Phase I dose-escalating study of ES-285 given as a three-hour intravenous infusion every three weeks in patients with advanced malignant solid tumors

Massard, Christophe; Salazar, Ramón; Armand, Jean‐Pierre; Majem, Margarita; Deutsch, Éric; García, Montse; Oaknin, Ana; Fernandez-Garcia, Eva; Soto, A.; Soria, Jean‐Charles

doi:10.1007/s10637-011-9772-8

Cited by 23 publications

(16 citation statements)

References 10 publications

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“…However, in a phase I trial of doxSA conducted in patients with advanced solid tumors, doxSA showed poor antitumor activity and caused many adverse reactions, including mild-to-moderate nausea, pyrexia, injection site reactions, and vomiting (27)(28)(29). In addition, some patients developed neuropathy and liver damage (27)(28)(29). Thus, these results provide clinical evidence that, at high doses, doxSA causes tissue damage.…”

Section: Discussionmentioning

confidence: 90%

“…Purified doxSA can induce rearrangement of actin stress fibers (25) and cause apoptosis and sup- pression of cancer cell proliferation (24). However, in a phase I trial of doxSA conducted in patients with advanced solid tumors, doxSA showed poor antitumor activity and caused many adverse reactions, including mild-to-moderate nausea, pyrexia, injection site reactions, and vomiting (27)(28)(29). In addition, some patients developed neuropathy and liver damage (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

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l-Serine Deficiency Elicits Intracellular Accumulation of Cytotoxic Deoxysphingolipids and Lipid Body Formation

Esaki

Sayano

Sonoda³

et al. 2015

Journal of Biological Chemistry

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Background: L-Serine deficiency affects sphingolipid homeostasis. Results: Reduced L-serine promotes the accumulation of 1-deoxysphingolipids and the formation of lipid bodies. Conclusion: Diminished capacity for L-serine synthesis leads to a higher L-alanine to L-serine ratio and elicits the synthesis of 1-deoxysphingolipids and lipid body formation. Significance: 1-Deoxysphingolipids occur in certain disease conditions characterized by a metabolic imbalance between L-alanine and L-serine.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

l-Serine Deficiency Elicits Intracellular Accumulation of Cytotoxic Deoxysphingolipids and Lipid Body Formation

Esaki

Sayano

Sonoda³

et al. 2015

Journal of Biological Chemistry

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“…In a recent study, plasma DSL levels have been shown to associate also with the incidence and severity of paclitaxel-induced peripheral neuropathy in breast cancer patients (Kramer et al 2015). DSL were shown to have pronounced neurotoxic effects on neurite formation in cultured sensory neurons (Penno et al 2010) and in phase I clinical trials where deoxy-sphinga-nine was tested for its chemotherapy potential; the trials were discontinued due to patients developing severe in some cases fatal neuropathy (Baird et al 2009; Schöffski et al 2011; Massard et al 2012). Studies in an animal model of HSAN1 and in HSAN1 patients suggest that oral supplementation with L-serine reduces plasma DSL concentration (Garofalo et al 2011) and raises the prospect of a treatment option to modulate plasma DSL levels.…”

Section: Introductionmentioning

confidence: 99%

Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

Hammad

Baker²,

Abiad

et al. 2016

Neuromol Med

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Plasma deoxy-sphingoid bases are elevated in type 2 diabetes patients and correlate with the stage of diabetic distal sensorimotor polyneuropathy; however, associations between deoxy-sphingolipids (DSL) and neuropathy in type 1 diabetes have not been examined. The primary aim of this exploratory pilot study was to assess the associations between multiple sphingolipid species including DSL and free amino acids and the presence of symptomatic neuropathy in a DCCT/EDIC type 1 diabetes subcohort. Using mass spectroscopy, plasma levels of DSL and free amino acids in DCCT/EDIC type 1 diabetes participants (n = 80), with and without symptoms of neuropathy, were investigated. Patient-determined neuropathy was based on 15-item self-administered questionnaire (Michigan Neuropathy Screening Instrument) developed to assess distal symmetrical peripheral neuropathy in diabetes. Patients who scored ≥4, or reported inability to sense their feet during walking or to distinguish hot from cold water while bathing were considered neuropathic. Plasma levels of ceramide, sphingomyelin, hexosyl- and lactosylceramide species, and amino acids were measured and analyzed relative to neuropathy status in the patient. Deoxy-C24-ceramide, C24- and C26-ceramide were higher in patients with neuropathy than those without neuropathy. Cysteine was higher in patients with neuropathy. No differences in other sphingolipids or amino acids were detected. The covariate-adjusted Odds Ratios of positive patient-reported neuropathy was associated with increased levels of deoxy-C24-, and deoxy-C24:1-ceramide; C22-, C24-, and C26-ceramide; and cysteine. Plasma deoxy-ceramide and ceramide species may have potential diagnostic and prognostic significance in diabetic neuropathy.

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“…When produced in excess, the 1-deoxysphingolipids accumulate. The neurotoxicity of 1-deoxysphingolipids was shown in dorsal root ganglion (DRG) neurons in vitro (13) and in phase I clinical trials, where 1-deoxysphinganine (spisulosine, E-285) was tested for its anticancer potential; the clinical trials were terminated because some patients had severe, and in some cases fatal, neurotoxicity (16)(17)(18). Individuals with HSAN1 primarily experience a loss of sensation distributed in the distal parts of the upper and lower limbs (19), and most have neuropathic pain.…”

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confidence: 99%

Neurotoxic 1‐deoxysphingolipids and paclitaxel‐induced peripheral neuropathy

et al. 2015

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Peripheral neuropathy is a major doselimiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses L-alanine instead of L-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 mM) and cisplatin (250 nM, 1 mM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C 24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1-deoxysphingolipids, the very-long-chain in particular, play a role as molecular intermediates of paclitaxel-induced peripheral neuropathy.-Kramer, R., Bielawski, J., Kistner-Griffin, E., Othman, A., Alecu, I., Ernst, D., Kornhauser, D., Hornemann, T., Spassieva, S. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. FASEB J. 29, 4461-4472 (2015). www.fasebj.org

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Phase I dose-escalating study of ES-285 given as a three-hour intravenous infusion every three weeks in patients with advanced malignant solid tumors

Abstract: Dose level VIII (200 mg/m(2)) was considered the MTD, and dose level IX (160 mg/m(2)) was defined as the RD. Limited antitumor activity was observed.

Cited by 23 publications

References 10 publications

l-Serine Deficiency Elicits Intracellular Accumulation of Cytotoxic Deoxysphingolipids and Lipid Body Formation

l-Serine Deficiency Elicits Intracellular Accumulation of Cytotoxic Deoxysphingolipids and Lipid Body Formation

Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study

Neurotoxic 1‐deoxysphingolipids and paclitaxel‐induced peripheral neuropathy

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