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Current Opinion in Oncology Mar 2010Brain metastases are an important cause of morbidity and mortality, and are the most common intracranial tumors in adults. The prognosis of patients with brain... (Review)
Review
PURPOSE OF REVIEW
Brain metastases are an important cause of morbidity and mortality, and are the most common intracranial tumors in adults. The prognosis of patients with brain metastases is very poor. The increasing incidence of brain metastases is directly related to the improvements in the treatment of systemic disease. Commonly, brain metastases are discovered after the diagnosis of cancer, often after other systemic metastases have developed. In this review article, we present the standard treatment approach and discuss new directions.
RECENT FINDINGS
The most widely used treatment for patients with brain metastases is whole-brain radiotherapy. Actually, surgery and radiotherapy remain the principal therapeutic interventions. In contrast, the benefit of chemotherapy has long been viewed with skepticism.In an effort to improve the therapeutic ratio, radiosensitizers are often used concurrently with external-beam radiation: motexafin gadolinium and efaproxaril.Novel anticancer agents are under clinical investigation.
SUMMARY
The management of patients with brain metastases with non-small cell lung cancer has improved over time, due to the development of new treatment options and a better knowledge of prognostic factors.In the next 5 years, the results of several ongoing multicenter randomized trials will become available to further define the role of various radiation sensitizers and chemotherapeutic agents in combination with stereotactic radiosurgery, whole-brain radiation therapy, or both.
Topics: Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Cranial Irradiation; Humans; Lung Neoplasms; Neurosurgical Procedures; Radiation-Sensitizing Agents
PubMed: 20009927
DOI: 10.1097/CCO.0b013e3283350106 -
Dalton Transactions (Cambridge, England... Dec 2009The synthesis of a new PEG-solubilized gadolinium texaphyrin (Gd-Tex) conjugate containing a malonate-Pt(NH(3))(2) moiety is described. The effect of the tumor...
The synthesis of a new PEG-solubilized gadolinium texaphyrin (Gd-Tex) conjugate containing a malonate-Pt(NH(3))(2) moiety is described. The effect of the tumor localizing Gd-Tex macrocycle on platinum activity was evaluated in cell culture. The malonate moiety, analogous to that present in carboplatin, is expected to release an aquated Pt(NH(3))(2) species under physiological conditions. The half-life in phosphate-buffered saline was found to be ca. 3 days at room temperature, and the hydrolytic product released from the conjugate was collected and confirmed as Pt-based by flameless atomic absorption spectrophotometry. Anti-proliferative activity was tested using A549 human lung cancer and A2780 human ovarian cancer cell lines. In both cell lines, the activity of the Gd-Tex conjugate was found to be similar to that of carboplatin. Efficacy against a Pt-resistant ovarian cell line greater than that displayed by carboplatin was also observed.
Topics: Antineoplastic Agents; Carboplatin; Cell Line, Tumor; Coordination Complexes; Drug Resistance, Neoplasm; Humans; Metalloporphyrins; Platinum
PubMed: 20023913
DOI: 10.1039/b912089k -
Oncology (Williston Park, N.Y.) May 2006Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain... (Review)
Review
Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.
Topics: Brain Neoplasms; Carcinoma, Renal Cell; Dacarbazine; Humans; Kidney Neoplasms; Metalloporphyrins; Neoplasm Metastasis; Radiation Oncology; Radiation-Sensitizing Agents; Radiosurgery; Temozolomide
PubMed: 16773845
DOI: No ID Found -
Journal of Pharmaceutical Sciences Mar 2005The biotransformation of motexafin gadolinium (MGd, Xcytrin) was investigated in subcellular rat and human liver fractions. Microsomal MGd metabolism was dependent on...
The biotransformation of motexafin gadolinium (MGd, Xcytrin) was investigated in subcellular rat and human liver fractions. Microsomal MGd metabolism was dependent on NADPH in both species. Cytosolic metabolism in rat and human livers was dependent on NADPH or NADH. Under anaerobic conditions, MGd metabolism increased in liver microsomes and purified enzyme preparations. Cytochrome P450 (CYP450) inhibitors ketoconazole, proadifen, and carbon monoxide increased NADPH-dependent MGd metabolism in microsomes. Treatment of rats with beta-naphthoflavone increased cytosolic metabolism of MGd twofold, but had no effect on microsomal metabolism. Conversely, in liver preparations from phenobarbital treated rats microsomal metabolism of MGd was enhanced twofold, but not in cytosolic preparations. Purified CYP450 reductase from phenobarbital-treated rabbit or untreated human livers metabolized MGd suggesting involvement of CYP450 reductase. Dicumarol, a potent DT-diaphorase inhibitor, inhibited MGd metabolism in both rat and human liver cytosol. These data suggest MGd metabolism in rat liver involves CYP450 reductase and/or DT-diaphorase. In human liver preparations only CYP450 reductase is directly involved in MGd metabolism. A metabolite identified in microsomes and cytosol is a metal-free, reduced form of MGd, indicating that both enzymes generate metabolite 1, which appears to be PCI-0108, a synthetic precursor to MGd.
