-
Clinical Genitourinary Cancer Sep 2008Thioredoxin reductase (Trx) has been implicated in activation of hypoxia-inducible factor-1alpha, which is overexpressed in > 85% of renal cell carcinomas (RCCs). We...
BACKGROUND
Thioredoxin reductase (Trx) has been implicated in activation of hypoxia-inducible factor-1alpha, which is overexpressed in > 85% of renal cell carcinomas (RCCs). We evaluated the safety and efficacy of motexafin gadolinium (MGd), a Trx inhibitor, as a single-agent therapy for metastatic RCC.
PATIENTS AND METHODS
Patients with metastatic RCC were infused daily with MGd 5 mg/kg on days 1-5 and days 15-19 of each 28-day cycle. Patients were evaluated for response on days 21-28 of every third cycle. Those with tumor response or stable disease (SD) continued treatment for < or = 12 cycles. Twenty-five patients with confirmed metastatic RCC were enrolled. All were evaluable for toxicity, and 20 were evaluable for response.
RESULTS
While no clinical responses were observed, 8 patients had SD after 3 treatment cycles, as did 4 after 6 cycles. Median overall survival was 10.1 months, and median progression- free survival was 2.7 months. The most common treatment-related toxicities were grade 1/2 pain, nausea, skin discoloration, fatigue, blisters, and headache. The most common grade 3 toxicity was hypophosphatemia, observed in 5 patients. MGd was reasonably tolerated, and disease stabilization was observed in several patients with metastatic RCC.
CONCLUSION
These results show promise for the use of MGd in combination with other molecularly targeted therapies in previously treated patients with metastatic RCC. However, further investigation of MGd alone for metastatic RCC is not recommended.
Topics: Adult; Aged; Carcinoma, Renal Cell; Drug Administration Schedule; Female; Humans; Kidney Neoplasms; Male; Metalloporphyrins; Middle Aged; Neoplasm Metastasis
PubMed: 18824428
DOI: 10.3816/CGC.2008.n.011 -
Journal of Thoracic Oncology : Official... Aug 2007Motexafin gadolinium is a novel antineoplastic drug that disrupts cancer cell antioxidant systems, thus contributing to cellular death. In patients with lung cancer,...
INTRODUCTION
Motexafin gadolinium is a novel antineoplastic drug that disrupts cancer cell antioxidant systems, thus contributing to cellular death. In patients with lung cancer, motexafin gadolinium has been shown to increase the time to neurologic progression when given in combination with whole-brain radiotherapy in randomized phase III studies. Preclinical data suggest that this drug might also enhance the antineoplastic effects of chemotherapy.
METHODS
In this one-arm, open label, phase I, dose-escalation study, we administered docetaxel (75 mg/m2), cisplatin (75 mg/m2), and motexafin gadolinium every 3 weeks to patients with metastatic non-small cell lung cancer. Twenty-one patients were treated at one of four motexafin dose levels.
RESULTS
The maximal tolerated motexafin dose was 10 mg/kg on day 1 of a 3-week cycle. Dose-limiting toxicities consisted of febrile neutropenia, hypertension, myocardial ischemia, and pneumonitis/pulmonary infiltrates. Other common grade 3-4 adverse events across all cohorts that did not appear to be exacerbated by motexafin gadolinium included granulocytopenia, fatigue, dehydration, nausea, and vomiting. Two episodes of myocardial ischemia and one sudden death of unknown cause were observed. Response rates were partial response (10%), stable disease (60%), and disease progression (30%).
CONCLUSIONS
The regimen studied was tolerable and showed activity in patients with metastatic non-small cell lung cancer. The recommended doses for future phase II trials are motexafin gadolinium 10 mg/kg, docetaxel 75 mg/m2, and cisplatin 75 mg/m2 intravenously on day 1 every 3 weeks. Caution is advised in patients with a history of cardiovascular disease.
Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Metalloporphyrins; Middle Aged; Prognosis; Survival Rate; Taxoids
PubMed: 17762342
DOI: 10.1097/JTO.0b013e31811f4719 -
Journal of Clinical Oncology : Official... Aug 2002Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation... (Clinical Trial)
Clinical Trial
Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points.
