The new vascular disrupting agent combretastatin-A1-disodium-phosphate (OXi4503) enhances tumour response to mild hyperthermia and thermoradiosensitization

2007 ◽  
Vol 23 (7) ◽  
pp. 599-606 ◽  
Author(s):  
S. L. Hokland ◽  
M. R. Horsman
Keyword(s):  
Tumour Response ◽  
Vascular Disrupting Agent ◽  
Mild Hyperthermia ◽  
Disodium Phosphate ◽  
Vascular Disrupting

Phase I study of CYT997, a novel cytotoxic and vascular disrupting agent, given as a 24-hour intravenous infusion to patients with advanced solid tumours

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14115-14115 ◽  
Author(s):  
J. Lickliter ◽  
G. Smith ◽  
M. Burge ◽  
A. Coulthard ◽  
D. Wyld ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Central Venous Access ◽  
Tumour Response ◽  
Venous Access ◽  
Microtubule Assembly ◽  
Vascular Disrupting Agent ◽  
Dose Levels ◽  
Vascular Disrupting

14115 Background: CYT997 is a novel tubulin-binding small molecule which inhibits microtubule assembly and also demonstrates potent vascular-disrupting activity in preclinical tumour models. Methods: CYT997 was administered by continuous infusion over 24 hours every 3 weeks to patients with advanced cancer. Dose escalation proceeded by a standard phase I design (3 patients per dose level) for the first 18 patients; subsequently, an accelerated titration design (1 patient per dose level) was utilized. Intrapatient dose escalation was permitted. Pharmacokinetic (PK) analyses were performed in the first cycle. Tumour response was determined every second cycle using RECIST criteria. Pharmacodynamic effects on the tumour vasculature were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 22 patients (M/F: 11/11; median age 57.5, range 28–75) were enrolled with tumour types including melanoma (4), renal cell (4), colorectal (2), non-small cell lung (2) and adenoid cystic (2) carcinomas, mesothelioma (2) and others (6). A total of 66 cycles of CYT997 were administered (median 2/patient, range 1–6) over 10 dose levels (7, 14, 23, 35, 49, 65, 86, 114, 152 and 202 mg/m2). No dose-limiting toxicity was observed. Because of grade-2 injection site reactions in 2 patients (one each at dose levels 3 and 4), all subsequent patients received CYT997 via a central venous access device. Other toxicities included grade-2 renal toxicity at dose- level 8 in one patient with abnormal baseline renal function and grade-1 QTc prolongation in one patient at dose-level 10. No myelosuppression, gastrointestinal toxicity or clinically-significant cardiac toxicity were observed. PK data revealed dose-related increases in Cmax and AUC values. Six patients had stable disease after 4 cycles of CYT997. Conclusions: CYT997 was well tolerated at the doses studied and accrual to the 269 mg/m2 dose level will now proceed. No significant financial relationships to disclose.

The Novel Vascular Disrupting Agent ANG501 Induces Cell Cycle Arrest and Enhances Endothelial Cell Sensitivity to Radiation

2009 ◽  
Vol 2 ◽  
pp. CGM.S2596 ◽  
Author(s):  
Shona T. Dougherty ◽  
Sean E. Walker ◽  
Peter D. Davis ◽  
Graeme J. Dougherty
Keyword(s):  
Cell Cycle ◽  
Endothelial Cells ◽  
Normal Cell ◽  
Cell Cycle Progression ◽  
Stress Proteins ◽  
Vascular Disrupting Agent ◽  
Heat Shock Stress ◽  
Cell Cycling ◽  
Vascular Disrupting

The efficacy of approaches in which vascular disrupting agents (VDA) are used in combination with conventional chemotherapy and/or radiation therapy in the treatment of cancer might be improved if there were a better understanding of the cellular and molecular changes induced in normal and malignant cells as a result of VD A exposure. Toward this goal, murine endothelial cells were treated in vitro with ANG501, a novel stilbene VDA developed in our laboratory, and alterations in gene expression determined by genome-wide microarray analysis and subsequently confirmed by Western blot analysis. Among the genes that were shown to be induced upon brief exposure to non-cytotoxic doses of ANG501 were several involved in the control of cell cycle progression and apoptosis, including p21Wafl and the heat shock/stress proteins hsp25, hsp70 and anti-B-crystallin. Reflecting such induction, functional studies confirmed that normal cell cycling is temporarily inhibited following treatment with ANG501 such that the majority of cells accumulate at the radiation-sensitive G2/M phase of the cell cycle at 6 hr. The effects were transient and by 24 hr normal cell cycling had largely resumed. Combination experiments confirmed that endothelial cells treated 6 hr previously with ANG501 were more readily killed by radiation. Importantly, significant effects were evident at clinically relevant radiation doses. Taken together these findings emphasize the need to consider the radiosensitizing activity of VD As when developing therapies in which these promising compounds are used in combination with radiation.

Combretastatin A4 phosphate: a novel vascular disrupting agent

2010 ◽  
Vol 6 (8) ◽  
pp. 1219-1228 ◽  
Author(s):  
Govardhanan Nagaiah ◽  
Scot C Remick
Keyword(s):  
Vascular Disrupting Agent ◽  
Combretastatin A4 ◽  
Vascular Disrupting

scholarly journals Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent

2010 ◽  
Vol 103 (5) ◽  
pp. 597-606 ◽  
Author(s):  
J D Lickliter ◽  
A B Francesconi ◽  
G Smith ◽  
M Burge ◽  
A Coulthard ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Vascular Disrupting Agent ◽  
Vascular Disrupting

scholarly journals The protective role of sphingosine-1-phosphate against the action of the vascular disrupting agent combretastatin A-4 3-O-phosphate

Oncotarget ◽  
2017 ◽  
Vol 8 (56) ◽  
pp. 95648-95661 ◽  
Author(s):  
Joanna Shepherd ◽  
Matthew Fisher ◽  
Abigail Welford ◽  
Donald M. McDonald ◽  
Chryso Kanthou ◽  
...  
Keyword(s):  
Protective Role ◽  
Vascular Disrupting Agent ◽  
Sphingosine 1 Phosphate ◽  
Vascular Disrupting

scholarly journals Intra-individual comparison of therapeutic responses to vascular disrupting agent CA4P between rodent primary and secondary liver cancers

2018 ◽  
Vol 24 (25) ◽  
pp. 2710-2721 ◽  
Author(s):  
Ye-Wei Liu ◽  
Frederik De Keyzer ◽  
Yuan-Bo Feng ◽  
Feng Chen ◽  
Shao-Li Song ◽  
...  
Keyword(s):  
Vascular Disrupting Agent ◽  
Individual Comparison ◽  
Liver Cancers ◽  
Therapeutic Responses ◽  
Vascular Disrupting

scholarly journals Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors

2013 ◽  
Vol 19 (17) ◽  
pp. 4832-4842 ◽  
Author(s):  
Cristiana Sessa ◽  
Patricia Lorusso ◽  
Anthony Tolcher ◽  
Françoise Farace ◽  
Nathalie Lassau ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Vascular Disrupting Agent ◽  
Vascular Disrupting

3035 Vascular Disrupting Agent ASA 404 evaluated in human isolated ventilated and perfused lung lobes containing NSCLC

2015 ◽  
Vol 51 ◽  
pp. S608 ◽  
Author(s):  
P. Hohenberger ◽  
S. Elleni ◽  
F. Marc ◽  
R. Eva ◽  
F. Peter ◽  
...  
Keyword(s):  
Vascular Disrupting Agent ◽  
Perfused Lung ◽  
Vascular Disrupting ◽  
Lung Lobes
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