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Drugs in R&D 2004Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It... (Review)
Review
Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It is cytotoxic in haematological malignancies by selectively localising in cancer cells that have high rates of metabolism. Motexafin gadolinium inhibits cellular respiration resulting in the production of reactive oxygen species and inducing apoptosis. It is being developed by Pharmacyclics in the US. Bulk motexafin gadolinium is supplied to Pharmacyclics by the US company, Celanese, through a manufacturing and supply agreement between the two companies. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), the importance of having an agent for the treatment of brain metastases from lung cancer was highlighted. Results of a phase III study were presented that showed that motexafin gadolinium treatment was associated with a delay in time to neurological and neurocognitive progression in lung cancer patients. This was an important finding, as 46.6% of lung cancer patients already have brain metastases at the time of initial diagnosis, compared with only 2.7% of breast cancer patients. Brain metastases are also often the only site of metastatic disease in patients with lung cancer. In December 2002, Pharmacyclics began a phase III trial of motexafin gadolinium in patients with brain metastases (brain cancer in phase table) from lung cancer in the US, Europe, Canada and Australia. The trial is known as the Study of neurologic progression with Motexafin gadolinium And Radiation Therapy (SMART) and will compare whole-brain irradiation with whole-brain irradiation plus motexafin gadolinium in 550 patients. The primary efficacy endpoint is time to neurological progression and the secondary endpoints are survival and neurocognitive function. In January 2003, the US FDA completed its Special Protocol Assessment (SPA) of the SMART trial with a positive result and by June 2003, enrollment had begun. In addition, phase I trials are underway in children with intrinsic pontine glioma and adults with head and neck, lung and pancreatic cancers. A phase II trial is also being conducted in the US in patients with glioblastoma multiforme. Enrollment in this trial has been completed and preliminary results have been reported. Pharmacyclics has completed enrollment and follow-up of adults in its pivotal phase III trial of motexafin gadolinium as a radiation sensitiser for the treatment of brain metastases. The trial was conducted at 35 centres in Europe, Canada and the US. Full results from this initial phase III trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida, USA, held in May 2002. Pharmacyclics also announced in October 2002, at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), that motexafin gadolinium significantly prolonged time to neurological progression when added to whole brain radiation therapy and reduced the number of deaths in patients with brain tumour. Pharmacyclics announced in September 2000 that it has initiated two NCI-sponsored phase I trials conducted under a Cooperative Research and Development Agreement (CRADA) between Pharmacyclics and the NCI. The first trial, conducted in patients with stage IIIA non-small cell lung cancer, was designed to determine the safety of two different dosing regimens of motexafin gadolinium during preoperative radiotherapy after induction chemotherapy. The second study was designed to examine the use of motexafin gadolinium in combination with stereotactic Gamma Knife radiosurgery in patients with primary glioblastoma mutiforme. Two phase I clinical trials have also been conducted for the treatment of newly diagnosed glioblastoma multiforme at the UCLA Jonsson Comprehensive Cancer Center, USA. These phase I studies were sponsored by the NCI and were conducted under a CRADA with the NCI. Pharmacyclics has also completed multicentre US phase II clinical trials of motexafin gadolinium fin gadolinium in patients with metastatic tumours of the brain who require whole brain radiotherapy. Motexafin gadolinium is in a phase II trial in patients with lymphomas and multiple myeloma in the US.
Topics: Animals; Drugs, Investigational; Humans; Metalloporphyrins; Neoplasms; Radiation-Sensitizing Agents
PubMed: 14725495
DOI: 10.2165/00126839-200405010-00012 -
Expert Opinion on Investigational Drugs Jul 2003Motexafin gadolinium (MGd, PCI-0120, Xcytrin, a metallotexaphyrin developed by Pharmacyclics, is a redox active drug that selectively targets tumour cells with a... (Review)
Review
Motexafin gadolinium (MGd, PCI-0120, Xcytrin, a metallotexaphyrin developed by Pharmacyclics, is a redox active drug that selectively targets tumour cells with a potential action as a radiosensitiser. In vitro and in vivo models showed radiation enhancement when radiation followed MGd administration. Phase I and II clinical studies showed that MGd was well-tolerated with a maximum-tolerated dose set at 6.3 mg/kg. Acute side effects of discolouration of the sclera, skin and urine are reversible. The clinical efficacy was determined in an international Phase III trial for brain metastases with a significant difference in time to neurological progression for lung cancer brain metastases in favour of MGd and whole brain radiation versus whole brain radiation only. For the treatment of glioblastoma multiforme, promising results are found in a Phase I trial with a median survival of 17.3 months. Further investigation of the combination of MGd and radiotherapy will be worthwhile.
Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Metalloporphyrins; Radiation-Sensitizing Agents
PubMed: 12831354
DOI: 10.1517/13543784.12.7.1205 -
Current Opinion in Oncology Nov 2004Redox regulation has been shown to be an important component of malignant cell survival and is a system that may be pharmacologically manipulated for the treatment of... (Review)
Review
PURPOSE OF REVIEW
Redox regulation has been shown to be an important component of malignant cell survival and is a system that may be pharmacologically manipulated for the treatment of cancer. Motexafin gadolinium is a member of a class of rationally designed porphyrin-like molecules called texaphyrins. The rationale for its use in cancer therapy is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells and it has a novel mechanism of action as it induces redox stress, triggering apoptosis in a broad range of cancers.
RECENT FINDINGS
In vitro studies have shown that motexafin gadolinium is synergistic with radiation and varied chemotherapeutic agents. A phase III international study has shown that the onset of neurologic progression is significantly delayed in patients with brain metastases from lung cancer treated with whole-brain radiation and motexafin gadolinium (compared with radiation alone). Recent preclinical data have shown that motexafin gadolinium alone is cytotoxic to cancers such as multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia through redox and apoptotic pathways. Multiple clinical trials examining motexafin gadolinium as a single agent and in combination with radiation and/or chemotherapy for the treatment of solid and hematopoietic tumors are underway.
SUMMARY
Motexafin gadolinium is a novel tumor-targeted agent that disrupts redox balance in cancer cells by futile redox cycling. Motexafin gadolinium is currently in numerous hematology/oncology clinical trials for use as a single agent and in combination with chemotherapy and/or radiation therapy.
Topics: Antineoplastic Agents; Brain Neoplasms; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Gadolinium; Humans; Lung Neoplasms; Metalloporphyrins; Radiation-Sensitizing Agents
PubMed: 15627019
DOI: 10.1097/01.cco.0000142073.29850.98 -
Expert Opinion on Pharmacotherapy Feb 2007Motexafin gadolinium (MGd) is a novel, MRI-detectable, anticancer agent that enhances the cytotoxic potential of radiation therapy through several mechanisms, including... (Review)
Review
Motexafin gadolinium (MGd) is a novel, MRI-detectable, anticancer agent that enhances the cytotoxic potential of radiation therapy through several mechanisms, including depleting intracellular reducing metabolites that are necessary for repairing the oxidative damage induced by irradiation. It has tumor-specific uptake, normal tissue sparing, and tolerable and reversible toxicities in clinical trials. MGd's use in conjunction with whole-brain radiation therapy (WBRT) has demonstrated an improvement in neurocognitive decline, neurologic progression, and quality of life in patients with brain metastases from NSCLC. Its use in conjunction with radiosurgery and whole brain radiation therapy in the setting of brain metastases is currently being studied, as is MGd with radiation and temozolomide in patients with glioblastoma multiforme. MGd is also being actively investigated as a single agent or in combination with chemotherapy or radiation therapy in other tumors, including pediatric brain tumors, NSCLC, lymphoma, renal cell carcinoma, and pancreatic and biliary tumors.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Contrast Media; Gadolinium; Humans; Metalloporphyrins; Photosensitizing Agents
PubMed: 17266469
DOI: 10.1517/14656566.8.3.351 -
Seminars in Cancer Biology Dec 2006Motexafin gadolinium (MGd, Xcytrin) is an aromatic macrocycle that has a strong affinity for electrons, i.e., it is easily reduced. In the presence of oxygen, MGd... (Review)
Review
Motexafin gadolinium (MGd, Xcytrin) is an aromatic macrocycle that has a strong affinity for electrons, i.e., it is easily reduced. In the presence of oxygen, MGd accepts electrons from various cellular reducing metabolites and forms superoxide and other reactive oxygen species (ROS) by redox cycling. The reaction with NADPH is dramatically accelerated by various oxido-reductases including thioredoxin reductase. In vitro studies with various cancer cell lines have shown an increase in ROS and intracellular free zinc in cells treated with MGd. MGd increases cytotoxicity of ionizing radiation and various chemotherapy agents and may be directly cytotoxic to tumor cells under certain conditions. MGd selectively localizes in tumors, perhaps due to their metabolic perturbations. MGd treatment in murine models enhances tumor response to radiation and chemotherapy agents. In controlled, randomized clinical trials, combining MGd treatment with ionizing radiation improves time to neurologic progression in lung cancer patients with brain metastases. The molecular target for MGd appears to be thioredoxin reductase which, when inhibited, results in cellular redox stress, cytotoxicity and an increase in tumor responsiveness to a variety of treatments.