PURPOSE
Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation therapy. This lead-in phase to a randomized trial served to evaluate radiologic, neurocognitive, and neurologic progression end points and to evaluate the safety and radiologic response of motexafin gadolinium administered concurrently with 30 Gy in 10-fraction whole-brain radiation therapy for the treatment of brain metastases.
PATIENTS AND METHODS
Motexafin gadolinium (5.0 mg/kg/d for 10 days) was administered before each radiation treatment in this prospective international trial. Patients were evaluated by MRI, neurologic examinations, and neurocognitive tests. Prospective criteria and centralized review procedures were established for radiologic, neurocognitive, and neurologic progression end points.
RESULTS
Twenty-five patients with brain metastases from lung (52%) and breast (24%) cancer, recursive partitioning analysis class 2 (96%), and an average of 11 brain metastases were enrolled. Neurocognitive function was highly impaired at presentation. Motexafin gadolinium was well tolerated. Freedom from neurologic progression was 77% at 1 year. Median survival was 5.0 months. In 29% of patients, the cause of death was brain metastasis progression. The radiologic response rate was 68%. Motexafin gadolinium's tumor selectivity was established with MRI.
CONCLUSION
(1) Centralized neurologic progression scoring that incorporated neurocognitive tests was implemented successfully. (2) Motexafin gadolinium was well tolerated. (3) Local control, measured by radiologic response rate, neurologic progression, and death caused by progression of brain metastasis, seemed to be improved compared with historical results. A randomized phase III trial using these methods for evaluation of efficacy has just been completed.
Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Cognition; Cranial Irradiation; Disease-Free Survival; Female; Humans; Magnetic Resonance Imaging; Male; Metalloporphyrins; Middle Aged; Neoadjuvant Therapy; Prospective Studies; Survival Rate
PubMed: 12177105
DOI: 10.1200/JCO.2002.07.500 -
Molecular Pharmacology Jan 2007Heme oxygenase-1 (HO1), which oxidizes heme to biliverdin, CO, and free iron, conveys protection against oxidative stress and is antiapoptotic. Under stress conditions,...
Heme oxygenase-1 (HO1), which oxidizes heme to biliverdin, CO, and free iron, conveys protection against oxidative stress and is antiapoptotic. Under stress conditions, some porphyrin derivatives can inhibit HO1 and trigger cell death. Motexafin gadolinium (MGd) is an expanded porphyrin that selectively targets cancer cells through a process of futile redox cycling that decreases intracellular reducing metabolites and protein thiols. Here, we report that hematopoietic-derived cell lines that constitutively express HO1 are more susceptible to MGd-induced apoptosis than those that do not. MGd used in combination with tin protoporphyrin IX, an inhibitor of HO1, resulted in synergistic cell killing. Consistent with these cell culture observations, we found that MGd is an inhibitor of heme oxygenase-1 activity in vitro. We demonstrate that inhibition of HO1 reflects an interaction of MGd with NADPH-cytochrome P450 reductase, the electron donor for HO1, that results in diversion of reducing equivalents from heme oxidation to oxygen reduction. In accord with this mechanism, MGd is also an in vitro inhibitor of CYP2C9, CYP3A4, and CYP4A1. Inhibition of HO1 by MGd may contribute to its anticancer activity, whereas its in vitro inhibition of a broad spectrum of P450 enzymes indicates that a potential exists for drug-drug interactions.
Topics: Antineoplastic Agents; Cell Division; Cell Line, Tumor; Chromatography, High Pressure Liquid; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Humans; Kinetics; Metalloporphyrins; NADPH-Ferrihemoprotein Reductase; Oxidoreductases Acting on CH-CH Group Donors; Oxygen Consumption; Spectrophotometry
PubMed: 17018578
DOI: 10.1124/mol.106.028407 -
Investigational New Drugs Jul 2006Motexafin gadolinium (Xcytrin) is an expanded porphyrin macrocyclic compound under development for the treatment of several types of cancer. Currently clinical trials...
