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Methods and Findings in Experimental... 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... (Review)
Review
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 Studies 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: Abetimus sodium, Ad5-FGF4, adeno-Interferon gamma, AE-941, AERx, alemtuzumab, alicaforsen sodium, almotriptan, alpharadin, anakinra, anatumomab mafenatox, ANG-453, anti-CTLA-4 Mab, AP-12009, aprepitant, aripiprazole, arsenic trioxide, astemizole, atlizumab, atomoxetine hydrochloride; Bevacizumab, BG-9928, BMS-188667, botulinum toxin type B, BufferGel; Caffeine, CDP-870, cetuximab, cilomilast, ciluprevir, clofarabine, continuous erythropoiesis receptor activator, CP-461; Darbepoetin alfa, deferasirox, desloratadine, desoxyepothilone B, diflomotecan, dolasetron, drotrecogin alfa (activated), duloxetine hydrochloride; ED-71, efalizumab, efaproxiral sodium, EKB-569, eletriptan, EMD-72000, enfuvirtide, erlotinib hydrochloride, escitalopram oxalate, etoricoxib; Fampridine, ferumoxytol, fondaparinux sodium; Gadofosveset sodium, gastrazole, gefitinib, gemtuzumab ozogamicin, gepirone hydrochloride glutamine; hLM609, HSPPC-96, human insulin; IDD-1, imatinib mesylate, indisulam, inhaled insulin, ixabepilone; Keratinocyte growth factor; Lapatinib, laquinimod, LDP-02, LE-SN38, levetiracetam, levosimendan, licofelone, liposomal doxorubicin, liposomal NDDP, lopinavir, lumiracoxib, LY-156735; Morphine hydrochloride, morphine-6-glucuronide, motexafin gadolinium, MS-27-275, MVA-5T4, MVA-Muc1-IL-2; Nemifitide ditriflutate, neridronic acid nitronaproxen, NSC-683864, NSC-703940, NVP-LAF-237; Oblimersen sodium, ocinaplon, oncomyc-NG, OPC-28326, ortataxel, ospemifene; Palonosetron hydrochloride, PEG-filgrastim peginterferon alfa-2(a), peginterferon alfa-2b, pegsunercept, pemetrexed disodium, pregabalin, prilocaine, pyridoxamine; RDP-58, recombinant glucagon-like peptide-1 (7-36) amide, recombinant human ApoA-I milano/phospholipid complex; SB-715992, soblidotin, sodium dichloroacetate, St. John's Wort extract; TAS-102, terfenadine, TG-1024, TG-5001, 4'-Thio-ara-C, tipranavir, topixantrone hydrochloride, trabectedin, transdermal selegiline, trimethoprim, troxacitabine, TT-232; Vatalanib succinate, vinflunine; Ximelagatran; Ziprasidone hydrochloride, Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Databases, Factual; Humans; Statistics as Topic
PubMed: 14988742
DOI: No ID Found -
Minimally Invasive Neurosurgery : MIN Dec 2007The characteristics of an ideal contrast agent for use in the intraoperative MRI would be tumor-specificity and intracellular localization, combined with extended tumor...
OBJECTIVE
The characteristics of an ideal contrast agent for use in the intraoperative MRI would be tumor-specificity and intracellular localization, combined with extended tumor enhancement, but with rapid elimination from the blood. The radiation sensitizing properties of Motexafin gadolinium (MGd) have been investigated in a number of clinical trials involving patients with brain metastases. These studies clearly show that MGd is detectable in magnetic resonance images many days following administration. The aim of this experimental study was to test whether Motexafin gadolinium (MGd) could serve as an efficient intraoperative contrast agent avoiding problems that arise with surgically induced intracranial enhancement.
METHODS
F98 orthotopic brain tumors or surgical lesions were induced in Fisher rats. T1-weighted MRI studies were performed with either a single or multiple daily doses of MGd. The last contrast dose was administered either 7 or 24 hours prior to scanning in both tumor-bearing or surgically-treated animals. All scans were T1-weighted nce (TR=495 ms; TE=1 ms.) with a slice thickness of 1.0 mm. Three tubes containing 2.3, 0.23 and 0.023 mg/mL of MGd (in physiological saline) respectively, were used as standards to calibrate the scans.
RESULTS
Animals receiving either 30 or 60 mg/kg MGd i.v. developed clinical signs of impaired motor activity, and increasing lethargy and were euthanized 48 hours after MGd administration due to their poor and deteriorating condition. MGd given i.p. was tolerated up to a dose of 140 mg/kg. Despite multiple dosages and several administration modes (i.p., i.v.) no significant enhancement was observed if the scans were performed 7 or 24 hours following the last MGd dose. Clear enhancement was seen though when the scans were performed 30 min following MGd administration, indicating that the agent was being taken up by the tumor. Scans of necrotic lesions though were positive though 7 hours following MGd injection. MGd scans had no significant enhancement following surgically-induced lesions while scans with conventional contrast agents showed both meningeal and intraparenchymal enhancement.
