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Current Opinion in Ophthalmology Jun 2001Photodynamic therapy uses a photoactivating agent to selectively treat choroidal neovascularization. In April 2000, the United States Food and Drug Administration... (Review)
Review
Photodynamic therapy uses a photoactivating agent to selectively treat choroidal neovascularization. In April 2000, the United States Food and Drug Administration approved verteporfin photodynamic therapy for the treatment of subfoveal, predominately classic, choroidal neovascularization caused by age-related macular degeneration. The treatment of choroidal neovascularization from other causes such as myopia, angioid streaks, and idiopathy, and presumed ocular histoplasmosis syndrome is still under investigation. Other photoactivating agents are being evaluated. Photodynamic therapy has been shown to halt the progression of visual loss in patients with age-related macular degeneration who have subfoveal predominately classic choroidal neovascularization. The socio-economic impact of verteporfin approval has yet to be determined.
Topics: Choroidal Neovascularization; Humans; Macular Degeneration; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Porphyrins; Verteporfin
PubMed: 11389347
DOI: 10.1097/00055735-200106000-00010 -
Oncology (Williston Park, N.Y.) Oct 1999That hypoxic tissues are more resistant to the effects of radiation than well-oxygenated tissues has been known for many decades, and repeated in vitro demonstrations... (Review)
Review
That hypoxic tissues are more resistant to the effects of radiation than well-oxygenated tissues has been known for many decades, and repeated in vitro demonstrations have confirmed that to achieve the same degree of cytotoxicity, hypoxic cells require about three times the radiation dose that well-oxygenated cells need. Hypoxic cell sensitizers enhance the tissue response to standard radiation, generally by mimicking the effects of oxygen, which induces the formation and stabilization of toxic DNA radicals. Although many hypoxic cell sensitizers like the nitroimidazoles have been evaluated in combination with radiation, these agents have had no or only minimal therapeutic impact due to either their limited potency or their toxicity at biologically relevant concentrations. This article reviews several new modalities that either increase oxygen delivery or sensitize hypoxic tissues. These modalities, all currently in early clinical evaluations, include: (1) tirapazamine, a bioreductive agent; (2) gadolinium texaphyrin, a hypoxic cell sensitizer with biolocalization properties using magnetic resonance imaging; (3) RSR13, an allosteric modifier of hemoglobin; and (4) bovine hemoglobin modified by the attachment of polyethylene glycol polymers.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Clinical Trials as Topic; Combined Modality Therapy; DNA Damage; Hemoglobins; Humans; Metalloporphyrins; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines
PubMed: 10550828
DOI: No ID Found -
Methods and Findings in Experimental... Oct 2005Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have 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 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: (-)-Epigallocatechin gallate, (Z)-4-hydroxytamoxifen; Ad.muIFN-beta AD-237, adalimumab, adefovir dipivoxil, agalsidase alfa, alemtuzumab, almotriptan, ALVAC vCP1452, alvimopan hydrate, ambrisentan, anakinra, anti-IFN-gamma MAb; Bimatoprost, BMS-188797, BMS-214662, bortezomib, bosentan, bovine lactoferrin; Caffeine, canertinib dihydrochloride, canfosfamide hydrochloride, cannabidiol, caspofungin acetate, cetuximab, cH36, ChimeriVax-JE, ciclesonide, cilansetron, cinacalcet hydrochloride, clopidogrel, CpG-7909, Cypher; Daptomycin, darbepoetin alfa, darifenacin hydrobromide, decitabine, denufosol tetrasodium, Dexamet, diindolemethane, drotrecogin alfa (activated), duloxetine hydrochloride, DX-9065a; E-7010, edaravone, efalizumab, eicosapentaenoic acid/docosahexaenoic acid, elacridar, eletriptan, emtricitabine, epratuzumab, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, ezetimibe; Fludarabine, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gavestinel sodium, gefitinib, granisetron-Biochronomer; Human Albumin, human insulin; Imatinib mesylate, indiplon, interleukin-2 XL, isatoribine, ISS-1018, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lanthanum carbonate, L-arginine hydrochloride, liposomal doxorubicin, LY-450139; Magnesium sulfate, melatonin, motexafin gadolinium, mycophenolic acid sodium salt; Natalizumab, nesiritide, niacin/lovastatin; OGX-011, olmesartan medoxomil, omalizumab, ospemifene; PACAP38, panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, patupilone, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, pirfenidone, posaconazole, prasterone, pregabalin; R-112, ramelteon, ranolazine, rasagiline mesilate, rebimastat, roflumilast, rosuvastatin calcium, rotigotine hydrochloride, rupatadine fumarate; S-3013, S-3304, semustine, sitaxsentan sodium, St. John's Wort extract; Tadalafil, tamoxifen, Taxus, Tc-99m-EDDA-HYNIC-TOC, TH-9507, tiotropium bromide, tipifarnib, tocilizumab, tolvaptan, torcetrapib, TR-14035, tramadol hydrochloride/acetaminophen, treprostinil diethanolamine, troglitazone, troxacitabine; Valdecoxib, valganciclovir hydrochloride, vandetanib, vardenafil hydrochloride hydrate, VAS-991, veglin, vinflunine, voriconazole; White sweet potato extract; Ximelagatran.