Motexafin gadolinium (Xcytrin) is an expanded porphyrin macrocyclic compound under development for the treatment of several types of cancer. Currently clinical trials and non-clinical pharmacology and toxicology studies are ongoing. The goals of this open label, four arm, non-crossover bioavailability study were to explore motexafin gadolinium pharmacokinetics, determine the i.p. bioavailability, and define a pharmacokinetic model suitable for descriptive and predictive use. Mice received one or seven daily i.v. or i.p. injections (40 mg/kg) then blood samples were collected and analyzed. Plasma concentration data were modelled using population pharmacokinetic methods and a two compartment model was the most appropriate model. The stability and predictive performance of the model were evaluated using bootstrap procedures. The accuracy of the predicted concentrations was 8.3%. Motexafin gadolinium was rapidly cleared from the plasma and although T(1/2beta) was 12.9 h there was no accumulation following seven doses. The i.p. bioavailability was 87.4% and higher plasma concentrations were sustainable for a longer period with i.p. dosing. V(c) was larger than the blood volume and the tissue compartment volume was 38% of V(c), suggesting motexafin gadolinium was not widely distributed into less well perfused tissues. The pharmacokinetic profile in this study was similar to that in oncology patients administered multiple doses of motexafin gadolinium. The unbiased model yields reliable parameter estimates and insight into the pharmacokinetics of motexafin gadolinium in mice, is suitable for both descriptive and predictive purposes, and is a valuable tool in the planning, analysis, and interpretation of pharmacology and toxicology studies in mice.
Topics: Animals; Antineoplastic Agents; Biological Availability; Female; Humans; Injections, Intraperitoneal; Injections, Intravenous; Male; Metalloporphyrins; Mice; Population; Reproducibility of Results
PubMed: 16538526
DOI: 10.1007/s10637-006-5383-1 -
Cancer Letters Aug 2011Motexafin gadolinium (MGd) sensitizes malignant cells to ionizing radiation, although the underlying mechanisms for uptake and sensitization are both unclear. Here we...
Motexafin gadolinium (MGd) sensitizes malignant cells to ionizing radiation, although the underlying mechanisms for uptake and sensitization are both unclear. Here we show that MGd is endocytosed by the clathrin-dependent pathway with ensuing lysosomal membrane permeabilization, most likely via formation of reactive oxygen species involving redox-active metabolites, such as ascorbate. We propose that subsequent apoptosis is a synergistic effect of irradiation and high MGd concentrations in malignant cells due to their pronounced endocytic activity. The results provide novel insights into the mode of action of this promising anti-cancer drug, which is currently under clinical trials.
Topics: Antineoplastic Agents; Ascorbic Acid; Cell Line; Endocytosis; Flow Cytometry; Humans; Lysosomes; Metalloporphyrins; Microscopy, Fluorescence; Reactive Oxygen Species
PubMed: 21492999
DOI: 10.1016/j.canlet.2011.03.023 -
Investigational New Drugs Apr 2011To assess the safety, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT), of motexafin gadolinium (MGd), given in combination with doxorubicin, in patients...
PURPOSE
To assess the safety, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT), of motexafin gadolinium (MGd), given in combination with doxorubicin, in patients with advanced solid tumors.
STUDY DESIGN
The combination of MGd and doxorubicin was administered every 28 days (cycle 1) and then every 21 days (subsequent cycles). The dose of MGd, given daily for 3 days, was escalated from 1.0 mg/kg/d to 3.3 mg/kg/d, while the dose of doxorubicin was held at 30 mg/m².
RESULTS
Fifteen patients received 37 cycles of treatment, for a median of 2 cycles per patient (range 0-6 cycles). Three patients (20%) completed 6 cycles of therapy. The MTD was identified as MGd, 2 mg/kg/day and doxorubicin, 30 mg/m². Dose limiting toxicities included grade 3 hypertension, pneumonia, bacteremia, and elevated GGT. Serious adverse events also included pulmonary embolism and urinary tract infection requiring hospitalization. There was no exacerbation of cardiac toxicity. No patients attained a response to treatment. Six patients (54%) had stable disease. The median time to disease progression, or to last assessment, was 49 days (range 8-195 days).