CONCLUSION
This study suggests that MGd is not sequestered in viable tumor for the necessary time interval required to allow delayed imaging in this model. The agent does seem to remain in necrotic tissue for longer time intervals. MGd therefore would not be suitable as a contrast agent in intraoperative MRI for the detection of remaining tumor tissue during surgery.
Topics: Animals; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Cerebrovascular Circulation; Contrast Media; Disease Models, Animal; Encephalitis; Female; Glioma; Injections, Intraperitoneal; Injections, Intravenous; Magnetic Resonance Imaging; Male; Metabolic Clearance Rate; Metalloporphyrins; Monitoring, Intraoperative; Photic Stimulation; Photochemotherapy; Predictive Value of Tests; Rats; Rats, Inbred F344
PubMed: 18210352
DOI: 10.1055/s-2007-993158 -
International Journal of Radiation... Apr 2015The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy...
Phase 1/2 trials of Temozolomide, Motexafin Gadolinium, and 60-Gy fractionated radiation for newly diagnosed supratentorial glioblastoma multiforme: final results of RTOG 0513.
PURPOSE
The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls.
METHODS AND MATERIALS
Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method.
RESULTS
In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy.
CONCLUSIONS
Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemoradiotherapy; Dacarbazine; Disease-Free Survival; Dose Fractionation, Radiation; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Metalloporphyrins; Multivariate Analysis; Supratentorial Neoplasms; Temozolomide
PubMed: 25832688
DOI: 10.1016/j.ijrobp.2014.12.050 -
Journal of Neuro-oncology Nov 2011To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and...
Safety and feasibility of motexafin gadolinium administration with whole brain radiation therapy and stereotactic radiosurgery boost in the treatment of ≤ 6 brain metastases: a multi-institutional phase II trial.
To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for patients with ≤ 6 brain metastases. We conducted an international study of WBRT (37.5 Gy in 15 fractions) and SRS (15-21 Gy) with the addition of MGd (5 mg/kg preceding each fraction beginning week 2). The primary endpoint was to evaluate the rate of irreversible grade 3 or any grade ≥ 4 neurotoxicity and establish feasibility in preparation for a phase III trial. Sixty-five patients were enrolled from 14 institutions, of which 45 (69%) received SRS with MGd as intended and were available for evaluation. Grade ≥ 3 neurotoxicity attributable to radiation therapy within 3 months of SRS was seen in 2 patients (4.4%), including generalized weakness and radionecrosis requiring surgical management. Immediately following the course of MGd plus WBRT, new brain metastases were detected in 11 patients (24.4%) at the time of the SRS treatment planning MRI. The actuarial incidence of neurologic progression at 6 months and 1 year was 17 and 20%, respectively. The median investigator-determined neurologic progression free survival and overall survival times were 8 (95% CI: 5-14) and 9 months (95% CI: 6-not reached), respectively. We observed a low rate of neurotoxicity, demonstrating that the addition of MGd does not increase the incidence or severity of neurologic complications from WBRT with SRS boost.
Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Feasibility Studies; Female; Follow-Up Studies; Humans; International Agencies; Male; Metalloporphyrins; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Radiosurgery; Survival Rate; Treatment Outcome
PubMed: 21523486
DOI: 10.1007/s11060-011-0590-9 -
Mini Reviews in Medicinal Chemistry Jul 2011The biological properties of the lanthanides, primarily based on their similarity to calcium, have been the basis for research into potential therapeutic applications of... (Review)
Review
The biological properties of the lanthanides, primarily based on their similarity to calcium, have been the basis for research into potential therapeutic applications of lanthanides since the early part of the twentieth century. Up to date, cerium nitrate has been used as a topical cream with silver sulfadiazene for the treatment of burn wounds. A lanthanide texaphyrin complex (motexafin gadolinium) has been evaluated through Phase III clinical trials for the treatment of brain metastases in non-small cell lung cancer. Lanthanum carbonate (Fosrenol) as a phosphate binder has been approved for the treatment of hyperphosphatemia in renal dialysis patients in both the USA and Europe. This review will highlight therapeutic applications of the lanthanides for burn wounds, cancer, hyperphosphatemia, immune function, magnetic resonance imaging (MRI) contrast agents and osteoporosis, and discuss their future potential in the medical fields.
Topics: Burns; Clinical Trials as Topic; Contrast Media; Humans; Hyperphosphatemia; Lanthanoid Series Elements; Neoplasms; Osteopetrosis
PubMed: 21679137
DOI: 10.2174/138955711796268804 -
International Journal of Radiation... Apr 2001Experiments were undertaken to determine if metabolic changes induced by Motexafin gadolinium (Gd-Tex(+2), XCYTRIN) predict time intervals between drug and radiation...
