A phase I study of triapine in combination with irinotecan in refractory tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12011-12011 ◽  
Author(s):  
W. R. Schelman ◽  
K. Holen ◽  
D. Mulkerin ◽  
J. Kolesar ◽  
J. Thomas ◽  
...  
Keyword(s):  
Dose Level ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Treatment Plan ◽  
Resonance Spectroscopy ◽  
Eligibility Criteria ◽  
Paramagnetic Resonance ◽  
Molecule Inhibitor ◽  
Level 1 ◽  
Grade 3 ◽  
Tumor Types

12011 Background: Triapine is a small molecule inhibitor of ribonucleotide reductase and has anti-tumor activity alone and in combination with other agents in advanced solid tumors. Based on its ability to limit DNA repair, Triapine has been postulated to act synergistically with irinotecan. This study was conducted to determine the toxicities and efficacy of Triapine with irinotecan. Correlative studies included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy. Methods: This study used standard eligibility criteria with the following exceptions: patients must have had no prior irinotecan and no G6PD deficiency. The treatment plan consisted of irinotecan on day 1 with Triapine on days 1- 3 of a 21-day cycle. Starting dose (level 1) was irinotecan (150 mg/m2) and Triapine (85 mg/m2/day). RECIST was used to measure response. Results: 10 patients have been enrolled; 5 men, 5 women. Tumor types: 4 pancreatic, 2 cholangio, 1 esophageal, 1 sarcoma, 1 lung, 1 ovarian. Grade 3–4 toxicities at least possibly related to Triapine at any dose level were as follows: neutropenia (3), leukopenia (2), fatigue, hypoxia, nausea, vomiting, thrombocytopenia, abdominal cramping, hypocalcemia, and thrombosis. The first patient enrolled at level 1 developed a DLT (Grade 3 hypoxia). Consequently, irinotecan and Triapine doses were reduced to 100 mg/m2 and 60 mg/m2/day, respectively (level -1). One of 6 patients experienced a DLT at this dose level. Further patients were then enrolled at level 1. There were 2 DLTs of 4 patients at level 1. One partial response (NSCLC) was seen. Conclusions: Unacceptable toxicities were seen at dose level 1; however, dose level -1 was well tolerated. The trial has therefore been amended in order to evaluate a higher dose of irinotecan (150 mg/m2) with the level -1 dose of Triapine (60 mg/m2/day). Accrual continues at this dose level. Antitumor activity in NSCLC was noted at level 1. [Table: see text]

A phase I study of vorinostat in combination with bortezomib in refractory solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3573-3573 ◽  
Author(s):  
W. R. Schelman ◽  
J. Kolesar ◽  
K. Schell ◽  
R. Marnocha ◽  
J. Eickhoff ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Solid Tumors ◽  
Dose Level ◽  
Treatment Plan ◽  
Hdac Inhibitors ◽  
26S Proteasome ◽  
Clinical Activity ◽  
Eligibility Criteria ◽  
Objective Evidence ◽  
Level 1

3573 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) inhibitor that has anti- tumor activity in hematologic malignancies and advanced solid tumors. Based on studies showing that HDAC inhibitors increase the activity of the 26S proteasome, vorinostat has been postulated to act synergistically with bortezomib. This study was conducted to determine the toxicities and efficacy of vorinostat with bortezomib. Correlative studies included pharmacokinetics and the effects of vorinostat/bortezomib on cell cycle, proteasome inhibition, histone acetylation, gene expression and apoptosis. Methods: This study used standard eligibility criteria except pts must have had no prior bortezomib. The treatment plan consisted of vorinostat given orally on days 1–14 with bortezomib IV on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (Step A, level 1) was once-daily vorinostat (400 mg) and bortezomib (0.7 mg/m2). Step B consisted of twice-daily dosing of vorinostat (200mg) with bortezomib at MTD established in Step A. RECIST was used to measure response. Effects on G2/M-phase arrest in buccal mucosa cells (BMC) were measured using flow cytometry. Samples were collected on days 1 and 9, at 0, 2 and 4 hr following treatment. Results: 22 pts have been enrolled; 14 men, 8 women. Tumor types: 5 sarcoma, 5 colorectal, 3 pancreatic, 2 lung, 1 breast, 1 ovarian, 1 bladder, 1 gastric, 1 germ cell, 1 mesothelioma, 1 GIST. Grade 3–4 toxicities at least possibly related to vorinostat at any dose level were as follows: fatigue (3), n/v (1), thrombocytopenia (1), and hyponatremia (1). One pt was unevaluable. DLTs included fatigue (3), hyponatremia (1) and elevated ALT (1). The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. One pt with refractory soft tissue sarcoma had a PR > 9 mo. There was no effect on cell cycle arrest observed with vorinostat in BMCs. Conclusions: The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. Accrual continues at Step B, dose level 1. Subjective and objective evidence of clinical activity has been observed in pts with refractory solid tumors. (Supported by NCI grant UO1 CA062491, NCI SAIC contract 25XS097 and GCRC M01 RR03186.) No significant financial relationships to disclose.

