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International Journal of Radiation... Feb 2006Radiation therapy plays a critical role in the local and regional control of malignant tumors. Its efficacy, however, is limited by a number of factors, including... (Review)
Review
PURPOSE
Radiation therapy plays a critical role in the local and regional control of malignant tumors. Its efficacy, however, is limited by a number of factors, including toxicity, tumor hypoxia, and tumor genetics. Recent attempts to enhance the efficacy of radiation therapy have focused on biologic agents that modulate reduction/oxidation reactions within tumor cells.
METHODS AND MATERIALS
We review five promising redox modulators that are in development. Tirapazamine and AQ4N are known as "hypoxic cell sensitizers" and are toxic in areas of low oxygen tension. RSR13 facilitates delivery of oxygen to tumor cells, thereby rendering them more sensitive to radiation. Motexafin gadolinium, with a porphyrin-like structure, selectively accumulates in tumor cells and thereby enhances radiation-induced DNA damage. HIF-1 inhibitors target a transcription factor that regulates hypoxia-related events and cell survival.
RESULTS
Our review of each agent included a thorough search of published preclinical and clinical data, including that presented in abstracts and posters at international meetings. Our objectives were not to identify a superior mechanism or drug, but rather to summarize the available safety and efficacy data.
CONCLUSION
Clearly, there is an unmet need for safer agents that augment the efficacy of radiation therapy. This review highlights five promising redox modulators that are in development. None has yet been approved by the Food and Drug Administration. These drugs were selected for discussion because they exemplify the current investigative landscape of radiosensitizers and are indicative of future directions in this area. These radiation sensitizers have the potential to succeed where others have failed, by locally increasing the radiosensitivity of tumor cells without enhancing that of surrounding normal tissues.
Topics: Aniline Compounds; Anthraquinones; Cell Hypoxia; Clinical Trials as Topic; DNA Damage; Drug Approval; Drug Therapy, Combination; Humans; Hypoxia-Inducible Factor 1; Maximum Tolerated Dose; Metalloporphyrins; Neoplasms; Oxidation-Reduction; Propionates; Radiation-Sensitizing Agents; Tirapazamine; Triazines
PubMed: 16414370
DOI: 10.1016/j.ijrobp.2005.10.013 -
Methods and Findings in Experimental... Nov 20065-Methyltetrahydrofolate, (R)-flurbiprofen; Ad5CMV-p53, adalimumab, alefacept, alemtuzumab, Alequel, alicaforsen sodium, almotriptan, anakinra, aprepitant, aripiprazole,...
5-Methyltetrahydrofolate, (R)-flurbiprofen; Ad5CMV-p53, adalimumab, alefacept, alemtuzumab, Alequel, alicaforsen sodium, almotriptan, anakinra, aprepitant, aripiprazole, armodafinil; Bevacizumab, bortezomib, bosentan; Canfosfamide hydrochloride, ciclesonide, clofarabine, Cypher; Darbepoetin alfa, diclofenac potassium, drotrecogin alfa (activated), duloxetine hydrochloride; Eel calcitonin, eletriptan, eplerenone, everolimus, ezetimibe; Frovatriptan; Gefitinib, gamma-hydroxybutyrate sodium; HKI-272, HYB-165; Ibutamoren mesylate, imatinib mesylate, interleukin-21, ixabepilone; KRN-951; L-Arginine hydrochloride, levodopa/carbidopa/entacapone; Micafungin sodium, motexafin gadolinium, mycophenolic acid sodium salt; Nesiritide; Peginterferon alfa-2a, pitavastatin calcium, pralatrexate, pregabalin, pVAX/L523S-Ad.L523S; Rasagiline mesylate, recombinant human nerve growth factor, regadenoson, rF-PSA, rimonabant, rizatriptan, rofecoxib, rosuvastatin calcium, rV-B7.1, rV-PSA; Sipuleucel-T, sirolimus-eluting stent, solifenacin succinate, sorafenib, sunitinib malate; Talactoferrin alfa, Taxus, tegaserod maleate, teriparatide, tipifarnib; Valdecoxib, vandetanib, vatalanib succinate; WT1-peptide vaccine; Xaliproden hydrochloride. (c) 2006 Prous Science. All rights reserved.
