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Chemical Communications (Cambridge,... Nov 2002Motexafin gadolinium (MGd) oxidizes ascorbate, in neutral buffer and in cell culture, forming reactive oxygen species and a coordination polymer with oxalate.
Motexafin gadolinium (MGd) oxidizes ascorbate, in neutral buffer and in cell culture, forming reactive oxygen species and a coordination polymer with oxalate.
Topics: Ascorbic Acid; Metalloporphyrins; Molecular Structure; Oxalic Acid; Photosensitizing Agents; Polymers; Reactive Oxygen Species; Tumor Cells, Cultured
PubMed: 12510321
DOI: 10.1039/b208760j -
International Journal of Radiation... Nov 2003To investigate the responses of two experimental rat tumors to single and fractionated X-ray doses whether or not combined with Motexafin gadolinium (MGd), and the...
PURPOSE
To investigate the responses of two experimental rat tumors to single and fractionated X-ray doses whether or not combined with Motexafin gadolinium (MGd), and the distribution of MGd in R3327-MATLyLu (MLL) tumors using MRI.
METHODS
L44 lung tumor in BN rats and MLL prostate tumor in Copenhagen rats were grown subcutaneously. MGd at concentrations of 8.7 to 25.1 micro mol/kg was administered 2 h before or just before treatments with single and fractionated X-ray doses. Tumor volume growth delay was the endpoint used. The two-dimensional distribution of the MGd concentration in time was analyzed simultaneously in slices through the center of MLL tumors using MRI. Directly after the MRI experiments, tumor sections were stained for cytoplasm, nuclei, and microvessel endothelium.
RESULTS
MGd at different concentrations administered a few minutes or 2 h before X-ray doses produced no radiation enhancement in the two tumor models. The MGd concentration as determined by MRI was maximal 5 min after injection and decreased slowly thereafter. In a representative section at the center of the MLL tumor, the microvessel density is nearly homogeneous and correlates with a nearly homogeneous MGd distribution. Hardly any MGd is taken up in underlying muscle tissue.
CONCLUSION
No radiosensitization was observed for the different irradiation regimens. The distribution of MGd is nearly homogeneous in the MLL tumor and hardly any MGd is taken up in underlying muscles. Our negative results on radiosensitivity in our two tumor models raise questions about the efficacy of MGd as a general radiosensitizing agent.
Topics: Animals; Body Weight; Drug Screening Assays, Antitumor; Female; Lung Neoplasms; Magnetic Resonance Imaging; Male; Metalloporphyrins; Prostatic Neoplasms; Radiation-Sensitizing Agents; Rats
PubMed: 14529785
DOI: 10.1016/s0360-3016(03)00661-8 -
Journal of Thoracic Oncology : Official... Apr 2011Motexafin gadolinium (MGd) disrupts redox-dependent pathways by inhibiting oxidative stress-related proteins leading to apoptosis. MGd selectively targets tumor cells,...
BACKGROUND
Motexafin gadolinium (MGd) disrupts redox-dependent pathways by inhibiting oxidative stress-related proteins leading to apoptosis. MGd selectively targets tumor cells, disrupting energy metabolism and repair mechanisms, rendering cells more prone to apoptosis. Preclinical studies with MGd and pemetrexed show significant tumor growth delay in lung cancer cell lines.
METHODS
Patients with non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0 to 1, who had received one previous platinum containing regimen and normal organ function were treated with MGd 15 mg/kg and pemetrexed 500 mg/m q21days. Patients were allowed to receive more than one regimen if the initial treatment was in the adjuvant or curative setting and administered >12 months earlier. The primary end point was to demonstrate a 40% rate of 6-month progression free survival (PFS).
RESULTS
Seventy-two patients (30 women, 42 men), performance status 0/1 (30/42), and a median age of 63 years were enrolled. Most patients (96%) were current or former smokers. All histologic types were represented (squamous/adenocarcinoma/other: 28%, 42%, 31%). Number of prior regimens: 1: 69%; 2: 26%, and >2: 4%. Median number of cycles administered was (range) 2 (1-12).
TOXICITY
grade 3/4 neutropenia was noted in 8.3% with febrile neutropenia in 1.4%, thrombocytopenia in 8.3%, fatigue in 9.7%, and pneumonia in 11.1%. There were no complete responses, 8.1% had partial response, 56.5% had stable disease, and 35.5% had progressive disease as their best response. Twenty-three percent of patients were progression free at 6 months and the median PFS was 2.6 months with an overall survival of 8.1 months.