Topics: Clinical Trials as Topic; Drug Therapy; Humans
PubMed: 16273137
DOI: No ID Found -
Leukemia & Lymphoma Dec 2009Chronic lymphocytic leukemia (CLL) cells are susceptible to oxidative stress. The expanded porphyrin, motexafin gadolinium (MGd), reacts with intracellular reducing...
Chronic lymphocytic leukemia (CLL) cells are susceptible to oxidative stress. The expanded porphyrin, motexafin gadolinium (MGd), reacts with intracellular reducing metabolites and protein thiols to generate reactive oxygen species (ROS). A phase II trial administered MGd 5 mg/kg/day IV for 5 days every 3 weeks until disease progression to patients with previously treated CLL and small lymphocytic lymphoma. Thirteen patients (median age 66 years) with a median of four prior therapies (range 2-9) were enrolled. Modest anti-tumor activity was seen in three patients, with improvement in lymphocytosis, lymphadenopathy and/or splenomegaly, but no patient achieved a partial or complete response by NCI 96 criteria. Flow cytometry confirmed tumor uptake of MGd. Serial increase in AKT phosphorylation in patient samples following MGd treatment was not observed, suggesting intracellular generation of ROS was not optimal. Therefore, this schedule of administration achieved MGd uptake into primary tumor cells in vivo, but clinical activity was modest.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 17; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Flow Cytometry; Humans; Immunoblotting; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Metalloporphyrins; Middle Aged; Phosphorylation; Proto-Oncogene Proteins c-akt; Treatment Outcome
PubMed: 19860624
DOI: 10.3109/10428190903288464 -
Photodiagnosis and Photodynamic Therapy Dec 2008Clinical use of radio- or photo-sensitizing agents in anti-cancer treatments may be limited by patient specific variability in the pharmacokinetics (PK) of the...
Clinical use of radio- or photo-sensitizing agents in anti-cancer treatments may be limited by patient specific variability in the pharmacokinetics (PK) of the sensitizing compound. Previously, our group reported motexafin gadolinium (MGd) concentrations in mouse tissues measured noninvasively by the optical pharmacokinetic system (OPS) in vivo, nondestructively by OPS in situ, and destructively by HPLC ex vivo. This study utilized those reported data to develop compartmental PK models of MGd disposition in plasma, tumor, and skin. The model predicted both the rapid initial distribution and slow elimination phases of MGd in plasma, the fast transport of MGd out of the skin (with no MGd detectable after 120 min), and MGd retention at long times in the tumor (with detectable MGd at 24 h). The same compartmental structure was used to model MGd concentrations vs. time as measured by OPS in situ and HPLC ex vivo. In vivo tumor MGd concentrations measured using OPS were estimated by a linear combination of the model predicted PK profiles in plasma and tumor tissue, which suggests that tissue-specific PK knowledge may be needed in order to interpret volume-averaged optical measurements in vivo. The PK modeling techniques presented here are extensible to other optically active compounds and, potentially, to the development of patient-specific treatment schedules.
Topics: Animals; Breast Neoplasms; Computer Simulation; Elasticity Imaging Techniques; Female; Humans; Image Interpretation, Computer-Assisted; Metabolic Clearance Rate; Metalloporphyrins; Mice; Mice, SCID; Models, Biological; Photosensitizing Agents; Skin; Tissue Distribution
PubMed: 19356671
DOI: 10.1016/j.pdpdt.2008.11.005 -
The Cochrane Database of Systematic... Jul 2006Brain radiotherapy is used to treat cancer patients who have brain metastases resulting from various primary malignancies. (Review)
Review
BACKGROUND
Brain radiotherapy is used to treat cancer patients who have brain metastases resulting from various primary malignancies.
OBJECTIVES
To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) in adult patients with multiple metastases to the brain.
SEARCH STRATEGY
CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CANCERLIT, and CINAHL were searched.
SELECTION CRITERIA
Randomized controlled trials (RCTs) in which adult patients with multiple metastases to the brain from any primary cancer and treated with WBRT were included. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of a single brain metastasis.
DATA COLLECTION AND ANALYSIS
Two review authors independently abstracted information for each predetermined outcome: overall survival at six months, intracranial progression-free duration, local brain response, local brain control, quality of life, symptom control, neurological function, and the proportion of patients able to reduce the daily dexamethasone dose. Adverse effects were also collected.