Topics: Antineoplastic Agents; Humans; Metalloporphyrins; Neoplasms; Oxidation-Reduction
PubMed: 17112739
DOI: 10.1016/j.semcancer.2006.09.002 -
Current Treatment Options in Oncology Jul 2005Redox mechanisms have been shown to be important in malignant cell survival and are a system that may be modified for the treatment of hematologic malignancies.... (Review)
Review
Redox mechanisms have been shown to be important in malignant cell survival and are a system that may be modified for the treatment of hematologic malignancies. Motexafin gadolinium (MGd) is a synthetic expanded porphyrin that selectively accumulates in tumor cells and oxidizes various intracellular metabolites, including ascorbate, nicotinamide adenine dinucleotide phosphate, glutathione, and protein thiols, to generate reactive oxygen species in a process known as futile redox cycling. The rationale for its use in hematologic malignancies is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells, and it has a novel mechanism of action of inducing redox stress and triggering apoptosis in a broad range of malignancies. MGd induces apoptosis in B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and highly resistant myeloma cell lines. Furthermore, MGd is additive or synergistic with ionizing radiation, several chemotherapy agents, and rituximab in vitro and in vivo tumor models. Through gene expression profiling, various stress-related genes are upregulated in response to MGd, including genes encoding metallothioneins, heat shock proteins, and heme oxygenase. Preliminary results from clinical trials with MGd in hematopoietic malignancies have shown that it is well tolerated, with minimal hematologic side effects in both; it has single agent activity in very heavily pretreated chronic lymphocytic leukemia /small lymphocytic lymphoma patients, and it has induced prompt complete remissions in combination with 90Yttrium-ibritumomab (Y-90 Zevalin; Biogen Idec Inc., Cambridge, MA) for relapsed non-Hodgkin's lymphoma in the first two cohorts of patients enrolled. Various clinical trials studying MGd as a single agent and in combination with radiation and/or chemotherapy for the treatment of hematologic malignancies are ongoing.
Topics: Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Drug Synergism; Gene Expression Profiling; Hematologic Neoplasms; Humans; Metalloporphyrins; Oxidative Stress; Reactive Oxygen Species
PubMed: 15967082
DOI: 10.1007/s11864-005-0033-y -
Expert Review of Anticancer Therapy Jun 2007Despite advances in the field of oncology, progress for patients with brain metastases and most primary brain tumors has been slow. New efforts to enhance the... (Review)
Review
Despite advances in the field of oncology, progress for patients with brain metastases and most primary brain tumors has been slow. New efforts to enhance the therapeutic index of radiation therapy are under way, including the use of radiosensitizers. Motexafin gadolinium (Xcytrin) is one such novel agent with several unique properties that enhance the cytotoxic potential of radiation therapy, as well as several chemotherapeutic agents, and possibly has independent cytotoxicity in certain lymphoid malignancies. Motexafin gadolinium is very well tolerated with tumor specific uptake. The rationale for the use of this drug as well as its current and future role as a radiation enhancer in the management of brain tumors is reviewed.