CONCLUSIONS
The combination of MGd and pemetrexed was well tolerated with toxicity similar to that of pemetrexed alone. However, the study did not achieve its end point of 40% 6-month PFS. The response rate, PFS, and overall survival did not seem markedly different than prior phase II and phase III studies of pemetrexed alone. Consequently, there are no further plans for development of this combination.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Metalloporphyrins; Middle Aged; Neoplasm Staging; Pemetrexed; Pilot Projects; Prognosis; Salvage Therapy; Survival Rate
PubMed: 21289521
DOI: 10.1097/JTO.0b013e31820a443f -
Drugs Jul 2011The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well... (Review)
Review
The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the superoxide anion radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage. There are several anticancer agents in development that target cellular redox regulation. The overall cellular redox state is regulated by three systems that modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides; two of these are dependent on glutathione and the third on thioredoxin. Drugs targeting S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. Of these agents, NOV-002 and canfosfamide have been assessed in phase III trials, while a number of others are undergoing evaluation in early phase clinical trials. Alternatively, agents including PX-12, dimesna and motexafin gadolinium are being developed to target thioredoxin, which is overexpressed in many human tumours, and this overexpression is associated with aggressive tumour growth and poorer clinical outcomes. Finally, arsenic derivatives have demonstrated antitumour activity including antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms, and the induction of high levels of oxidative stress and apoptosis by an as yet undefined mechanism. In this article we review anticancer drugs currently in development that target cellular redox activity to treat cancer.
Topics: Antioxidants; Humans; Molecular Targeted Therapy; Neoplasms; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 21812504
DOI: 10.2165/11592590-000000000-00000 -
PloS One 2013Transjugular intrahepatic portosystemic shunt (TIPS) has become an important and effective interventional procedure in treatment of the complications related to portal...
BACKGROUND
Transjugular intrahepatic portosystemic shunt (TIPS) has become an important and effective interventional procedure in treatment of the complications related to portal hypertension. Although the primary patency of TIPS has been greatly improved due to the clinical application of cover stent-grafts, the long-term patency is still suboptimal. This study was to investigate the feasibility of using magnetic resonance imaging (MRI)-monitored intra-shunt local agent delivery of motexafin gadolinium (MGd) into shunt-vein walls of TIPS. This new technique aimed to ultimately inhibit shuntstenosis of TIPS.
METHODOLOGY
Human umbilical vein smooth muscle cells (SMCs) were incubated with various concentrations of MGd, and then examed by confocal microscopy and T1-map MRI. In addition, the proliferation of MGd-treated cells was evaluated. For in vivo validation, seventeen pigs underwent TIPS. Before placement of the stent, an MGd/trypan-blue mixture was locally delivered, via a microporous balloon, into eleven shunt-hepatic vein walls under dynamic MRI monitoring, while trypan-blue only was locally delivered into six shunt-hepatic vein walls as serve as controls. T1-weighted MRI of the shunt-vein walls was achieved before- and at different time points after agent injections. Contrast-to-noise ratio (CNR) of the shunt-vein wall at each time-point was measured. Shunts were harvested for subsequent histology confirmation.
PRINCIPAL FINDINGS
In vitro studies confirmed the capability of SMCs in uptaking MGds in a concentration-dependent fashion, and demonstrated the suppression of cell proliferation by MGds as well. Dynamic MRI displayed MGd/blue penetration into the shunt-vein walls, showing significantly higher CNR of shunt-vein walls on post-delivery images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01), which was confirmed by histology.
CONCLUSION
Results of this study indicate that MRI-monitored intra-shunt local MGd delivery is feasible and MGd functions as a potential therapeutic agent to inhibit the proliferation of SMCs, which may open alternative avenues to improve the long-term patency of TIPS.
Topics: Animals; Cells, Cultured; Contrast Media; Magnetic Resonance Imaging; Metalloporphyrins; Swine
PubMed: 23468986
DOI: 10.1371/journal.pone.0057419 -
Organic & Biomolecular Chemistry Sep 2005Conjugates between methotrexate (MTX, Matrex, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-l-glutamic acid), an antifolate cancer chemotherapeutic to...
Conjugates between methotrexate (MTX, Matrex, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-l-glutamic acid), an antifolate cancer chemotherapeutic to which resistance is often observed, and motexafin gadolinium (MGd), an experimental agent demonstrating selective tumor localization, are described. These systems were prepared in order to test whether linking these two species would produce agents with enhanced activity relative to MTX alone. Both ester- and amide-linked conjugates were synthesized starting from MGd and MTX. The ester conjugate showed greater in vitro anti-proliferative activity against the A549 lung carcinoma cell line at short incubation times than did MTX alone. Neither the amide conjugate, nor MGd, showed any observable activity under these in vitro conditions. These results are rationalized in terms of enhanced cellular uptake of both the ester and amide conjugates that is coupled with an effective rate of release (e.g., inherent or enzyme-mediated hydrolysis) in the case of the ester-linked conjugate, but not the corresponding amide system.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Metalloporphyrins; Methotrexate; Molecular Structure; Time Factors
PubMed: 16132091
DOI: 10.1039/b503664j -
International Journal of Radiation... Nov 2001To examine the mechanism of radiation enhancement by motexafin gadolinium (Gd-Tex) in vitro.
