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Expert Opinion on Drug Discovery Feb 2011Motexafin gadolinium is a radiation sensitizer that is in the class of drugs known as texaphyrins. Though this drug is currently not FDA approved in the management of...
INTRODUCTION
Motexafin gadolinium is a radiation sensitizer that is in the class of drugs known as texaphyrins. Though this drug is currently not FDA approved in the management of brain tumors, several prospective studies have been done showing promise with this agent, which this review highlights.
AREAS COVERED
This paper provides a clinical context by reviewing the background of radiosensitizers, followed by a review of the preclinical discovery of motexafin gadolinium and its clinical testing. We also highlight its most promising applications and comment on the reasons for the observed clinical outcomes.
EXPERT OPINION
Motexafin gadolinium is a novel radiosensitizer with clearly documented efficacy, particularly in patients with brain metastases. If this agent had been tested upfront in patients diagnosed with brain metastases from NSCLC who had not been delayed by the administration of systemic chemotherapy, it may have become part of the standard of care in this setting. Continued investigations using this agent are under way and remain promising.
PubMed: 22647136
DOI: 10.1517/17460441.2011.546395 -
International Journal of Radiation... Jan 2013To evaluate the effects on 1-year event-free survival (EFS) and overall survival (OS) of combining motexafin and gadolinium (MGd), a potent radiosensitizer, with daily...
PURPOSE
To evaluate the effects on 1-year event-free survival (EFS) and overall survival (OS) of combining motexafin and gadolinium (MGd), a potent radiosensitizer, with daily fractionated radiation therapy in children with newly diagnosed intrinsic pontine gliomas.
METHODS AND MATERIALS
Patients with newly diagnosed intrinsic pontine glioma were treated with MGd daily for 5 consecutive days each week, for a total of 30 doses. Patients received a 5- to 10-min intravenous bolus of MGd, 4.4 mg/kg/day, given 2 to 5 h prior to standard dose irradiation. Radiation therapy was administered at a daily dose of 1.8 Gy for 30 treatments over 6 weeks. The total dose was 54 Gy.
RESULTS
Sixty eligible children received MGd daily, concurrent with 6 weeks of radiation therapy. The estimated 1-year EFS was 18%±5%, and the estimated 1-year OS was 53%±6.5%. The most common grade 3 to 4 toxicities were lymphopenia, transient elevation of liver transaminases, and hypertension.
CONCLUSIONS
Compared to historical controls, the addition of MGd to a standard 6-week course of radiation did not improve the survival of pediatric patients with newly diagnosed intrinsic pontine gliomas.
Topics: Adolescent; Brain Stem Neoplasms; Child; Child, Preschool; Disease-Free Survival; Dose Fractionation, Radiation; Drug Administration Schedule; Female; Glioma; Humans; Hypertension; Infant; Infusions, Intravenous; Liver; Lymphopenia; Male; Metalloporphyrins; Pons; Radiation-Sensitizing Agents
PubMed: 23092726
DOI: 10.1016/j.ijrobp.2012.09.004 -
Nature Communications Oct 2023Gadolinium (Gd)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient...
Gadolinium (Gd)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient radiosensitization efficacy. Little attention has been given to using nanovesicles to improve its efficacy. Herein, Gd-Tex is transformed into building blocks "Gd-Tex-lipids" to self-assemble nanovesicles called Gd-nanotexaphyrins (Gd-NTs), realizing high density packing of Gd-Tex in a single nanovesicle and achieving high Gd-Tex accumulation in tumors. To elucidate the impact of O concentration on Gd-Tex radiosensitization, myoglobin (Mb) is loaded into Gd-NTs (Mb@Gd-NTs), resulting in efficient relief of tumor hypoxia and significant enhancement of Gd-Tex radiosensitization, eventually inducing the obvious long-term antitumor immune memory to inhibit tumor recurrence. In addition to Gd, the versatile Mb@Gd-NTs can also chelate Lu (Mb@Lu/Gd-NTs), enabling SPECT/MRI dual-modality imaging for accurately monitoring drug delivery in real-time. This "one-for-all" nanoplatform with the capability of chelating various trivalent metal ions exhibits broad clinical application prospects in imaging-guided radiosensitization therapy.
Topics: Humans; Gadolinium; Myoglobin; Oxygen; Radiation-Sensitizing Agents; Neoplasms; Magnetic Resonance Imaging
PubMed: 37794000
DOI: 10.1038/s41467-023-41782-w -
Cancer Research May 2005To gain a better understanding of the mechanism of action of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling... (Comparative Study)
Comparative Study
To gain a better understanding of the mechanism of action of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer.
Topics: Acetates; Antineoplastic Agents; Cadmium; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Gene Expression; Gene Expression Profiling; Humans; Lung Neoplasms; Lymphoma, B-Cell; Male; Metalloporphyrins; Neoplasms; Oxidation-Reduction; Prostatic Neoplasms; Thioctic Acid; Zinc; Zinc Acetate
PubMed: 15867382
DOI: 10.1158/0008-5472.CAN-04-4099 -
Clinical Cancer Research : An Official... Jan 2006We present preclinical data showing the in vitro intranuclear uptake of motexafin gadolinium by glioblastoma multiforme cells, which could serve as a prelude to the...