A multicenter phase 2 consortium (P2C) study of triapine in patients (pts) with advanced adenocarcinoma of the pancreas

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14118-14118
Author(s):  
D. L. Groteluschen ◽  
M. R. Mahoney ◽  
H. C. Pitot ◽  
D. Laheru ◽  
J. Kolesar ◽  
...  
Keyword(s):  
Electron Paramagnetic Resonance Spectroscopy ◽  
Single Agent ◽  
Chelating Agent ◽  
Iron Chelator ◽  
Resonance Spectroscopy ◽  
Eligibility Criteria ◽  
Paramagnetic Resonance ◽  
First Line Therapy ◽  
Gemcitabine Refractory ◽  
Adenocarcinoma Of The Pancreas

14118 Background: Triapine is a small molecule iron chelator that has been shown to inhibit ribonucleotide reductase (RR) at the M2 subunit. Early trials suggested activity in pancreatic cancer. The P2C initiated a study of single agent Triapine as both first-line therapy and for pts with gemcitabine-refractory disease. Correlatives included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy (EPR). Methods: Standard eligibility criteria were used, however, pts with G6PD deficiency were excluded. Triapine was given 96 mg/m2 IV over 2 hours, days 1–4 and 15–18, repeated q 28 days. Primary goals - evaluate survival (S) at 6 mos (previously untreated pts) and 4 mos (refractory pts). Interim analyses were planned when 28 previously untreated and 20 refractory pts were enrolled. Results: 14 eligible pts were enrolled in 10 mos (13 refractory, 9 male). The previously untreated pt received only 1 cycle secondary to progressive disease. Of the 13 refractory pts, 7 pts received at most 2 cycles; 6 received 1. Disease progression precluded further treatment in 11 pts. 6 pts had Gr 4 toxicities at least possibly related to drug, including: neutropenia-4, hyperkalemia-1, hyponatremia-1, leukopenia-1, thrombocytopenia-1, hypophosphatemia-1. 6 pts had a Gr 3 fatigue. One refractory patient expired on study. No responses were seen. Estimated 4 mos S in refractory pts is 16% (95% CI 3–94). EPR studies showed that Triapine led to a loss of the RR tyrosine radical EPR signal. Conclusions: Enrollment was suspended due to excess toxicity and lack of activity in pts refractory to gemcitabine. Correlative studies confirm the mechanism of action of Triapine as a chelating agent on RR. Supported by NCI Grant N01 CM17104 and the NCI Translational Research Fund. No significant financial relationships to disclose.

A phase I study of vorinostat in combination with bortezomib in refractory solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2531-2531
Author(s):  
J. A. Ninan ◽  
H. Bailey ◽  
J. Kolesar ◽  
R. Marnocha ◽  
J. Eickhoff ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Treatment Plan ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Eligibility Criteria ◽  
Combination Methods ◽  
Starting Dose ◽  
Grade 3 ◽  
Subjective Evidence ◽  
Tumor Types

2531 Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an oral histone deacytlase (HDAC) inhibitor that has anti-tumor activity in hematologic malignancies and advanced solid tumors. Vorinostat has been postulated to act synergistically with bortezomib at the level of aggresome inhibition with creation of reactive oxygen species. We previously conducted a study of this combination with once-daily dosing of vorinostat with bortezomib (Step A). This study (Step B) was conducted to evaluate twice daily dosing of vorinostat during administration of bortezomib to determine safety and efficacy, pharmacokinetics, and activity this combination. Methods: This study used standard eligibility criteria except patients must have had no prior bortezomib. The treatment plan initially consisted of vorinostat given orally twice daily on days 1–14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at level 1, and the protocol was amended to administer vorinostat twice daily on days 1–4 and 8–11. Starting dose was vorinostat 200 mg and bortezomib 1 mg/m2. RECIST was used to measure response. Results: 29 pts have been enrolled; 13 men and 16 women. Tumor types include: Prostate (1), Colorectal (3), Pancreatic (6), Sarcoma (7), Biliary (1), Thymus (1), GIST (2), Mesothelioma (1), ovarian (1), Neuroendocrine (1), Lung (1), Head and Neck (1), Breast (2), and Cervical (1). Grade 3–4 toxicities possibly related to SAHA at any dose level were as follows: thrombocytopenia (5), fatigue (3), increased ALT (1), elevated INR (1), anemia, (1), hypotension (1), diarrhea (3), anorexia (1), dizziness (1), nausea/vomiting (1), and hypoalbuminemia (1). The only dose limiting toxicities included elevated ALT (1), fatigue (1). There were two deaths but neither was felt to be related to the drug. The MTD for Step B was established at vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Conclusions: The MTD for Step B was established at vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Subjective evidence of clinical activity has been observed in patients with refractory solid tumors. These studies were supported by NCI, UO1, CA062491, SAIC 25XS097, and 1ULRR025011. No significant financial relationships to disclose.

