Early tumor and leukemia response to alkyl-lysophospholipids in a phase I study

Berdel, Wolfgang E.; Schlehe, H; Fink, U.; Emmerich, B.; Maubach, P.; Emslander, H. P.; Daum, S; Rastetter, Johann

doi:10.1002/1097-0142(19821115)50:10<2011::aid-cncr2820501006>3.0.co;2-k

Cited by 39 publications

(4 citation statements)

References 7 publications

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“…Hexadecylphosphocholine (HePC) and ET‐18‐OCH 3 were the prototypes of a new etherlipid‐derived substance family with pronounced antiproliferative effects on neoplastic cells. HePC showed excellent antiproliferative activities in many human and animal cell lines and tumor models (1–5). In several phase II/III investigations, HePC was tested in patients with mammary carcinoma (6,7), colorectal carcinoma (8,9), nonsmall cell lung carcinoma (10), and cutaneous lymphoma (11).…”

Section: Introductionmentioning

confidence: 99%

Effects of etherlipid analogs on cell membrane functions

2003

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Hexadecylphosphocholine and other etherlipid-derived substances show a pronounced antiproliferative activity on neoplastic cells and a broad spectrum of other biological effects on many cell types in vitro and in vivo. Though the precise molecular mechanism by which these etherlipid analogs act still remains unresolved, it seems clear that it most probably involves some essential function of the cell membrane. We investigated the effect of different etherlipids with and without cytotoxic activity in etherlipid-susceptible and -resistant tumor cell lines on three important membrane functions. We observed various inhibitory activities on endocytosis and the uptake of small precursor molecules as sugars, amino acids, and alcohols by toxic and nontoxic substances in resistant as well as susceptible cells. There was no correlation between the antiproliferative characteristics of the compounds and the effects on these membrane transport functions. Furthermore, the substances reduced the number of membrane tumor necrosis factor-alpha receptors regardless of their antiproliferative properties. The results of these investigations suggest that etherlipid analogs may interfere with many membrane functions in an unspecific manner. Therefore, many of the previously reported biological effects of etherlipids have to be viewed under a different light. Future investigation on these compounds should always contain appropriate control substances and cell models to really prove the specificity of the observed effects.

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Section: Introductionmentioning

confidence: 99%

Effects of etherlipid analogs on cell membrane functions

2003

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“…Eleven patients were treated intravenously, and five were given oral therapy. ET-18-OCH 3 was aseptically cancers with remission durations of 5 and 6 months, and a reduction of peripheral leukemic blasts to less than 10% in an acute myelomonocytic leukemia [331][332][333]. There were no chromosomal changes in cytogenetic studies [310].…”

Section: Phase I Studiesmentioning

confidence: 95%

“…In the period 1979-1982, sixteen patients suffering from advanced solid tumors or leukemias, with metastatic or widespread disease, and found in poor general health (Karnofsky performance score below 50 in most of the patients), the majority (fourteen) refractory to prior treatment, were treated in a phase I pilot study with ET-18-OCH 3 [331][332][333]. Eleven patients were treated intravenously, and five were given oral therapy.…”

Section: Phase I Studiesmentioning

confidence: 99%

Biological Activities, Mechanisms of Action and Biomedical Prospect of the Antitumor Ether Phospholipid ET-18-OCH3 (Edelfosine), A Proapoptotic Agent in Tumor Cells

