Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy.

Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-ß-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed.

In vitro and in vivo efficacy of ether lipid edelfosine against Leishmania spp. and SbV-resistant parasites.

BACKGROUND: The leishmaniases are a complex of neglected tropical diseases caused by more than 20 Leishmania parasite species, for which available therapeutic arsenal is scarce and unsatisfactory. Pentavalent antimonials (SbV) are currently the first-line pharmacologic therapy for leishmaniasis worldwide, but resistance to these compounds is increasingly reported. Alkyl-lysophospoholipid analogs (ALPs) constitute a family of compounds with antileishmanial activity, and one of its members, miltefosine, has been approved as the first oral treatment for visceral and cutaneous leishmaniasis. However, its clinical use can be challenged by less impressive efficiency in patients infected with some Leishmania species, including L. braziliensis and L. mexicana, and by proneness to develop drug resistance in vitro. METHODOLOGY/PRINCIPAL FINDINGS: We found that ALPs ranked edelfosine>perifosine>miltefosine>erucylphosphocholine for their antileishmanial activity and capacity to promote apoptosis-like parasitic cell death in promastigote and amastigote forms of distinct Leishmania spp., as assessed by proliferation and flow cytometry assays. Effective antileishmanial ALP concentrations were dependent on both the parasite species and their development stage. Edelfosine accumulated in and killed intracellular Leishmania parasites within macrophages. In vivo antileishmanial activity was demonstrated following oral treatment with edelfosine of mice and hamsters infected with L. major, L. panamensis or L. braziliensis, without any significant side-effect. Edelfosine also killed SbV-resistant Leishmania parasites in in vitro and in vivo assays, and required longer incubation times than miltefosine to generate drug resistance. CONCLUSIONS/SIGNIFICANCE: Our data reveal that edelfosine is the most potent ALP in killing different Leishmania spp., and it is less prone to lead to drug resistance development than miltefosine. Edelfosine is effective in killing Leishmania in culture and within macrophages, as well as in animal models infected with different Leishmania spp. and SbV-resistant parasites. Our results indicate that edelfosine is a promising orally administered antileishmanial drug for clinical evaluation.

Phase I and pharmacokinetic study of the cytotoxic ether lipid ilmofosine administered by weekly two-hour infusion in patients with advanced solid tumors.

PURPOSE: A Phase I trial was performed to determine the dose-limiting toxicity and maximum tolerated dose, and to describe the pharmacokinetics of the alkyl-lysophospholipid, ilmofosine, when administered as a weekly 2-h infusion in patients with solid tumors. EXPERIMENTAL DESIGN: Thirty-nine patients were entered into a trial of ilmofosine administered weekly for 4 weeks followed by a 2-week rest period. Dose escalation occurred in 10 levels from 12 to 650 mg/m(2). RESULTS: Thirty-six patients were evaluable for toxicity. The median number of cycles per patient was 1 (range, 1-4). Dose-limiting gastrointestinal toxicity occurred at 650 mg/m(2) with grade 3 nausea in two patients and grade 3 vomiting and diarrhea in one patient. Grade 2 diarrhea was observed in four of six patients treated at 550 mg/m(2). In addition, two patients treated at 550 mg/m(2) and two patients treated at 650 mg/m(2) experienced a decline in performance status of two or more levels that was determined to be due to treatment. There were no tumor responses. Stabilization of disease for at least 8 weeks occurred in six patients. Plasma concentrations of ilmofosine and its sulfoxide metabolite were evaluated by high-pressure liquid chromatography. The elimination of both compounds was biexponential with terminal half-lives of approximately 40 h for ilmofosine and 48 h for the sulfoxide. The area under the concentration-time curve was dose-proportional for each compound, and there was no evidence of saturable kinetics. CONCLUSIONS: The dose-limiting toxicity of ilmofosine is gastrointestinal and the recommended dose for Phase II trials is 450 mg/m(2) as a 2-h weekly infusion. The relatively long half-life of ilmofosine and its active metabolite support the use of this intermittent schedule.

A phase II trial of ilmofosine in non-small cell bronchogenic carcinoma.

We have conducted a study of ilmofosine (1-hexadecylthio; 2-methoxyethyl-rac-glycero-3-phosphocholine) in non-small cell bronchogenic carcinoma, using a schedule of continuous infusion for 5 days and a dose of 300 mg/m2/day. Toxicities were gastrointestinal (nausea, vomiting, diarrhea), fatigue and liver function abnormalities. These were severe and resulted in the removal of some patients from study. No consistent pattern of bone marrow suppression was seen. No tumor regressions occurred in 14 evaluable patients including 5 with no prior therapy. We conclude that ilmofosine is inactive in this tumor at this dose and schedule.