Topics: Animals; Cytosol; Humans; Liver; Metalloporphyrins; Microsomes, Liver; NAD(P)H Dehydrogenase (Quinone); NADPH-Ferrihemoprotein Reductase; Rats; Rats, Sprague-Dawley; Subcellular Fractions
PubMed: 15666291
DOI: 10.1002/jps.20274 -
Journal of Magnetic Resonance Imaging :... Jan 2008To evaluate the potential of using motexafin gadolinium (MGd) to characterize atherosclerotic plaques of deep-seated arteries with MRI. (Comparative Study)
Comparative Study
PURPOSE
To evaluate the potential of using motexafin gadolinium (MGd) to characterize atherosclerotic plaques of deep-seated arteries with MRI.
MATERIALS AND METHODS
We exposed vascular endothelial cells (EC) and smooth muscle cells (SMC) in vitro to varying concentrations of MGd. The fluorescence properties of MGd were then exploited using confocal microscopy to image exposed cells. For an in vivo validation study, we performed surface coil-based and intravascular coil-based high-resolution MRI of the iliac arteries and the abdominal aorta of three atherosclerotic Yucatan pigs. Subsequently, MGd enhancement of the target vessel walls was quantitatively evaluated and MR images were correlated with histology of the target vessels.
RESULTS
The in vitro study confirmed the intracellularization of MGd in both cell types and determined the optimum MGd dosage of 0.004 mmol/kg that produced the sufficiently high intracellular fluorescent intensity. The in vivo study showed a steady increase of MGd enhancement to approximately 25% at three hours postinjection of MGd. MRI showed areas of strong enhancement along the lumen boundary, which corresponded to fibrous tissue seen in histology.
CONCLUSION
This study provides initial evidence that MGd may enhance MR vessel wall imaging for the characterization of plaque in deep-seated arteries.
Topics: Animals; Aorta, Abdominal; Arteriosclerosis; Cells, Cultured; Contrast Media; Gadolinium DTPA; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Metalloporphyrins; Swine
PubMed: 18050320
DOI: 10.1002/jmri.21174 -
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 -
Clinical Advances in Hematology &... Jan 2007Brain metastases are a frequent sequelae of many solid tumors. Whole-brain radiotherapy (WBRT) has been the standard treatment for decades, with modest long-term... (Review)
Review
Brain metastases are a frequent sequelae of many solid tumors. Whole-brain radiotherapy (WBRT) has been the standard treatment for decades, with modest long-term complications observed using doses no greater than 3 Gy/fraction. Surgical resection may be beneficial in select populations of patients with single brain metastases, controlled systemic disease, and good performance status. Radiosurgery has demonstrated consistent improvement in local control, with some reports showing a survival benefit when combined with WBRT. However, the role of radiosurgery as a single modality is unclear, particularly given concerns that higher rates of distant brain relapse result in increased risk of neurologic compromise and death from neurologic causes. Increasingly, the importance of neurocognitive assessment with brain metastases is being recognized, and recent data have strongly correlated neurocognitive dysfunction with tumor progression. Systemic agents showing activity in brain metastases including temozolomide, RSR13, motexafin gadolinium, and lapatinib are being explored.