scholarly journals Tauroursodeoxycholic Acid (TUDCA)—Lipid Interactions and Antioxidant Properties of TUDCA Studied in Model of Photoreceptor Membranes

Membranes ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 327
Author(s):  
Michał J. Sabat ◽  
Anna M. Wiśniewska-Becker ◽  
Michał Markiewicz ◽  
Katarzyna M. Marzec ◽  
Jakub Dybas ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Plasma Membranes ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Protective Action ◽  
Antioxidant Properties ◽  
Model Membranes ◽  
Dynamics Simulation ◽  
Resonance Spectroscopy ◽  
Paramagnetic Resonance ◽  
Tauroursodeoxycholic Acid

Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid containing taurine conjugated with the ursodeoxycholic acid (UDCA), has been known and used from ancient times as a therapeutic compound in traditional Chinese medicine. TUDCA has recently been gaining significant interest as a neuroprotective agent, also exploited in the visual disorders. Among several mechanisms of TUDCA’s protective action, its antioxidant activity and stabilizing effect on mitochondrial and plasma membranes are considered. In this work we investigated antioxidant activity of TUDCA and its impact on structural properties of model membranes of different composition using electron paramagnetic resonance spectroscopy and the spin labeling technique. Localization of TUDCA molecules in a pure POPC bilayer has been studied using a molecular dynamics simulation (MD). The obtained results indicate that TUDCA is not an efficient singlet oxygen (1O2 (1Δg)) quencher, and the determined rate constant of its interaction with 1O2 (1Δg) is only 1.9 × 105 M−1s−1. However, in lipid oxidation process induced by a Fenton reaction, TUDCA reveals substantial antioxidant activity significantly decreasing the rate of oxygen consumption in the system studied. In addition, TUDCA induces slight, but noticeable changes in the polarity and fluidity of the investigated model membranes. The results of performed MD simulation correspond very well with the experimental results.

scholarly journals Ambient base-free glycerol oxidation over bimetallic PdFe/SiO2 by in situ generated active oxygen species

2021 ◽  
Author(s):  
Ricci Underhill ◽  
Mark Douthwaite ◽  
Richard J. Lewis ◽  
Peter J. Miedziak ◽  
Robert D. Armstrong ◽  
...  
Keyword(s):  
Heterogeneous Catalysts ◽  
Bimetallic Catalyst ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Active Oxygen Species ◽  
Catalytic Performance ◽  
Resonance Spectroscopy ◽  
Oxygen Species ◽  
Paramagnetic Resonance ◽  
Temperature Oxidation

AbstractLow temperature oxidation of alcohols over heterogeneous catalysts is exceptionally challenging, particularly under neutral conditions. Herein, we report on an efficient, base-free method to oxidise glycerol over a 0.5%Pd-0.5%Fe/SiO2 catalyst at ambient temperature in the presence of gaseous H2 and O2. The exceptional catalytic performance was attributed to the in situ formation of highly reactive surface-bound oxygenated species, which promote the dehydrogenation on the alcohol. The PdFe bimetallic catalyst was determined to be significantly more active than corresponding monometallic analogues, highlighting the important role both metals have in this oxidative transformation. Fe leaching was confirmed to occur over the course of the reaction but sequestering experiments, involving the addition of bare carbon to the reactions, confirmed that the reaction was predominantly heterogeneous in nature. Investigations with electron paramagnetic resonance spectroscopy suggested that the reactivity in the early stages was mediated by surface-bound reactive oxygen species; no homogeneous radical species were observed in solution. This theory was further evidenced by a direct H2O2 synthesis study, which confirmed that the presence of Fe in the bimetallic catalyst neither improved the synthesis of H2O2 nor promoted its decomposition over the PdFe/SiO2 catalyst.

Sign in / Sign up

Export Citation Format

Share Document