MAIN RESULTS
Eight published reports (nine trials) showed no benefit of altered dose-fractionation schedules as compared to control fractionation (3000 cGy in 10 fractions) of WBRT on the probability of survival at six months. These studies also showed no difference in symptom control nor neurologic improvement among the different dose-fractionation schemes. The addition of radiosensitizers, in five RCTs, did not confer additional benefit to WBRT in either overall median survival times or brain tumor response rates. The addition of the radiosensitizer motexafin gadolinium did not improve quality of life nor time to neurologic progression overall. For the radiosensitizer misonidazole, there was no improvement in Karnofsky performance score outcomes. Three RCTs found no benefit in overall survival with the use of WBRT and a radiosurgery boost as compared to WBRT alone for selected patients with multiple brain metastases (up to four brain metastases). Overall, however, there was a statistically significant improvement in local brain control favoring the whole brain radiotherapy and radiosurgery boost arm. Only one trial of radiosurgery boost with WBRT reported an improved Karnofsky performance score outcome and improved ability to reduce dexamethasone dose. One RCT examined the use of WBRT and prednisone versus prednisone alone and produced inconclusive results.
AUTHORS' CONCLUSIONS
None of the RCTs with altered dose-fractionation schemes as compared to standard delivery (3000 cGy in ten fractions) found a benefit in terms of overall survival, neurologic function, or symptom control. The use of radiosensitizers or chemotherapy in conjunction with WBRT remains experimental. A radiosurgery boost with WBRT may improve local disease control in selected patients, although survival remains unchanged. The benefit of WBRT as compared to supportive care alone has not been studied in RCTs. It may be that supportive care alone, without WBRT, may be appropriate for some patients, particularly those with advanced disease and poor performance status.
Topics: Adult; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Dose Fractionation, Radiation; Humans; Radiation-Sensitizing Agents; Radiosurgery; Randomized Controlled Trials as Topic; Survival Analysis
PubMed: 16856022
DOI: 10.1002/14651858.CD003869.pub2 -
Arteriosclerosis, Thrombosis, and... May 2001Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The...
Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium-loaded cells with 732-nm light (2 J/cm(2)) impaired cellular viability and growth (IC(50) 5 to 20 micromol/L). Depletion of intracellular glutathione potentiated (P=0.035) and the addition of antioxidant N-acetylcysteine attenuated (P=0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7+/-2% to 34+/-3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.
Topics: Animals; Apoptosis; Arteriosclerosis; Cell Division; Cell Line; Cell Survival; Cells, Cultured; Cytochrome c Group; Humans; Macrophages; Membrane Potentials; Metalloporphyrins; Mice; Mitochondria; Muscle, Smooth, Vascular; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents
PubMed: 11348871
DOI: 10.1161/01.atv.21.5.759 -
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 -
Clinical Advances in Hematology &... Nov 2007Effective treatment of glioblastoma multiforme (GBM) is complicated by multiple factors, including the diffusely infiltrative nature of the disease, which limits... (Review)
Review
Effective treatment of glioblastoma multiforme (GBM) is complicated by multiple factors, including the diffusely infiltrative nature of the disease, which limits complete surgical resection; the difficulty in overcoming the blood-brain barrier with systemic therapies; and the challenge of identifying novel means of treating the residual hypoxic tumor cells that are relatively resistant to radiotherapy (RT) and chemotherapy. Clear survival advantages have been demonstrated with postresection RT to doses of 5,000-6,000 cGy, but further attempts at dose escalation over 6,000 cGy have resulted in increased toxicity without a survival benefit. In an effort to improve local control of tumor and limit toxicity to normal brain tissue, novel imaging techniques (eg, chemical shift imaging) are being explored in order to better define RT fields. Brachytherapy and stereotactic radiosurgery are effective therapies for relapsed GBM but have undefined roles outside of clinical trials in treating newly diagnosed GBM. Stereotactic RT may have a survival advantage in subgroups that have undergone a gross total resection and have favorable (recursive partitioning analysis class IV) disease. In contrast, experience with hyperfractionated RT in GBM has shown that survival outcomes may actually be unfavorable in certain patient subgroups. Novel means of delivering RT, including radioimmunotherapy, have demonstrated efficacy with acceptable toxicity. Systemic agents are being explored as potential radiosensitizers, with the recent emergence of temozolomide as a model radiosensitizing agent having a positive impact on survival. Ongoing investigations are evaluating temozolomide in combination with other systemic agents, and additional agents (eg, motexafin gadolinium, mammalian target of rapamycin inhibitors, farnesyltransferase inhibitors) have shown promising activity in combination with RT.
Topics: Brain Neoplasms; Dose-Response Relationship, Radiation; Glioblastoma; Humans; Radiation-Sensitizing Agents; Radiotherapy; Randomized Controlled Trials as Topic
PubMed: 18185489
DOI: No ID Found -
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