This protocol is designed to assess the safety and efficacy of amonafide in combination with cytarabine in subjects with previously untreated secondary AML.

Start Date01 Aug 2005

Sponsor / Collaborator

Antisoma, Inc.

NCT00087854 / CompletedPhase 1/2

Dose-Defining Study of a NAT2 Phenotype-Based Dosing Regimen of Intravenous Amonafide L-Malate Administered Weekly in Men With Androgen-Independent Prostate Cancer (AIPC)

The purpose of this study is to assess the safety and efficacy of Amonafide in men with androgen-independent prostate cancer, assigned to individualized doses of Amonafide based on acetylator phenotype information (doses adjusted on individual metabolism).

Start Date01 Mar 2004

Sponsor / Collaborator

Antisoma, Inc.

100 Clinical Results associated with Antisoma, Inc.

0 Patents (Medical) associated with Antisoma, Inc.

Literatures (Medical) associated with Antisoma, Inc.

15 Apr 2011·Cancer Research

Abstract 5384: Amonafide demonstrates a clearly differentiated chemoresistance and chemosensitivity profile when compared to classical TopoII inhibitors

Author: Chau, MyDoanh ; Christensen, Jennifer ; Green, Colin F. ; Ajami, Alfred

AbstractBackground: Amonafide is a novel DNA intercalator that induces apoptosis by mechanisms involving Topo II. Previous pharmacogenomic studies have shown differences between amonafide and classical TopoII inhibitors. Here data from publicly available gene expression studies have been analyzed to determine the chemoresistance and chemosensitivity profiles of amonafide compared to other agents.Methods: Data were mined from the Stanford, MIT-Broad and NCI databases. A subset of genes associated with drug efflux, chemo-sensitivity & -resistance was selected from the array data. Effects on gene expression were assessed by determining Pearson correlation coefficients (PCC) for gene-drug pairs.Results: For drug efflux genes & 15 genes associated with cell regulation, amonafide, and 5-azacytidine (azaC) had a positive correlation between expression & cytotoxicity; doxorubicin (Dox), and daunorubicin (Dnr) showed a negative correlation; cytarabine (araC) was unaffected. The chemo-sensitivity and -resistance profiles were determined by identifying the 15 genes with the highest correlation for each of the 5 drugs vs the other 4. Amonafide & aza-C differed clearly from araC, Dnr & Dox. Genes conferring chemosensitivity to amonafide had a negative correlation for araC, Dnr, and Dox. Genes with a positive correlation for araC, Dnr, and Dox, had a negative correlation with amonafide & azaC. A similar pattern of differences was seen for chemoresistance.Conclusions: Amonafide is a unique chemical entity whose cytotoxicity is not affected by multi-drug resistance expression. Amonafide may evade many of the pharmacogenomic drivers confering resistance to ara-C and anthracyclines. It should therefore retain greater efficacy in combination with araC and as an alternative to anthracyclines, especially in the treatment of myeloid leukemias.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5384. doi:10.1158/1538-7445.AM2011-5384

15 Apr 2010·Cancer Research

Abstract 3665: The novel DNA intercalator amonafide (AS1413), disrupts the cell cycle by mechanisms distinct from those of Topo II inhibitors daunorubicin and etoposide

