliance with the Guide for the Care and Use of Laboratory Animals. For in vitro confirmation, human arterial smooth muscle cells (SMCs) were used to determine capability of SMCs in uptake of motexafin gadolinium (MGd) and its optimal dose. For ex vivo evaluation, a 2-mL mixture of MGd and trypan blue was locally infused into coronary artery walls of six cadaveric pig hearts with MR monitoring and an MR imaging guidewire, surface coils, or both. For in vivo validation, the balloon catheter was placed into coronary arteries of seven living pigs, and the MGd and trypan blue mixture was infused into arterial walls with MR guidance. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of coronary artery walls were recorded by using different coils between pre- and postcontrast infusion, with subsequent histologic confirmation. Paired Student t tests were used to compare average SNRs and CNRs of arterial walls before and after contrast agent infusion with different coils.
RESULTS
SMCs could take up MGd with the optimal concentration at 150 µmol/L. Average SNR with the MR imaging guidewire and surface coil combination was significantly higher than that with the MR imaging guidewire only or with surface coils only (P < .05), and average SNR and CNR of postinfusion MR imaging was significantly higher than that of preinfusion MR imaging (P < .05). Histologic analysis was used to confirm successful intracoronary infiltration of MGd and trypan blue within coronary artery walls.
CONCLUSION
MR imaging can be used to delineate locally infused contrast agent distribution in coronary artery walls. This establishes groundwork for development of molecular MR imaging-guided intracoronary therapy.
Topics: Animals; Contrast Media; Coronary Vessels; In Vitro Techniques; Magnetic Resonance Imaging; Metalloporphyrins; Microscopy, Confocal; Signal-To-Noise Ratio; Swine; Tryptophan
PubMed: 23513243
DOI: 10.1148/radiol.13121451 -
Proceedings of the National Academy of... Mar 2020Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2)...
Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.
Topics: A549 Cells; Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; HCT116 Cells; Humans; Metalloporphyrins; Mice, Nude; Oxaliplatin; Prodrugs; Tissue Distribution; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 32179677
DOI: 10.1073/pnas.1914911117 -
Proceedings of the National Academy of... Feb 2002Here, we show that motexafin gadolinium (Gd-Tex), a compound that promotes intracellular oxidative stress, selectively induces apoptosis in HIV-1-infected CD4(+) T cells...
Here, we show that motexafin gadolinium (Gd-Tex), a compound that promotes intracellular oxidative stress, selectively induces apoptosis in HIV-1-infected CD4(+) T cells in IL-2-stimulated cultures of peripheral blood mononuclear cells infected in vitro with HIV-1. This selective induction of apoptosis, which we detect by FACS analysis of intracellular HIV/p24 and concomitant surface and apoptosis marker expression, is abrogated by the glutathione precursor, N-acetyl-l-cysteine. Importantly, it occurs at Gd-Tex concentrations that are not cytotoxic to uninfected cells in the culture. These findings suggest that Gd-Tex may have therapeutic utility as an anti-HIV agent capable of selectively targeting and removing HIV-infected cells in an infected host.
Topics: Acetylcysteine; Annexin A5; Antineoplastic Agents; Apoptosis; CD4-Positive T-Lymphocytes; Cell Separation; Coloring Agents; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; HIV-1; Metalloporphyrins; Models, Chemical; Oxidative Stress; Oxygen; T-Lymphocytes, Helper-Inducer; Time Factors
PubMed: 11854523
DOI: 10.1073/pnas.261711499