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Molecular Cancer Therapeutics May 2006Motexafin gadolinium (MGd, Xcytrin) is a tumor-selective expanded porphyrin that targets oxidative stress-related proteins. MGd treatment of the follicular...
Motexafin gadolinium (MGd, Xcytrin) is a tumor-selective expanded porphyrin that targets oxidative stress-related proteins. MGd treatment of the follicular lymphoma-derived cell line HF-1 resulted in growth suppression and apoptosis whereas MGd treatment of the Burkitt's lymphoma-derived cell line Ramos resulted in growth suppression but not apoptosis. Because phosphorylation status of Akt/protein kinase B is regulated by oxidative stress, we monitored total and phosphorylated Akt (pAkt) in MGd-treated HF-1 and Ramos cells. Levels of pAkt increased within 30 minutes after MGd treatment of HF-1 but after 4 hours began to show a progressive decline to below baseline levels before cells underwent apoptosis. In MGd-treated Ramos cells, pAkt increased approximately 2-fold within 4 hours and remained persistently elevated. Because pAkt activates survival pathways, we determined if MGd-induced cell death could be enhanced by inhibiting phosphorylation of Akt. The addition of specific inhibitors of Akt phosphorylation (Akt inhibitor 1 or SH-5) reduced pAkt levels in MGd-treated HF-1 and Ramos cells and synergistically enhanced MGd-induced cell death. MGd was also evaluated in combination with celecoxib, an inhibitor of Akt phosphorylation, or docetaxel, a microtubule inhibitor that can decrease Akt phosphorylation. The combination of MGd/celecoxib or MGd/docetaxel resulted in decreased Akt phosphorylation and in synergistic cytotoxicity compared with either agent alone. These data point to a potential protective role for pAkt in MGd-induced apoptosis and suggest that MGd activity may be enhanced by combining it with agents that inhibit Akt phosphorylation.
Topics: Antineoplastic Agents; Apoptosis; Celecoxib; Cell Line, Tumor; Cyclooxygenase Inhibitors; Docetaxel; Drug Synergism; Humans; Lymphoma; Metalloporphyrins; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrazoles; Sulfonamides; Taxoids
PubMed: 16731749
DOI: 10.1158/1535-7163.MCT-05-0280 -
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 -
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 -
Radiology May 2016To investigate the possibility of using motexafin gadolinium (MGd)-enhanced molecular magnetic resonance (MR) imaging and optical imaging to identify the true margins of...
PURPOSE
To investigate the possibility of using motexafin gadolinium (MGd)-enhanced molecular magnetic resonance (MR) imaging and optical imaging to identify the true margins of gliomas.
MATERIALS AND METHODS
The animal protocol was approved by the institutional animal care and use committee. Thirty-six Sprague-Dawley rats with gliomas were randomized into six groups of six rats. Five groups were euthanized 15, 30, 60, 120, and 240 minutes after intravenous administration of 6 mg/kg of MGd, while one group received only saline solution as a control group. After craniotomy, optical imaging and T1-weighted MR imaging were performed to identify the tumor margins. One-way analysis of variance was used to compare optical photon intensity and MR imaging signal-to-noise ratios. Histologic analysis was performed to confirm the intracellular uptake of MGd by tumor cells and to correlate the tumor margins delineated on both optical and MR images.
RESULTS
Both optical imaging and T1-weighted MR imaging showed tumor margins. The highest optical photon intensity (2.6 × 10(8) photons per second per mm(2) ± 2.3 × 10(7); analysis of variance, P < .001) and MR signal-to-noise ratio (77.61 ± 2.52; analysis of variance, P = .006) were reached at 15-30 minutes after administration of MGd, with continued tumor visibility at 2-4 hours. Examination with confocal microscopy allowed confirmation that the fluorescence of optical images and MR imaging T1 enhancement exclusively originated from MGd that accumulated in the cytoplasm of tumor cells.
CONCLUSION
MGd-enhanced optical and MR imaging can allow determination of glioma tumor margins at the optimal time of 15-120 minutes after administration of MGd. Clinical application of these results may allow complete removal of gliomas in a hybrid surgical setting in which intraoperative optical and MR imaging are available.