A phase II trial of autologous bone marrow transplantation (ABMT) in acute leukemia with edelfosine purged bone marrow.

Alkyl-lysophospholipid compounds which are selectively cytotoxic to neoplastic cells and relatively sparing of normal marrow progenitor cells are appealing as purging agents to rid remission marrows of residual leukemic cells. A multi-institutional phase II study was conducted in 57 patients with acute leukemia (50 AML and 7 ALL) in which remission marrows were purged in vitro and reinfused after ablative chemotherapy. The median time for granulocyte recovery to 500/microliter was 33 days and for platelet recovery to 25000/microliter was 46 days. The overall DFS and survival was 37% and 46% respectively. Transplantation in first remission gave a better survival than transplant in a subsequent remission.

Phase I trial of ilmofosine as a 24 hour infusion weekly.

Ilmofosine, an ether lipid derivative of lysophosphatidylcholine has antineoplastic activity in vitro and in vivo. Maximum efficacy in preclinical models is associated with prolonged exposure to the drug. In a Phase I trial of a weekly 2 hour infusion schedule of ilmofosine, a syndrome of lethargy, diminished performance status, and mild hepatotoxicity was dose-limiting at 550 mg/m2. To avoid the higher drug concentrations associated with a brief infusion, a Phase I study of a weekly 24 hour infusional schedule was undertaken in an attempt to maximize dose-intensity. Doses were escalated from 550 to 800 mg/m2. Toxicities included nausea, anorexia, fatigue, and minor elevations of liver function tests. The dose limiting toxicity at 800 mg/m2 was a syndrome of severe abdominal pain. No neutropenia or thrombocytopenia was observed except in one patient who was found to have a myelodysplastic syndrome, thought not to be related to drug therapy. The more prolonged infusion schedule of ilmofosine did not result in a substantial increase in the tolerable dose.

Phase I trial of the thioether phospholipid analogue BM 41.440 in cancer patients.

BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is a new thioether phospholipid, which has been shown to possess antineoplastic, antimetastatic, anti-invasive and immunomodulating properties in several tumor models. The mechanism whereby this compound exerts its direct antineoplastic effect is thought to be related to specific interference with the normal phospholipid metabolism, preferentially of neoplastic cells. BM 41.440 was evaluated in a multicenter phase I study in patients (pts) with refractory cancers. In phase I A, 34 pts were orally treated with doses ranging from 0.5 to 7.0 mg/kg body weight (bw). Three different formulations were tested. The maximum-tolerated dose (MTD) was ca. 5 mg/kg bw. The limiting side effects were nausea and vomiting. There was no evidence for systemic toxicities like myelosuppression, nephro-, neuro-, hepatotoxicity or hematological side effects. The current phase I B is designed to determine the MTD of BM 41.440 administered orally on a daily schedule for at least eight weeks. So far, 19 pts have entered this trial at dose levels ranging from 1.0 to 5.0 mg/kg bw/day. Some pts receiving 1.0 and 2.5 mg/kg bw/day, respectively, have been treated, up to now, for more than nine months. Clinical progress was followed with at-least-weekly blood counts, chemistry profiles, urine analysis, liver function tests and recordings of side effects. Tumor parameters were evaluated at eight-week intervals. In parallel, pharmacokinetic investigations were performed in some pts in phase I A and IB. First results on tolerability and therapeutic efficacy of the long-term BM 41.440 treatment are reported in this intermediate evaluation.

Clinical phase I pilot study of the alkyl lysophospholipid derivative ET-18-OCH3.

Sixteen patients suffering from widespread malignant disease, the majority pretreated and found in poor general health, were treated in a phase I pilot study with the alkyl lysophospholipid derivative 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3). Eleven patients were treated intravenously, and five were given oral therapy. Prolonged IV administration of 15-20 mg/kg/day at a concentration of 5 mg ET-18-OCH3 per 1 ml 20% human serum albumin could be continued safely. The maximum-tolerated dose was either 50 mg/kg as a single injection or 20 mg/kg during daily dispensions. Grade 2-4 toxicity, as pulmonary edema and impairment of hepatic function, then occurred during daily treatment. Toxicity was reversible. Mitogen stimulation and mixed lymphocyte culture studies revealed possible immunosuppressive effects of higher doses of ET-18-OCH3. There were no chromosomal changes in cytogenetic studies. Frequent post-mortem examinations revealed no further toxicity. IV and oral treatment showed few encouraging response data since there were two partial remissions in non-small cell lung cancers and a reduction of leukemic blasts to less than 10% in an acute myelomonocytic leukemia.