CONCLUSIONS
The combination of MGd and doxorubicin was fairly well tolerated. However, due to emerging preclinical data suggesting that MGd inhibits ribonucleotide reductase, further development of the combination of MGd plus doxorubicin is not recommended.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Demography; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Male; Metalloporphyrins; Middle Aged; Neoplasms; Treatment Outcome
PubMed: 19997959
DOI: 10.1007/s10637-009-9364-z -
Oxidative Medicine and Cellular... 2019Redox homeostasis is essential for the maintenance of diverse cellular processes. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells as a... (Review)
Review
Redox homeostasis is essential for the maintenance of diverse cellular processes. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells as a result of hypermetabolism, but the redox balance is maintained in cancer cells due to their marked antioxidant capacity. Recently, anticancer therapies that induce oxidative stress by increasing ROS and/or inhibiting antioxidant processes have received significant attention. The acceleration of accumulative ROS disrupts redox homeostasis and causes severe damage in cancer cells. In this review, we describe ROS-inducing cancer therapy and the anticancer mechanism employed by prooxidative agents. To understand the comprehensive biological response to certain prooxidative anticancer drugs such as 2-methoxyestradiol, buthionine sulfoximine, cisplatin, doxorubicin, imexon, and motexafin gadolinium, we propose and visualize the drug-gene, drug-cell process, and drug-disease interactions involved in oxidative stress induction and antioxidant process inhibition as well as specific side effects of these drugs using pathway analysis with a big data-based text-mining approach. Our review will be helpful to improve the therapeutic effects of anticancer drugs by providing information about biological changes that occur in response to prooxidants. For future directions, there is still a need for pharmacogenomic studies on prooxidative agents as well as the molecular mechanisms underlying the effects of the prooxidants and/or antioxidant-inhibitor agents for effective anticancer therapy through selective killing of cancer cells.
Topics: 2-Methoxyestradiol; Animals; Antineoplastic Agents; Homeostasis; Humans; Neoplasms; Oxidants; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 31929855
DOI: 10.1155/2019/5381692 -
Journal of Clinical Pharmacology Mar 2005The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was...
The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was administered intravenously for 2 to 6.5 weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP-PK) methods. The POP-PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight-normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied < or =13% from the population mean CL or V1 estimate. It was concluded that a 3-compartment, open, POP-PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alkaline Phosphatase; Anticonvulsants; Antineoplastic Agents; Brain Neoplasms; Clinical Trials as Topic; Creatinine; Data Interpretation, Statistical; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Metabolic Clearance Rate; Metalloporphyrins; Middle Aged; Models, Biological; Neoplasm Metastasis; Phenytoin; Sex Factors; Software
PubMed: 15703365
DOI: 10.1177/0091270004271946 -
Journal of Chromatography. B,... Dec 2000We present new HPLC methods for the quantitation in human plasma of two investigative metallotexaphyrin agents, motexafin gadolinium (Gd-Tex) and motexafin lutetium...
We present new HPLC methods for the quantitation in human plasma of two investigative metallotexaphyrin agents, motexafin gadolinium (Gd-Tex) and motexafin lutetium (Lu-Tex). Each assay uses: the other texaphyrin analogue as an internal standard; protein precipitation with acetonitrile:methanol (50:50, v/v); an ODS reversed-phase column; an isocratic mobile phase of 100 mM ammonium acetate, pH 4.3:acetonitrile:methanol (59:21:20, v/v/v); and absorbance detection at 470 nm. The Gd-Tex assay has a lower limit of quantitation (LLOQ) of 0.01 microM and is linear between 0.01 and 30 microM. The Lu-Tex assay has an LLOQ of 0.1 microM and is linear between 0.1 and 30 microM. The assays are suited for in vivo preclinical studies and clinical trials because they require minimal amounts of plasma, are sensitive, and involve a 30-mm run time. These assays are important tools for evaluating the potential of Gd-Tex and Lu-Tex as a radiation enhancer and photosensitizer, respectively.
Topics: Chromatography, High Pressure Liquid; Humans; Metalloporphyrins; Photosensitizing Agents
PubMed: 11145051
DOI: 10.1016/s0378-4347(00)00390-x