Topics: Clinical Trials as Topic; Drug Therapy; Humans
PubMed: 17200730
DOI: No ID Found -
Frontiers in Bioscience : a Journal and... Jan 2006Redox regulation has been shown to be an important component of malignant cell survival. Tipping the cellular redox balance through pharmacologic regulation in favor of... (Review)
Review
Redox regulation has been shown to be an important component of malignant cell survival. Tipping the cellular redox balance through pharmacologic regulation in favor of increasing intracellular reactive oxygen species (ROS) and/or depleting protective reducing metabolites (such as glutathione and nicotinamide adenine dinucleotide phosphate) may lead to oxidative stress and resultant induction of apoptosis for the treatment of cancer. We review the biology and importance of ROS with regard to malignant and normal cells. Moreover, we discuss pre-clinical and clinical data regarding novel therapeutic agents that modulate the cellular redox system including buthionine sulfoximine, ascorbic acid, arsenic trioxide, imexon, and motexafin gadolinium as single-agents and in combination. Continued research is needed to better understand the mechanisms and specific apoptotic pathways involved in ROS-induced cell death, as well as, to determine the most rationale and effective combination of redox-active agents.
Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Buthionine Sulfoximine; Cell Death; Dose-Response Relationship, Drug; Glutathione; Hexanones; Humans; Metalloporphyrins; Models, Biological; Models, Chemical; Neoplasms; Oxidation-Reduction; Oxidative Stress; Oxides; Reactive Oxygen Species
PubMed: 16146732
DOI: 10.2741/1798 -
European Journal of Cancer (Oxford,... Sep 2004The generation of reactive oxygen species (ROS) can be exploited therapeutically in the treatment of cancer. One of the first drugs to be developed that generates ROS... (Review)
Review
The generation of reactive oxygen species (ROS) can be exploited therapeutically in the treatment of cancer. One of the first drugs to be developed that generates ROS was procarbazine. It is oxidised readily in an oxic environment to its azo derivative, generating ROS. Forty years ago, Berneis reported a synergistic effect in DNA degradation when procarbazine was combined with radiation; this was confirmed in preclinical in vivo modes. Early uncontrolled clinical trials suggested an enhancement of the radiation effect with procarbazine, but two randomised trials failed to confirm this. The role of ROS in cancer treatments and in the development of resistance to chemotherapy is now better understood. The possibility of exploiting ROS as a cancer treatment is re-emerging as a promising therapeutic option with the development of agents such as buthionine sulfoximine and motexafin gadolinium.
Topics: Antineoplastic Agents; Buthionine Sulfoximine; Combined Modality Therapy; DNA; Humans; Metalloporphyrins; Neoplasms; Oxidation-Reduction; Procarbazine; Reactive Oxygen Species
PubMed: 15315800
DOI: 10.1016/j.ejca.2004.02.031 -
Methods and Findings in Experimental... Apr 2008(-)-Epigallocatechin gallate, (-)-Gossypol; Ad.hIFN-beta, AF-37702, Agatolimod sodium, Agomelatine, Alvocidib hydrochloride, ARC-1779; Belimumab, BIBW-2992, Binodenoson,...
(-)-Epigallocatechin gallate, (-)-Gossypol; Ad.hIFN-beta, AF-37702, Agatolimod sodium, Agomelatine, Alvocidib hydrochloride, ARC-1779; Belimumab, BIBW-2992, Binodenoson, Bortezomib, Bosutinib, Brivaracetam; Cediranib, Clevidipine, CNTO-328, CP-751871, Curcumin; Darapladib, Deforolimus, Denosumab, Desvenlafaxine succinate, Dipyridamole/prednisolone, Dronedarone hydrochloride, DTPw-HBV/Hib 2.5; Ecogramostim, Elacytarabine, Eltrombopag, Eprodisate sodium; Farnesylthiosalicylic acid, Febuxostat, Fenretinide, Ferumoxytol, FMP2.1/AS02A, Forodesine hydrochloride, FP-0011; HuLuc-63, Human Fibroblast Growth Factor 1; Idraparinux sodium, Indium 111 (111In) ibritumomab tiuxetan, Interleukin-21, Ipilimumab, ISS-1018, ITF-2357; Lapaquistat acetate, Laropiprant, Liposomal vincristine, LY-518674; Masitinib mesylate, MAXY-G34, MGCD-0103, Midostaurin, Mitumprotimut-T, MK-0343, MLN-1202, MM-093, Motexafin gadolinium; NB-001, NB-002, Niacin/laropiprant; Oblimersen sodium, Ocrelizumab, Omacetaxine mepesuccinate; Panobinostat, Patupilone, PBI-1402, Perifosine, PHA-739358, Plerixafor hydrochloride, Prasugrel; Regadenoson, RHAMM R3 peptide, Rilonacept, Rivaroxaban, Romiplostim; Safinamide mesilate, Salinosporamide A, Selenite sodium, Sotrastaurin; Thrombin alfa, Tipifarnib, TRO-19622; Vatalanib succinate, Vernakalant hydrochloride, VRC-WNVDNA017-00-VP; YM-155, Yttrium 90 (90Y) ibritumomab tiuxetan; Zosuquidar trihydrochloride.
