Sunday, December 5, 2004, 06:00 PM
[1803] Organic Arsenic Lipid Derivatives Are More Potent and Less Toxic Than Inorganic Arsenic Trioxide in Preclinical Testing.
Session Type: Poster Session 16-II
Xiaodong Cheng, Mirna Golemovic, Francis Giles, Ralph Zingaro, Ming-Zhang Gao, Emil J. Freireich, Michael Andreeff, Hagop M. Kantarjian, Srdan Verstovsek. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Chemistry, Texas A&M University, College Station, TX, USA; Radiology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Blood & Marrow Transplantation, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Arsenic trioxide (ATO) is an inorganic arsenic derivative that is effective in patients with relapsed acute promyelocytic leukemia. It is being investigated as therapy for other cancers but the risk/benefit ratio for its use still has to be determined due to its significant side effects. In contrast, organic arsenic derivatives are known to be much less toxic. We have synthesized a series of eight organic arsenic lipid derivatives and have tested them in NIH 60 cell line screen. Based on its activity, we selected GMZ27 for further study in our laboratory and have confirmed its potent activity against human acute myeloid leukemia cell lines HL60 and NB4, which was significantly higher than that of arsenic trioxide. The IC50 (concentration that kills 50% of the cells) in MTS assay is 0.5 and 0.9 µm for GMZ27. Assessment of the mechanisms of action of GMZ27 in cell lines has shown that the GMZ27 was more potent inducer of superoxide than ATO. GMZ27 caused dissipation of mitochondrial transmembrane potential, cleavage of caspase 9, caspase 3 activation, PARP cleavage, and compromise in cell membrane integrity. However, its treatment also resulted in caspase 8 cleavage, suggesting that it affects both intrinsic and extrinsic apoptotic pathway. Its activity was related to the level of glutathione in the leukemic cells as pretreatment of the cells with BSO, which depletes intracellular glutathione, results in cells sensitivity to GMZ27. On the other hand, pretreatment with DDT, which increases intracellular glutathione, results in their resistance to GMZ27. GMZ27 had no effect on cells maturation and differentiation, and cell cycle. GMZ27 when tested against healthy donor mononuclear cells in a colony forming assay showed significantly less toxicity than arsenic trioxide. In vivo toxicity testing in Swiss Webster mice showed LD50 (dose that kills 50% of mice) to be 100 mg/kg for GMZ27, comparing to 10 mg/kg for ATO. In conclusion, organic arsenic lipid derivatives, and in particular GMZ27, may have more potent antileukemic activity and significantly less toxicity in vivo and in vitro than ATO and therefore further development of these medications is warranted.
Abstract #1803 appears in Blood, Volume 104, issue 11, November 16, 2004
Keywords: Experimental therapeutics|Leukemia|Leukemia cell line
Poster Session: Adult and Pediatric AML - Novel Agents and Immunotherapy (6:00 PM-7:30 PM)
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Sunday, December 5, 2004, 06:00 PM
[1815] Treatment of Acute Myelogenous Leukemia (Non-APL) with Intravenous Trisenox® (Arsenic Trioxide) and Ascorbic Acid: Preliminary Results.
Session Type: Poster Session 28-II
Dan Douer, Kristy Watkins, Robert Louie, Ilene Weitz, Ann Mohrbacher, Alexandra M. Levine. Division of Hematology, University of Southern California Keck School of Medicine, Los Anegels, CA, USA; Cell Therapeutics Inc., Seattle, WA, USA
Introduction: Arsenic trioxide (ATO) is an exceptionally active drug in acute promyelocytic leukemia (APL), inducing complete remissions in 85% of relapsed patients. ATO also has clinical activity in myelodysplastic syndrome (MDS). In non-APL AML cells lines, ATO induces apoptosis in vitro; however, in a small study of 11 non-APL AML patients, ATO showed no activity (Parmer et al Leuk Res 28:090, 2004). In some types of cancer cells, ATO-induced apoptosis has been shown to correlate inversely with the level of intracellular reduced glutathione (GSH) via generation of reactive oxygen species; cells with high concentrations of GSH are more resistant to ATO. Ascorbic acid (AA) increases apoptosis and overcomes resistance to ATO in multiple myeloma, non-APL AML and other cell lines by reducing intracellular GSH levels. AA alone has no activity in these cells. We therefore conducted a clinical trial in patients with non-APL AML combining ATO and AA.
Methods: ATO at a dose of 0.25 mg/kg is administrated intravenously over 1-3 hour with 1 gram of intravenous AA given within 30 minutes daily for five days a week (five days on/2 days off) for five weeks (25 doses – one cycle). These doses were based on a phase I/II trial of ATO+AA in patients with multiple myeloma (Behalis et al Clin Cancer Res 8:3658, 2002)). Responding patients receive an additional consolidation cycle of 25 doses followed by maintenance of two weeks of every month of ATO+ AA for 4 cycles. Patients who fail to respond after two cycles are considered treatment failures.
Results: Seven patients have so far enrolled: three (aged 36,52,59) had relapsed after chemotherapy, and four aged 66-84 (median 70), never received chemotherapy. For these untreated patients ATO+AA was given as front line treatment. In three of the four previously untreated patients the number of bone marrow blasts dropped from > 40% to < 5% (2 pts. after 1 cycle; 1 pt. after 2 cycles) At the time of this report only one of the responding patients received more than one cycle and had improvement in the peripheral blood counts. The three patients, who failed chemotherapy, did not respond to ATO+AA (one patient received only one cycle). Despite the high doses of ATO, higher than used in APL and MDS, the combination was very well tolerated with grade 3 toxicity in one patient only (sensory neuropathy). One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.
Conclusion: These preliminary results in patients with non-APL AML suggest that: (1) AA +ATO has anti-leukemia activity in untreated non-APL AML patients with minimal toxicity; (2) more than one cycle is probably needed to achieve a response in the peripheral blood counts; (3) in non-APL AML, ATO can cause the so called “differentiation syndrome” which should be anticipated and treated early. If confirmed in additional patients, ATO+AA might be a less toxic alternative upfront approach to intensive chemotherapy in elderly patients with non-APL AML.
Abstract #1815 appears in Blood, Volume 104, issue 11, November 16, 2004
Keywords: AML|Arsenic trioxide|Leukemia
Poster Session: Adult and Pediatric AML - Novel Agents and Immunotherapy (6:00 PM-7:30 PM) |