Topics: Animals; Brain Neoplasms; Contrast Media; Craniotomy; Disease Models, Animal; Glioma; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Metalloporphyrins; Microscopy, Confocal; Molecular Imaging; Random Allocation; Rats; Rats, Sprague-Dawley; Signal-To-Noise Ratio; Tumor Cells, Cultured
PubMed: 26599802
DOI: 10.1148/radiol.2015150895 -
Blood Feb 2005Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because redox mechanisms...
Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because redox mechanisms mediate apoptosis in multiple myeloma, we hypothesized that disruption of redox balance by MGd would result in cellular cytotoxicity in myeloma. We examined the effects of MGd on cellular cytotoxicity, apoptosis, reactive oxygen species (ROS) production, and intracellular drug uptake in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414) chemotherapy-sensitive (8226-RPMI) and highly chemotherapy-resistant (DOX-10V) myeloma cells. We found complete inhibition of proliferation and cytotoxicity in each sensitive and resistant cell line with 24-hour exposure to clinically relevant concentrations of 50 muM MGd and 50 to 100 microM ascorbate, which was required for the effect. The mechanism of cytotoxicity was related to induction of apoptosis as demonstrated by alteration in mitochondrial membrane potential and elevated annexin V expression. This was accompanied by depletion of intracellular glutathione and increased ROS production. Moreover, catalase substantially abrogated MGd-induced cell death. Using fluorescence microscopy and flow cytometry, we found intracellular uptake of MGd and intracellular ROS production. MGd also induced apoptosis in fresh malignant cells from patients with multiple myeloma. These studies provide a rationale for clinical investigation of this novel redox-mediating agent in patients with multiple myeloma and related disorders.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Gadolinium; Glutathione; Humans; Metalloporphyrins; Methotrexate; Multiple Myeloma; Reactive Oxygen Species
PubMed: 15388578
DOI: 10.1182/blood-2004-03-0964 -
International Journal of Radiation... Mar 2009To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell... (Randomized Controlled Trial)
Randomized Controlled Trial
Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial.
PURPOSE
To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer.
METHODS AND MATERIALS
In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received.
RESULTS
Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed.
CONCLUSION
In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.
Topics: Aged; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cognition Disorders; Combined Modality Therapy; Cranial Irradiation; Female; Humans; Lung Neoplasms; Metalloporphyrins; Middle Aged; Proportional Hazards Models
PubMed: 18977094
DOI: 10.1016/j.ijrobp.2008.05.068 -
Anticancer Research Apr 2010Loss of p53 renders cells more susceptible to acute oxidant stress induced by oxidant-generating agents such as motexafin gadolinium (MGd). We hypothesized that reactive...
BACKGROUND
Loss of p53 renders cells more susceptible to acute oxidant stress induced by oxidant-generating agents such as motexafin gadolinium (MGd). We hypothesized that reactive oxygen species (ROS)-generating MGd results in low-level p53 expression, making cells more susceptible to oxidant stress.
MATERIALS AND METHODS
Lymphoma cells were incubated with different concentrations of MGd with or without zinc (Zn) and ascorbate, and ROS, apoptosis, proteins, and oxidant genes were measured.
RESULTS
MGd, with ascorbate and Zn, induced apoptosis in lymphoma cells. This was accompanied by reduction of p53 protein but not message, and by reduction of p53 downstream targets p21, glutathione peroxidase 1 (GPx1), and p53 up-regulated modulator of apoptosis (PUMA). p53 protein reduction was reversed by MG132, and nutlin-3.
CONCLUSION
Our data are consistent with a pathway of cell death that is independent of p53-mediated induction of PUMA; the cellular response to reduce p53 represents a cell survival adjustment to ROS-mediated stress.
Topics: Apoptosis; Ascorbic Acid; Burkitt Lymphoma; Cell Line, Tumor; Gene Expression; Humans; Imidazoles; Leupeptins; Lymphoma, Follicular; Metalloporphyrins; Piperazines; Proto-Oncogene Proteins c-mdm2; Reactive Oxygen Species; Tumor Suppressor Protein p53; Zinc
PubMed: 20530418
DOI: No ID Found -
Journal of Clinical Oncology : Official... Apr 2001Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation... (Clinical Trial)
Clinical Trial
PURPOSE
Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival.