Topics: Clinical Trials as Topic; Humans
PubMed: 18597009
DOI: No ID Found -
Current Cancer Drug Targets Mar 2012Brain tumors, primary and metastatic, are a cause of significant mortality and morbidity. Radiotherapy (RT) forms an integral part of the treatment of brain tumors.... (Review)
Review
Brain tumors, primary and metastatic, are a cause of significant mortality and morbidity. Radiotherapy (RT) forms an integral part of the treatment of brain tumors. Intrinsic relative tumor radio-resistance, normal tissue tolerance and impact on neurocognitive function, all limit the efficacy of RT. Radiosensitizers can potentially increase efficacy on tumors while maintaining normal tissue toxicity, with or without inherent cytotoxicity. This article reviews the evolution of evidence with use of non-cytotoxic radiosensitizers in brain radiotherapy and their status at the end of the first decade of this millennium. Considering, the era of development and mechanism of action, these agents are classified as first, second and third-generation non-cytotoxic radiosensitizers. The last millennium involved elaboration of first-generation compounds including halogenated pyrimidines, hypoxic cell sensitizers (e.g. imidazoles) and glycolytic inhibitors (e.g. lonidamine). The first decade of this millennium has highlighted redox modulators like motexafin gadolinium and newer hypoxic cell sensitizers like efaproxiral, which have shown promise. However, phase III trials and meta-analyses have not identified a clear winner though the second-generation has shown some rays of hope. Recent research has focused on expanding the horizon by studying modulation of newer molecular pathways like DNA repair, microtubule stabilization, cytokine function and nuclear factor-kappa beta (NF-KB) in order to increase RT efficacy. The review concludes by summarizing the class of evidence and the level of recommendation available for use of non-cytotoxic radiosensitizers in brain RT.
Topics: Animals; Brain Neoplasms; Clinical Trials as Topic; Cytotoxins; Humans; Radiation-Sensitizing Agents
PubMed: 22268387
DOI: 10.2174/156800912799277494 -
Analytical and Bioanalytical Chemistry May 2006Liquid chromatography-fluorescence (LC-FLS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS) methods...
Validation and use of three complementary analytical methods (LC-FLS, LC-MS/MS and ICP-MS) to evaluate the pharmacokinetics, biodistribution and stability of motexafin gadolinium in plasma and tissues.
Liquid chromatography-fluorescence (LC-FLS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS) methods were developed and validated for the evaluation of motexafin gadolinium (MGd, Xcytrin) pharmacokinetics and biodistribution in plasma and tissues. The LC-FLS method exhibited the greatest sensitivity (0.0057 microg mL(-1)), and was used for pharmacokinetic, biodistribution, and protein binding studies with small sample sizes or low MGd concentrations. The LC-MS/MS method, which exhibited a short run time and excellent selectivity, was used for routine clinical plasma sample analysis. The ICP-MS method, which measured total Gd, was used in conjunction with LC methods to assess MGd stability in plasma. All three methods were validated using human plasma. The LC-FLS method was also validated using plasma, liver and kidneys from mice and rats. All three methods were shown to be accurate, precise and robust for each matrix validated. For three mice, the mean (standard deviation) concentration of MGd in plasma/tissues taken 5 hr after dosing with 23 mg kg(-1) MGd was determined by LC-FLS as follows: plasma (0.025+/-0.002 microg mL(-1)), liver (2.89+/-0.45 microg g(-1)), and kidney (6.09+/-1.05 microg g(-1)). Plasma samples from a subset of patients with brain metastases from extracranial tumors were analyzed using both LC-MS/MS and ICP-MS methods. For a representative patient, > or = 90% of the total Gd in plasma was accounted for as MGd over the first hour post dosing. By 24 hr post dosing, 63% of total Gd was accounted for as MGd, indicating some metabolism of MGd.