PURPOSE
To examine the mechanism of radiation enhancement by motexafin gadolinium (Gd-Tex) in vitro.
METHODS AND MATERIALS
Oxidation of ascorbate and NADPH by Gd-Tex was evaluated in a neutral buffer. Growth inhibition of human uterine cancer cell line MES-SA was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Clonogenic assays were used to measure radiation response in MES-SA, A549 human lung carcinoma, E89, a CHO cell line variant deficient in glucose-6-phosphate dehydrogenase activity, and murine lymphoma cell lines LYAR and LYAS.
RESULTS
Gd-Tex catalyzed the oxidation of NADPH and ascorbate under aerobic conditions, forming hydrogen peroxide. Decreased viability was observed in MES-SA cells incubated with Gd-Tex in media containing NADPH or ascorbate. Gd-Tex and ascorbate increased fluorescence in dichlorofluorescin acetate-treated cultures. Synergistic effects on the aerobic radiation response in MES-SA and A549 were seen using Gd-Tex in combination with L-buthionine-(S,R)-sulfoximine (BSO). Incubation with Gd-Tex in the presence of ascorbate increased the aerobic radiation response of E89 and the apoptosis-sensitive B-cell line (LYAS).
CONCLUSIONS
Gd-Tex sensitizes cells to ionizing radiation by increasing oxidative stress as a consequence of futile redox cycling. Optimization of the concentration of ascorbate (or other reducing species) may be required when evaluating Gd-Tex activity in vitro.
Topics: Animals; Antineoplastic Agents; Ascorbic Acid; CHO Cells; Cricetinae; Female; Humans; Hydrogen Peroxide; Metalloporphyrins; NADP; Oxidation-Reduction; Reactive Oxygen Species; Tumor Cells, Cultured; Uterine Neoplasms
PubMed: 11704327
DOI: 10.1016/s0360-3016(01)01810-7 -
Journal of Clinical Oncology : Official... Jul 2003This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd).
PATIENTS AND METHODS
Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated.
RESULTS
Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients.
CONCLUSION
The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.
Topics: Aged; Antineoplastic Agents; Brain Neoplasms; Cognition; Combined Modality Therapy; Disease Progression; Female; Humans; Lung Neoplasms; Male; Metalloporphyrins; Middle Aged; Survival; Treatment Outcome
PubMed: 12829672
DOI: 10.1200/JCO.2003.12.122 -
Journal of Photochemistry and... Sep 2007Efficient design of anti-cancer treatments involving radiation- and photo-sensitizing therapeutics requires knowledge of tissue-specific drug concentrations. This study... (Comparative Study)
Comparative Study
Efficient design of anti-cancer treatments involving radiation- and photo-sensitizing therapeutics requires knowledge of tissue-specific drug concentrations. This study investigates the use of the optical pharmacokinetic system (OPS) to measure concentrations of the anti-cancer agent motexafin gadolinium (MGd) in mouse tissues noninvasively and nondestructively using elastic-scattering spectroscopy. The magnitude of MGd absorbance was quantitated by integration of the MGd peak absorbance area, and MGd concentrations were estimated by comparison with standard curves that were validated by high performance liquid chromatography (HPLC). In tissue-simulating phantoms in vitro, MGd peak absorbance area correlated with MGd concentration. Female C.B-17 SCID mice, bearing subcutaneous MDA-MB-231 human breast cancer xenografts, were dosed with 23 mg/kg MGd i.v. At specific times between 5 min and 24h after dosing, noninvasive OPS measurements were made on skin overlaying the subcutaneous tumor and skin on the opposite flank in vivo, and following exsanguination, nondestructive measurements were made on tumor, skin, and internal tissues in situ. OPS measurements on tissues in vivo detected MGd present in both tissue and blood perfusing the tissue. Both the OPS and the HPLC detected selective localization of MGd in malignant tissues compared with surrounding non-malignant tissues, and neither technique detected MGd in brain tissue. Comparison of MGd concentrations measured by HPLC and OPS is complicated by mismatch between measured tissue volumes, heterogeneous spatial distribution of MGd in tissues, and blood-localized MGd at early time points. Tumor-specific MGd concentrations measured by HPLC correlated with those measured by OPS in vivo and in situ. Best fit lines to the concentration estimates (forced through zero) had slopes of 0.900 and 1.185, respectively; however, the variability was significant (r(2)=0.477 and 0.269). The clinical utility of the OPS to quantitate MGd concentrations remains to be validated.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Humans; Metalloporphyrins; Mice; Photosensitizing Agents; Skin Neoplasms; Spectrum Analysis; Time Factors; Tissue Distribution; Transplantation, Heterologous
PubMed: 17604637
DOI: 10.1016/j.jphotobiol.2007.05.002 -
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