Gajate¹,

Mollinedo

2002

CDM

153

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The antitumor ether lipid ET-18-OCH(3) (edelfosine) is the prototype of a new class of antineoplastic agents, synthetic analogues of lysophosphatidylcholine, that shows a high metabolic stability, does not interact with DNA and shows a selective apoptotic response in tumor cells, sparing normal cells. Unlike currently used antitumor drugs, ET-18-OCH(3) does not act directly on the formation and function of the replication machinery, and thereby its effects are independent of the proliferative state of target cells. Because of its capacity to modulate cellular regulatory and signaling events, including those failing in cancer cells, like defective apoptosis, ET-18-OCH(3), beyond its putative clinical importance, is an interesting model compound for the development of more selective drugs for cancer therapy. Although ET-18-OCH(3) enhances host defense mechanisms against tumors, its major antitumor action lies in a direct effect on cancer cells, inhibiting phosphatidylcholine biosynthesis and inducing apoptosis in tumor cells. Recent progress has allowed unraveling the molecular mechanism underlying the apoptotic action of ET-18-OCH(3), leading to the notion that ET-18-OCH(3) is selectively incorporated into tumor cells and induces cell death by intracellular activation of the cell death receptor Fas/CD95. This intracellular Fas/CD95 activation is a novel mechanism of action for an antitumor drug and represents a new way to target tumor cells in cancer chemotherapy that can be of interest as a new framework in designing novel antitumor drugs. ET-18-OCH(3) and some analogues are pleiotropic agents that affect additional biomedical important diseases, including parasitic and autoimmune diseases, suggesting new therapeutic indications for these compounds.

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“…The calculated costs for this trial was Deutsche Mark (DM) 60,000 (later exchange rate DM:Euro was 2:1), essentially caused by the IMP synthesis and a part-time special study-physician for clinical surveillance of the 16 patients. First results were internationally published in a peer-reviewed journal within 2 years [ 2 ]. The IMP studied did not make it to approval due to a small therapeutic window, but a successor within the same class of compounds later obtained approval [ 3 ].…”

Section: Trial Activation and Conduct Before 2004mentioning

confidence: 99%

Activation of Investigator-Initiated Clinical Trials with a Pharmaceutical for Cancer Patients before and after Post-Millennial Changes of Regulations in Germany and Europe

Berdel

2022

Cancers

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Shortly after the beginning of the year 2000, multiple legal changes with impacts on the regulatory framework of clinical trials became effective almost simultaneously. They included the European Union (EU) Clinical Trial Directive (CTD) 2001/20 followed by major changes in national drug laws, the change in the legal status of German University Hospitals (1998), and a new disease-related groups (DRG)-based reimbursement system for hospitals in Germany (2000). Together, these changes created enormous bureaucratic and financial inhibition of activation and conduct of academic investigator-initiated clinical trials (IIT). Examples for activating clinical trials in oncology before and after 2004 are outlined and discussed, focussing on extended time frames, the establishment of centralized responsibility structures and the exploding financial consequences. In addition, the evolution of trial numbers and the distribution of trial initiators between “commercial” and “academic” over time are discussed together with the occurrence of clinical registries. At the same time, progress in molecular biology led to a plethora of new targets for effective pharmacological therapy of life-threatening diseases such as cancer, and the overall number of clinical trials has not decreased. Yet, judging the regulatory and administrative hurdles between scientific study design and first-patient on trial before and after 2004 and weighing these against the lack of evidence that this regulation has achieved its goal to enhance patient safety and trial quality, the necessity to completely overhaul this CTD becomes obvious. A main goal of such an initiative should be to minimize bureaucracy. For the specific situation in Germany, relocation of responsibility and freedom to operate in University Hospitals and Medical Faculties back to the physician–scientists and reduction in interference by legal divisions should be a goal as well as increasing the public financial support for IITs.

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Early tumor and leukemia response to alkyl-lysophospholipids in a phase I study

Cited by 39 publications

References 7 publications

Effects of etherlipid analogs on cell membrane functions

Effects of etherlipid analogs on cell membrane functions

Biological Activities, Mechanisms of Action and Biomedical Prospect of the Antitumor Ether Phospholipid ET-18-OCH3 (Edelfosine), A Proapoptotic Agent in Tumor Cells

Activation of Investigator-Initiated Clinical Trials with a Pharmaceutical for Cancer Patients before and after Post-Millennial Changes of Regulations in Germany and Europe

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