PURPOSE
Experiments were undertaken to determine if metabolic changes induced by Motexafin gadolinium (Gd-Tex(+2), XCYTRIN) predict time intervals between drug and radiation wherein there is enhancement of radiation efficacy.
METHODS AND MATERIALS
We evaluated the effect of Gd-Tex(+2) on tumor metabolism and on tumor growth using a mouse mammary carcinoma model and (31)P nuclear magnetic resonance (NMR) experiments. Response to therapy was evaluated based on time for the tumor to regrow to pretreatment size and also tumor doubling time.
RESULTS
(31)P NMR experiments indicated that Gd-Tex(+2) effected tumor energy metabolism during the first 24 hours postadministration. A decrease in phosphocreatine was noted at 2 (p < 0.04), 6 (p < 0.006), and 24 (p < 0.001) hours post Gd-Tex(+2). A decrease in nucleoside triphosphates was noted only at 2 hours (p < 0.02), with subsequent recovery at 6 hours. Phosphocreatine in control (saline treated) tumors showed a significant decrease only at 24 hours (p < 0.01). Irradiation at 2 and 6 hours post Gd-Tex(+2) induced an enhanced effect compared to radiation alone as measured by analyzing the growth curves, maximum tumor volumes, and the time for the tumors to regrow to their initial volumes. Irradiation at 24 hours post Gd-Tex(+2) induced a modest enhancement in tumor growth delay compared to radiation alone.
DISCUSSION
NMR spectroscopy may be useful for monitoring tumor metabolism after treatment with Gd-Tex(+2) and administering radiation during the time of maximal efficacy of Gd-Tex(+2).
Topics: Animals; Energy Metabolism; Magnetic Resonance Spectroscopy; Male; Mammary Neoplasms, Animal; Metalloporphyrins; Mice; Mice, Inbred C3H; Phosphorus; Photosensitizing Agents; Radiation Tolerance; Radiobiology; Time Factors
PubMed: 11286846
DOI: 10.1016/s0360-3016(00)01566-2 -
Clinical Cancer Research : An Official... Oct 2001The effect of motexafin gadolinium (MGd), a redox mediator, on tumor response to doxorubicin (Dox) and bleomycin (Bleo) was investigated in vitro and in vivo. MES-SA...
The effect of motexafin gadolinium (MGd), a redox mediator, on tumor response to doxorubicin (Dox) and bleomycin (Bleo) was investigated in vitro and in vivo. MES-SA human uterine sarcoma cells were studied in vitro using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay. Rif-1, a murine fibrosarcoma cell line, was studied using a clonogenic survival assay. Tumor growth delay assays were performed using the EMT-6 murine mammary sarcoma cell line in BALB/c mice. MGd (25-100 microM) produced dose-dependent enhancement of Bleo cytotoxicity to MES-SA cells. The IC(50) for Bleo was reduced by approximately 10-fold using 100 microM MGd. In clonogenic assays using Rif-1 cells, MGd enhanced the activity of Bleo approximately 1000-fold. This effect was shown to be mediated, in part, by MGd inhibition of potentially lethal damage repair. MGd enhanced the tumor response to bleomycin and Dox in vivo. MGd had no significant effect on the systemic exposure to Dox (expressed in terms of the plasma area under the curve, 0-24 h) and did not increase Dox myelosuppression. MGd enhanced the effectiveness of the redox active drugs, Bleo and Dox.