Topics: Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Cognition Disorders; Humans; Radiosurgery; Randomized Controlled Trials as Topic
PubMed: 17339829
DOI: No ID Found -
Methods and Findings in Experimental... Nov 2004Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (PE)HRG214, 1E10, 21-Aminoepothilone B; Ad.Egr.TNF.11D, Ad100-B7.1/HLA, adalimumab, adefovir dipivoxil, alefacept, alemtuzumab, AMD-070, anhydrovinblastine, aripiprazole, asimadoline, atrasentan, AVE-5883; Bimatoprost, BNP-7787, bosentan, botulinum toxin type B, BR-1; Canfosfamide hydrochloride, ciclesonide, curcumin, cypher; D0401, darbepoetin alfa, darifenacin hydrobromide, D-D4FC, dendritic cell-based vaccine, desloratadine, dextrin sulfate, dolastatin 10, drospirenone drospirenone/estradiol, DS-992, duloxetine hydrochloride, dutasteride; E-7010, efalizumab, eletriptan, EM-1421, enfuvirtide, entecavir, etoricoxib, everolimus, exenatide, ezetimibe; Favid, fidarestat, fingolimod hydrochloride, FK-352; Gefitinib, gemifloxacin mesilate, gepirone hydrochloride, gimatecan; HE-2000; Imatinib mesylate, indisulam, insulin detemir, irofulven, ISIS-5132; Lapatinib, levocetirizine, liraglutide, lumiracoxib; Metformin/Glyburide, methionine enkephalin, MK-0431, morphine hydrochloride, motexafin gadolinium, mycobacterium cell wall complex; Naturasone, neridronic acid, nesiritide; Oblimersen sodium, olanzapine/fluoxetine hydrochloride, omalizumab, oral insulin; Paclitaxel poliglumex, PC-515, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ ribavirin, pegvisomant, pexelizumab, picoplatin, pramlintide acetate, prasterone, pregabalin; Quercetin; Ramelteon, ranirestat, RG228, rhGAD65, roflumilast, rubitecan; Sitaxsentan sodium, solifenacin succinate; Tadalafil, taxus, tipifarnib, tolevamer sodium, topixantrone hydrochloride; Valganciclovir hydrochloride, vardenafil hydrochloride hydrate, vildagliptin, voriconazole; XTL-001; Zoledronic acid monohydrate.
Topics: Databases, Factual; Double-Blind Method; Drug Administration Schedule; Humans; Pharmaceutical Preparations; Randomized Controlled Trials as Topic
PubMed: 15632957
DOI: No ID Found -
Current Opinion in Investigational... Dec 2004Radiotherapy is widely used in the management of tumors of the central nervous system (CNS) primarily because these tumors, in general, remain localized and are usually... (Review)
Review
Radiotherapy is widely used in the management of tumors of the central nervous system (CNS) primarily because these tumors, in general, remain localized and are usually not completely removed at surgery. Therefore, radiotherapy serves as a valuable adjunct. However, due to radiation resistance, survival for most patients with CNS tumors remains poor. Radiosensitizers are considered useful for CNS tumors because the majority of these tumors cause death due to local progression, thus emphasizing the significance of improving local control. In addition, these neoplasms consist of a rapidly growing cell population surrounded by slowly proliferating normal brain cells, thereby affording an opportunity for tumor-selectivity. Historically, several classes of radiation sensitizers, including S-phase halogenated pyrimidines, oxygen mimetics and others, have been tested without clear evidence of clinical benefit. Recently, two agents with very different mechanisms of action have gained attention and are currently in clinical trials; these agents, efaproxiral, a modulator of tumor hypoxia, and motexafin-gadolinium, a redox modulator, are the focus of this review.
Topics: Animals; Central Nervous System Neoplasms; Clinical Trials, Phase III as Topic; Drugs, Investigational; Humans; Radiation-Sensitizing Agents
PubMed: 15648950
DOI: No ID Found -
Methods and Findings in Experimental... Jun 2006Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved...
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 131-I-chlorotoxin; Ad5CMV-p53, adalimumab, albumin interferon alfa, alemtuzumab, aliskiren fumarate, aminolevulinic acid methyl ester, anakinra, AR-C126532, atomoxetine hydrochloride; Bevacizumab, bosentan, botulinum toxin type B, brimonidine tartrate/timolol maleate; Calcipotriol/betamethasone dipropionate, cangrelor tetrasodium, cetuximab, ciclesonide, cinacalcet hydrochloride, collagen-PVP, Cypher; Darbepoetin alfa, darusentan, dasatinib, denosumab, desloratadine, dexosome vaccine (lung cancer), dexrazoxane, dextromethorphan/quinidine sulfate, duloxetine hydrochloride; ED-71, eel calcitonin, efalizumab, entecavir, etoricoxib; Falciparum merozoite protein-1/AS02A, fenretinide, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gefitinib, ghrelin (human); hLM609; Icatibant acetate, imatinib mesylate, ipsapirone, irofulven; LBH-589, LE-AON, levocetirizine, LY-450139; Malaria vaccine, mapatumumab, motexafin gadolinium, muraglitazar, mycophenolic acid sodium salt; nab-paclitaxel, nelarabine; O6-Benzylguanine, olmesartan medoxomil, orbofiban acetate; Panitumumab, peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, peptide YY3-36, pleconaril, prasterone, pregabalin; Ranolazine, rebimastat, recombinant malaria vaccine, rosuvastatin calcium; SQN-400; Taxus, tegaserod maleate, tenofovir disoproxil fumarate, teriparatide, troxacitabine; Valganciclovir hydrochloride, Val-Tyr sardine peptidase, VNP-40101M, vorinostat.
Topics: Clinical Trials as Topic; Humans
PubMed: 16845450
DOI: No ID Found