PURPOSE
We present preclinical data showing the in vitro intranuclear uptake of motexafin gadolinium by glioblastoma multiforme cells, which could serve as a prelude to the future development of radiosensitizing techniques, such as gadolinium synchrotron stereotactic radiotherapy (GdSSR), a new putative treatment for glioblastoma multiforme.
EXPERIMENTAL DESIGN
In this approach, administration of a tumor-seeking Gd-containing compound would be followed by stereotactic external beam radiotherapy with 51-keV photons from a synchrotron source. At least two criteria must be satisfied before this therapy can be established: Gd must accumulate in cancer cells and spare the normal tissue; Gd must be present in almost all the cancer cell nuclei. We address the in vitro intranuclear uptake of motexafin gadolinium in this article. We analyzed the Gd distribution with subcellular resolution in four human glioblastoma cell lines, using three independent methods: two novel synchrotron spectromicroscopic techniques and one confocal microscopy. We present in vitro evidence that the majority of the cell nuclei take up motexafin gadolinium, a drug that is known to selectively reach glioblastoma multiforme.
RESULTS
With all three methods, we found Gd in at least 90% of the cell nuclei. The results are highly reproducible across different cell lines. The present data provide evidence for further studies, with the goal of developing GdSSR, a process that will require further in vivo animal and future clinical studies.
Topics: Brain Neoplasms; Cell Line, Tumor; Cell Nucleus; Glioblastoma; Humans; In Vitro Techniques; Magnetic Resonance Imaging; Metalloporphyrins; Microscopy, Confocal; Microscopy, Electron, Scanning Transmission; Radiation-Sensitizing Agents
PubMed: 16397044
DOI: 10.1158/1078-0432.CCR-05-0743 -
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 -
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 -
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 -
Clinical Cancer Research : An Official... Oct 2009Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets...
The novel expanded porphyrin, motexafin gadolinium, combined with [90Y]ibritumomab tiuxetan for relapsed/refractory non-Hodgkin's lymphoma: preclinical findings and results of a phase I trial.
PURPOSE
Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation.
EXPERIMENTAL DESIGN
We did preclinical studies examining motexafin gadolinium combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of motexafin gadolinium concurrently with standard [(90)Y]ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin's lymphoma.
RESULTS
In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through a mitochondrial-mediated caspase-dependent pathway, whereas cell death in Ramos and SUDHL4 cells was additive. Motexafin gadolinium/rituximab combined with radiation (1-3 Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47-87 years), and histologies were marginal-zone (n = 1), mantle-cell (n = 3), diffuse large cell (n = 6), and follicular lymphoma (n = 18). Of all patients, 86% were rituximab refractory. Therapy was well tolerated, and no dose-limiting toxicity was seen. Overall response rate was 57% [complete remission (CR), 43%], with median time-to-treatment failure of 10 months (1-48+ months) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n = 14), overall response rate was 86% (CR, 64%), with a median time-to-treatment failure of 14 months (2-48+ months).
CONCLUSIONS
This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Furthermore, tumor responses with [(90)Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Combined Modality Therapy; Drug Administration Schedule; Female; Humans; Lymphoma, Non-Hodgkin; Male; Metalloporphyrins; Middle Aged; Porphyrins; Radiation-Sensitizing Agents; Radioimmunotherapy; Recurrence; Treatment Outcome; Yttrium Radioisotopes
PubMed: 19825958
DOI: 10.1158/1078-0432.CCR-09-0905 -
Cancer Research Dec 2005There is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin...
There is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. Here, we report the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. We find that increased levels of oxidative stress and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. To better understand the molecular basis of these cellular responses, gene expression profiling analyses were conducted on Ramos cell cultures treated with MGd and/or zinc acetate. Cultures treated with MGd or zinc acetate alone elicited transcriptional responses characterized by induction of metal response element-binding transcription factor-1 (MTF-1)-regulated and hypoxia-inducible transcription factor-1 (HIF-1)-regulated genes. Cultures cotreated with MGd and zinc acetate displayed further increases in the levels of MTF-1- and HIF-1-regulated transcripts as well as additional transcripts regulated by NF-E2-related transcription factor 2. These data provide insights into the molecular changes that accompany the disruption of intracellular zinc homeostasis and support a role for MGd in treatment of B-cell hematologic malignancies.
Topics: Antineoplastic Agents; Apoptosis; DNA-Binding Proteins; Gene Expression Profiling; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lymphoma, B-Cell; Metalloporphyrins; NF-E2-Related Factor 2; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Response Elements; S Phase; Transcription Factors; Tumor Cells, Cultured; Zinc; Transcription Factor MTF-1
PubMed: 16357179
DOI: 10.1158/0008-5472.CAN-05-2754