Topics: Animals; Antineoplastic Agents; Chemistry, Clinical; Chromatography, Liquid; Drug Interactions; Humans; Kidney; Liver; Mass Spectrometry; Metalloporphyrins; Mice; Models, Chemical; Rats; Sensitivity and Specificity; Time Factors
PubMed: 16609840
DOI: 10.1007/s00216-006-0414-5 -
Cancer Chemotherapy and Pharmacology Apr 2006To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with...
Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers.
PURPOSE
To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated.
METHODS
Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography.
RESULTS
Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion.
CONCLUSION
Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.
Topics: Aged; Antineoplastic Agents; Area Under Curve; Biliary Tract Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Liver Function Tests; Male; Metalloporphyrins; Middle Aged; Pancreatic Neoplasms
PubMed: 16133531
DOI: 10.1007/s00280-005-0071-y -
The Journal of Pharmacology and... Jun 2001Motexafin gadolinium (MGd) is a unique therapeutic agent that localizes in cancer cells and increases tumor response to ionizing radiation and certain chemotherapeutics....
Motexafin gadolinium (MGd) is a unique therapeutic agent that localizes in cancer cells and increases tumor response to ionizing radiation and certain chemotherapeutics. The in vitro intracellular localization, accumulation, and retention of MGd in murine EMT6 mammary sarcoma and Rif-1 fibrosarcoma cell lines were studied using interferometric Fourier fluorescence microscopy. MGd cellular uptake was semiquantified using its characteristic fluorescence emission band centered at 758 nm. Colocalization studies were performed using mitochondrial, endoplasmic reticulum, Golgi apparatus, nuclear, and lysosomal fluorescent organelle probes, and verified using interferometric Fourier spectroscopy. Cellular uptake was gradual and increased significantly with incubation time. MGd localized primarily within the lysosomes and endoplasmic reticulum, and to a lesser extent within the Golgi apparatus and mitochondria. Mitochondrial staining was increased in media without serum. No nuclear uptake was detected in the Rif-1 cells, but after 48 h nuclear uptake was observed in 15% of EMT6 cells. These results indicated that MGd accumulates within cytoplasmic compartments. The sustained intracellular localization of MGd may, in part, account for its unique radiation and chemotherapy enhancement properties. Interferometric Fourier fluorescence microscopy is a potentially powerful tool in delineating and verifying localization sites of therapeutic agents.
Topics: Animals; Biological Transport; Cell Nucleus; Cell Survival; Culture Media, Serum-Free; Endoplasmic Reticulum; Fluorescent Dyes; Golgi Apparatus; Lysosomes; Metalloporphyrins; Mice; Microscopy, Fluorescence; Microscopy, Interference; Mitochondria; Neoplasm Transplantation; Neoplasms, Experimental; Photochemistry; Radiation-Sensitizing Agents; Sarcoma; Spectrometry, Fluorescence; Tumor Cells, Cultured
PubMed: 11356908
DOI: No ID Found -
Molecular Nutrition & Food Research Jan 2009The thioredoxin (Trx) system is a major antioxidant system integral to maintaining the intracellular redox state. It contains Trx, a redox active protein, which... (Review)
Review
The thioredoxin (Trx) system is a major antioxidant system integral to maintaining the intracellular redox state. It contains Trx, a redox active protein, which regulates the activity of various enzymes including those that function to counteract oxidative stress within the cell. Trx can also scavenge reactive oxygen species (ROS) and directly inhibits proapoptotic proteins such as apoptosis signal-regulating kinase 1 (ASK1). The oxidized form of Trx is reduced by thioredoxin reductase (TrxR). The cytoplasm and mitochondria contain equivalent Trx systems and inhibition of either system can lead to activation of apoptotic signaling pathways. There are a number of inhibitors with chemotherapy applications that target either Trx or TrxR to induce apoptosis in cancer cells. Suberoylanilide hydroxamic acid (SAHA) is effective against many cancer cells and functions by up-regulating an endogenous inhibitor of Trx. Other compounds target the selenocysteine-containing active site of TrxR. These include gold compounds, platinum compounds, arsenic trioxide, motexafin gadolinium, nitrous compounds, and various flavonoids. Inhibition of TrxR leads to an accumulation of oxidized Trx resulting in cellular conditions that promote apoptosis. In addition, some compounds also convert TrxR to a ROS generating enzyme. The role of Trx system inhibitors in cancer therapy is discussed in this review.
Topics: Antineoplastic Agents; Apoptosis; Free Radical Scavengers; Humans; Mitochondria; Neoplasms; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 18979503
DOI: 10.1002/mnfr.200700492