PATIENTS AND METHODS
Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range.
RESULTS
In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium's tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%.
CONCLUSION
Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.
Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Female; France; Humans; Male; Maximum Tolerated Dose; Metalloporphyrins; Middle Aged; Photosensitizing Agents; Prospective Studies; ROC Curve; Survival Rate; Tissue Distribution
PubMed: 11283141
DOI: 10.1200/JCO.2001.19.7.2074 -
Expert Opinion on Pharmacotherapy Sep 2009For a variety of reasons, the management of brain tumors, both primary and metastatic, remains a considerable challenge. As most systemic therapies do not cross the BBB...
For a variety of reasons, the management of brain tumors, both primary and metastatic, remains a considerable challenge. As most systemic therapies do not cross the BBB at therapeutic doses, radiation and surgery have played primary roles in the management of these diseases. Despite significant advances in surgical techniques and radiation delivery, outcomes for most adult brain tumors continue to be poor. In an effort to enhance the effects of radiation in the brain, a variety of radiation sensitizers, including motexafin gadolinium, have been investigated. In the following manuscript, we summarize motexafin gadolinium and its role in brain tumors.
Topics: Antineoplastic Agents; Brain Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Cranial Irradiation; Humans; Metalloporphyrins; Radiation-Sensitizing Agents
PubMed: 19640206
DOI: 10.1517/14656560903179325 -
International Journal of Radiation... Jul 2005To investigate the effects of motexafin gadolinium (MGd) on the levels of reactive oxygen species (ROS), glutathione (GSH), and DNA damage in EMT6 mouse mammary...
PURPOSE
To investigate the effects of motexafin gadolinium (MGd) on the levels of reactive oxygen species (ROS), glutathione (GSH), and DNA damage in EMT6 mouse mammary carcinoma cells. The ability of MGd to alter radiosensitivity and to inhibit DNA damage repair after X-ray irradiation was also evaluated.
METHODS AND MATERIALS
Reactive oxygen species and GSH levels were assessed by 2,7-dichlorofluorescein fluorescence flow cytometry and the Tietze method, respectively. Cellular radiosensitivity was assessed by clonogenic assays. Deoxyribonucleic acid damage and DNA damage repair were assessed in plateau-phase EMT6 cells by the Comet assay and clonogenic assays.
RESULTS
Cells treated with 100 mumol/L MGd plus equimolar ascorbic acid (AA) had significantly increased levels of ROS and a 58.9% +/- 3.4% decrease in GSH levels, relative to controls. Motexafin gadolinium plus AA treatment increased the hypoxic, but not the aerobic, radiosensitivity of EMT6 cells. There were increased levels of single-strand breaks in cells treated with 100 mumol/L MGd plus equimolar AA, as evidenced by changes in the alkaline tail moment (MGd + AA, 6 h: 14.7 +/- 1.8; control: 2.8 +/- 0.9). The level of single-strand breaks was dependent on the length of treatment. Motexafin gadolinium plus AA did not increase double-strand breaks. The repair of single-strand breaks at 2 h, but not at 4 h and 6 h, after irradiation was altered significantly in cells treated with MGd plus AA (MGd + AA, 2 h: 15.8 +/- 3.4; control: 5.8 +/- 0.6). Motexafin gadolinium did not alter the repair of double-strand breaks at any time after irradiation with 10 Gy.
CONCLUSIONS
Motexafin gadolinium plus AA generated ROS, which in turn altered GSH homeostasis and induced DNA strand breaks. The MGd plus AA-mediated alteration of GSH levels increased the hypoxic, but not aerobic, radiosensitivity of EMT6 cells. Motexafin gadolinium altered the kinetics of single-strand break repair soon after irradiation but did not inhibit potentially lethal damage repair in EMT6 cells.
Topics: Animals; Ascorbic Acid; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Comet Assay; DNA Damage; DNA Repair; Glutathione; Metalloporphyrins; Mice; Photosensitizing Agents; Radiation Tolerance; Reactive Oxygen Species; Time Factors
PubMed: 15990023
DOI: 10.1016/j.ijrobp.2005.04.014