Topics: Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Humans; Metalloporphyrins; Radiation-Sensitizing Agents
PubMed: 17555388
DOI: 10.1586/14737140.7.6.785 -
Expert Review of Anticancer Therapy Dec 2004Despite recent advances in both technology and molecular targeting, little progress has been made in the management of most malignancies of the brain, especially brain... (Review)
Review
Despite recent advances in both technology and molecular targeting, little progress has been made in the management of most malignancies of the brain, especially brain metastases. In an effort to increase the therapeutic ratio of external beam radiation treatments, radiosensitizers and enhancers have been investigated. Motexafin gadolinium is a new drug with radioenhancing properties and a unique mechanism of action that may increase the therapeutic index of whole brain radiotherapy for patients with brain metastases. The rationale for the use of this drug as well as its current and future role as a radiation enhancer in the management of brain tumors is reviewed.
Topics: Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Humans; Metalloporphyrins; Radiation-Sensitizing Agents
PubMed: 15606327
DOI: 10.1586/14737140.4.6.981 -
International Journal of Nanomedicine 2007Despite recent advances in technology, targeting, and chemotherapy, brain metastasis from non-small cell lung cancer (NSCLC) remains a significant problem. The vast... (Review)
Review
Despite recent advances in technology, targeting, and chemotherapy, brain metastasis from non-small cell lung cancer (NSCLC) remains a significant problem. The vast majority of patients with this diagnosis undergo whole brain radiation therapy (WBRT). However, outcomes are still quite poor with median survivals measured in only months. In an effort to enhance outcomes from external beam radiation treatments, radiosensitizers have been investigated. Motexafin gadolinium (MGd) (Xcytrin, Sunnyvale, CA, USA) is a novel radiation sensitizer with a unique mechanism of action that may increase the therapeutic index of WBRT for patients with brain metastases, particularly in those with NSCLC histologies. Here we review the rationale for the use of this drug as well as its current and future role as a radiation enhancer in the management of NSCLC brain metastasis.
Topics: Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Carriers; Drug Delivery Systems; Humans; Injections, Intralesional; Lung Neoplasms; Metalloporphyrins; Nanomedicine; Nanostructures; Photosensitizing Agents; Treatment Outcome
PubMed: 17722515
DOI: 10.2147/nano.2007.2.1.79 -
Apoptosis : An International Journal on... Oct 2005Motexafin gadolinium (MGd, Xcytrin) is a tumor-localizing redox mediator that catalyzes the oxidation of intracellular reducing molecules including NADPH, ascorbate,...
Motexafin gadolinium (MGd, Xcytrin) is a tumor-localizing redox mediator that catalyzes the oxidation of intracellular reducing molecules including NADPH, ascorbate, protein and non-protein thiols, generating reactive oxygen species (ROS). MGd localizes to tumors and cooperates with radiation and chemotherapy to kill tumor cells in tissue culture and animal models. In this report, we demonstrate that MGd triggers the mitochondrial apoptotic pathway in the HF-1 lymphoma cell line as determined by loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, activation of caspase-9 prior to caspase-8, cleavage of PARP and annexin V binding. There was minimal effect on MGd-induced apoptosis by the caspase inhibitor z-VAD-fmk, even though caspase-3 activity (as measured by DEVD-cleavage) was completely inhibited. However, MGd-induced apoptosis was reduced to baseline levels by the more potent caspase inhibitor Q-VD-OPh, demonstrating that MGd-induced apoptosis is indeed caspase-dependent. Apoptosis induced by dexamethasone, doxorubicin and etoposide (mediated through the mitochondrial pathway) was also more sensitive to inhibition by Q-VD-OPh than z-VAD-fmk. Our results demonstrating differential sensitivity of drug-induced apoptosis to caspase inhibitors suggest that the term "caspase-independent apoptosis" cannot be solely defined as apoptosis that is not inhibited by z-VAD-fmk as has been utilized in some published studies.
Topics: Amino Acid Chloromethyl Ketones; Annexin A5; Antineoplastic Agents; Apoptosis; Caspase Inhibitors; Caspases; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Metalloporphyrins; Mitochondria; Poly(ADP-ribose) Polymerases; Quinolines
PubMed: 16151646
DOI: 10.1007/s10495-005-0887-2