Author: Senderovich, Shai ; Ajami, Alfred ; Jones, David ; McLaughlin, Fiona

AbstractAmonafide-L-malate (amonafide, AS1413) is a novel DNA intercalator that induces apoptosis through mechanisms involving Topoisomerase II. Previous studies have indicated that amonafide has a number of important properties that differ from those of classical TopoII poisons: 1. Amonafide is not a substrate for Pgp, MRP-1 or BCRP, resistance mechanisms that may contribute to treatment failure with classical TopoII inhibitors. 2. Amonafide is a non-quinodal napthylamide derivative, which is structurally unrelated to anthracycline or anthracenedione classes of antileukemic agents. It therefore lacks the redox and free radical reactive pharmacophores associated with the cardiotoxicity of the anthracyclines. 3. While amonafide exerts cell killing by acting on the Topoisomerase II cycle, it does not form cleavable complexes. Further work on elucidating the action of amonafide on the Topoisomerase II cell cycle is outlined here.Cell cycle analysis was performed on the AML cell lines Thp1 and KG1. Cells were exposed to AS1413, etoposide or daunorubicin at IC50 doses for 24 hours (etoposide and daunorubicin) or 48 hours (amonafide). Amonafide exposure resulted in a G2/M cell cycle arrest. Further analysis of the G2/M checkpoint by microscopic analysis of metaphase spreads from cells exposed to IC50 levels of amonafide showed that approximately 10% of the cells were arrested in metaphase (with chromosomes clearly visible), a higher proportion than seen in untreated cells. Furthermore, there was evidence for DNA bridge formation between cells which were not fully divided, indicating inhibition in metaphase. In contrast, etoposide treatment resulted in a G2/M arrest, with no cells visible in metaphase. Daunorubicin exhibited a G1/S arrest; while this was unexpected, the mechanism of action of daunorubicin has been shown to be less cell cycle specific, so this effect may be specific for the cell lines tested here. Again, no cells were arrested in metaphase. Cell cycle regulators such as p21 were up-regulated to a greater extent after exposure to amonafide than after etoposide or daunorubicin treatment. Further investigation of pharmacodynamic markers indicative of AS1413 clinical activity will be carried out.Amonafide has shown activity in AML, a setting where anthracyclines are currently used. The findings outlined here and the other distinctive properties of amonafide, notably evasion of multi-drug resistance mechanisms, suggest that amonafide could offer a clinical profile distinct from that of classical TopoII poisons. The value of replacing an anthracycline with amonafide is currently being tested in a large randomised phase III trial comparing amonafide plus cytarabine with daunorubicin plus cytarabine in patients with secondary AML.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3665.

01 Nov 2006·Blood

Imidazoacridinones Are Bifunctional Targeting Agents Active in Leukemia Cells.

Author: Fernades, Daniel J. ; Chau, MyDoanh ; Stuart, Robert K. ; Ajami, Alfred M. ; Otake, Yoko

AbstractC-1311 (Symadex™) is the lead compound in clinical development from a new series of agents, the imidazoacridinones. It was previously reported that C-1311 was solely a topoisomerase II (TOP2) cleavable complex inhibitor and DNA damaging agent. However, contemporary analyses of C-1311 point to alternative structural parallelisms with the molecular scaffolds now seen as common motifs in receptor tyrosine kinase (RTK) inhibitors. To investigate this mechanism of action, a kinase inhibitor screening program was initiated, first in silico by molecular similarity matching, and then in vitro against recombinant RTKs. C-1311 was identified to cluster with RTK inhibitors, especially when sunitinib is used as a molecular “seed” for pattern recognition. The statistical similarity coefficients fall in the 0.7–0.8 positive probability range, compared to 0.2–0.4 for the classical TOP2 inhibitors. C-1311 was found to selectively inhibit wild-type (WT) FLT3 and its D835Y mutant at nanomolar concentrations of 8–15 nM IC50. FGFR2 was also targeted at approximately 100-fold greater IC50 value of 1.2 μM. Inhibition of PDGFR, FGFR1, and KIT was observed at about 3–4 μM IC50; other prominent kinases had values of greater than 10 μM. As a part of the dual mechanism reexamination, TOP2 decatenation of kDNA, DNA relaxation, and competition assays were performed to assess C-1311 interaction with TOP2. Results confirmed that C-1311 is not a cleavable complex inhibitor when compared to etoposide, suggesting that it may not be an inducer of the MLL cleavage. Additionally, the IC50 of C-1311 from the decatenation assay is 44 μM compared to 3, 12, and 149 μM for mitoxantrone, daunorubicin, and merbarone, respectively. Cellular screens were performed to assess the potency of C-1311 in myeloid and lymphoid leukemia cell lines. C-1311 was equally effective in both WT FLT3 expressing (RS4;11) and mutant FLT3 expressing (MV-4–11) cell lines. The dual function of C-1311 may contribute to the potency in these cell lines. These findings warrant further investigation of C-1311 in yet unexplored indications, including other hematological malignancies.

News (Medical) associated with Antisoma, Inc.

11 Dec 2007

·www.biospace.com

Xanthus Pharmaceuticals, Inc.'s Symadex Demonstrates Ability to Increase Spinal Cord Remyelination in Multiple Sclerosis Model

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Xanthus Pharmaceuticals, Inc. today presented preclinical data further supporting the potential for Symadex™ to reverse the clinical and pathological signs of multiple sclerosis (MS), including new data demonstrating increased spinal cord remyelination. The study was presented by Dr. Stephen J. Karlik, Ph.D., Professor of Diagnostic Radiology at the University of Western Ontario, London, Ontario and researchers from Xanthus at a meeting of the Multiple Sclerosis Society of Canada in Banff, Canada.

100 Deals associated with Antisoma, Inc.

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