Topics: Animals; Antineoplastic Agents; Bleomycin; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Female; Humans; Male; Metalloporphyrins; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental; Photosensitizing Agents; Rats; Rats, Sprague-Dawley; Treatment Outcome; Tumor Cells, Cultured
PubMed: 11595717
DOI: No ID Found -
Cancer Biology & Therapy Jan 2005Thioredoxin reductase (TRX) is a selenoprotein that reduces oxidized protein substrates in an NADPH-dependent process (cf. Fig. 1). The thioredoxins (TX) are a family of... (Review)
Review
Thioredoxin reductase (TRX) is a selenoprotein that reduces oxidized protein substrates in an NADPH-dependent process (cf. Fig. 1). The thioredoxins (TX) are a family of small redox active proteins that undergo reversible oxidation/reduction and help to maintain the redox state of cells. TX serves as a cofactor in many TRX-catalyzed reductions in a manner similar to glutathione (GSH) in thioltransferase reactions. For example, TX is a cofactor in protein disulfide reduction and DNA synthesis, but independently, it inhibits apoptosis, stimulates cell proliferation and angiogenesis, and increases transcription factor activity. The role of the TRX/TX system is limited by its reducing capacity as well as the additional supply of electrons in the form of NADPH provided by hexose monophosphate shunt (HMPS). TX is limited by the reduction capacity of its vicinal sulfhydryls and needs a source of electrons from the HMPS and TRX- coupled system to reduce disulfides. Oxidized TX is reduced by TRX and NADPH. Several lines of evidence suggest that the coupled HMPS/TRX/TX system represents an important target for cancer therapy. TX overexpression has been reported in several malignancies and may be associated with aggressive tumor growth and poor survival. In some cells, TX is an important factor in conferring resistance to chemotherapy and in stimulating production of hypoxia-inducible factor (HIF-1). Several inhibitors of the TRX/TX system have been evaluated in experimental cancer models: these include HMPS inhibitors, carbohydrate analogues, NADP synthesis blockers, vicinal thiol reactants, cisplatin, and TRX inhibitors. More recently, the targeted anti-cancer agent motexafin gadolinium has been identified. Motexafin gadolinium is a redox mediator that selectively localizes to cancer cells, and reacts with reducing metabolites and vicinal thiols to generate reactive oxygen species that ultimately block the TRX enzyme as well as the analogous glutaredoxin activity. In cell and animal models, motexafin gadolinium is directly cytotoxic to various tumor cells and enhances the activity of radiation therapy and chemotherapy. This drug is now in a broad range of clinical trials investigating its therapeutic potential when used as a single agent or in combination with either chemotherapy or radiation therapy. Promising clinical activity has been reported in a clinical trial with motexafin gadolinium and whole brain radiation therapy for treatment of brain metastases from solid tumors. These findings suggest that the TRX/TX system may represent an attractive target for development of new cancer therapeutics.
Topics: Antineoplastic Agents; Glycolysis; Humans; Metalloporphyrins; Neoplasms; Thioredoxin-Disulfide Reductase; Thioredoxins
PubMed: 15684606
DOI: 10.4161/cbt.4.1.1434 -
European Journal of Medicinal Chemistry Mar 2024Radiotherapy (RT) stands as a cornerstone in the clinical armamentarium against various cancers due to its proven efficacy. However, the intrinsic radiation resistance... (Review)
Review
Radiotherapy (RT) stands as a cornerstone in the clinical armamentarium against various cancers due to its proven efficacy. However, the intrinsic radiation resistance exhibited by cancer cells, coupled with the adverse effects of RT on normal tissues, often compromises its therapeutic potential and leads to unwanted side effects. This comprehensive review aims to consolidate our understanding of how radiosensitizers inhibit the thioredoxin (Trx) system in cellular contexts. Notable radiosensitizers, including gold nanoparticles (GNPs), gold triethylphosphine cyanide ([Au(SCN) (PEt)]), auranofin, ceria nanoparticles (CONPs), curcumin and its derivatives, piperlongamide, indolequinone derivatives, micheliolide, motexafin gadolinium, and ethane selenide selenidazole derivatives (SeDs), are meticulously elucidated in terms of their applications in radiotherapy. In this review, the sensitization mechanisms and the current research progress of these radiosensitizers are discussed in detail, with the overall aim of providing valuable insights for the judicious application of Trx system inhibitors in the field of cancer radiosensitization therapy.
Topics: Humans; Gold; Metal Nanoparticles; Neoplasms; Radiation-Sensitizing Agents; Thioredoxins; Cyanates
PubMed: 38387331
DOI: 10.1016/j.ejmech.2024.116218 -
Biochemical and Biophysical Research... Feb 2009Motexafin gadolinium (MGd) is an expanded porphyrin anticancer agent which selectively targets tumor cells and works as a radiation enhancer, with promising results in...
Motexafin gadolinium (MGd) is an expanded porphyrin anticancer agent which selectively targets tumor cells and works as a radiation enhancer, with promising results in clinical trials. Its mechanism of action is oxidation of intracellular reducing molecules and acting as a direct inhibitor of mammalian ribonucleotide reductase (RNR). This paper focuses on the mechanism of inhibition of RNR by MGd. Our experimental data present at least two pathways for inhibition of RNR; one precluding subunits oligomerization and the other direct inhibition of the large catalytic subunit of the enzyme. Co-localization of MGd and RNR in the cytoplasm particularly in the S-phase may account for its inhibitory properties. These data can elucidate an important effect of MGd on the cancer cells with overproduction of RNR and its efficacy as an anticancer agent and not only as a general radiosensitizer.
Topics: Animals; Antineoplastic Agents; Enzyme Inhibitors; HeLa Cells; Humans; Metalloporphyrins; Mice; Oxidative Stress; Protein Subunits; Ribonucleotide Reductases
PubMed: 19121624
DOI: 10.1016/j.bbrc.2008.12.128