Phase II Trial of Orally Administered Miltefosine in Advanced Colorectal Cancer

Becher, R.; Kloke, Karen M.; Füger, A.; Bremer, K.; Drozd, Anna; Kleeberg, Ulrich R.; Fritze, Dieter; Rieche, K; Sindermann, H.

doi:10.1159/000218217

Cited by 9 publications

(5 citation statements)

References 7 publications

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“…The glycerol moiety in ALP has proven to be not essential for the antitumor activity and a second generation containing a phosphoester chain was designed and synthesized. Miltefosine (hexadecylphosphocholine, HePC) was evaluated asan oral therapy in clinical studies against soft tissue sarcomas ( 98 ) and advanced colorectal cancer ( 99 ); however, the doses required for the antitumor effects were too toxic. Miltefosine, either used alone or in conjunction with other therapies, proved to be effective and tolerable as a local treatment for cutaneous breast cancer ( 100 ).…”

Section: Allosteric Inhibitorsmentioning

confidence: 99%

Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)

Nițulescu

Margină

Juzenas

et al. 2015

International Journal of Oncology

323

268

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Targeted cancer therapies are used to inhibit the growth, progression, and metastasis of the tumor by interfering with specific molecular targets and are currently the focus of anticancer drug development. Protein kinase B, also known as Akt, plays a central role in many types of cancer and has been validated as a therapeutic target nearly two decades ago. This review summarizes the intracellular functions of Akt as a pivotal point of converging signaling pathways involved in cell growth, proliferation, apoptotis and neo-angiogenesis, and focuses on the drug design strategies to develop potent anticancer agents targeting Akt. The discovery process of Akt inhibitors has evolved from adenosine triphosphate (ATP)-competitive agents to alternative approaches employing allosteric sites in order to overcome the high degree of structural similarity between Akt isoforms in the catalytic domain, and considerable structural analogy to the AGC kinase family. This process has led to the discovery of inhibitors with greater specificity, reduced side-effects and lower toxicity. A second generation of Akt has inhibitors emerged by incorporating a chemically reactive Michael acceptor template to target the nucleophile cysteines in the catalytic activation loop. The review outlines the development of several promising drug candidates emphasizing the importance of each chemical scaffold. We explore the pipeline of Akt inhibitors and their preclinical and clinical examination status, presenting the potential clinical application of these agents as a monotherapy or in combination with ionizing radiation, other targeted therapies, or chemotherapy.

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Section: Allosteric Inhibitorsmentioning

confidence: 99%

Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)

Nițulescu

Margină

Juzenas

et al. 2015

International Journal of Oncology

323

268

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“…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). HePC and other etherlipid analogs show various other biological effects on neoplastic cells in addition to their cytotoxic or cytostatic properties: HePC can induce apoptosis in malignant cell lines (12–16) and it inhibits the invasive growth of neoplastic cells into normal tissue (17).…”

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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“…HePC showed excellent antineoplastic activity in human tumor cell lines in vitro and in vivo and in some chemically induced rat tumor models (1–3). In phase II/III trials HePC was tested in patients with mammary carcinoma (4), colorectal carcinoma (5), non small cell lung carcinoma (6) and cutaneous lymphoma (7).…”

Section: Introductionmentioning

confidence: 99%

Hexadecylphosphocholine does not influence phospholipase D and sphingomyelinase activity in human leukemia cells

Berkovic

Binder

et al. 2002

J Exp Therapeutics

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Hexadecylphosphocholine (HePC) is the first representative of the alkylphosphocholines (APC), a new group of biologically active compounds. HePC has pronounced antiproliferative effects on neoplastic cells in vitro and in vivo. The molecular mechanism by which HePC exerts its biological effects is still under investigation. Recently there has been growing evidence that HePC probably interferes with cellular signalling via phospholipases. It has been shown to inhibit both forms of phospholipase C (PLC), the phosphatidylinositol- and the phosphatidylcholine-specific PLC, and phospholipase A2. Here we present data showing that HePC inhibits the activity of phospholipase D in vitro, whereas the action of this enzyme in leukemic cell lines is not affected. Furthermore HePC does not seem to disturbed the activity of sphingomyelinase, another enzyme of phospholipid metabolism which has been shown to play an important role in cellular signalling as well.

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Phase II Trial of Orally Administered Miltefosine in Advanced Colorectal Cancer

Cited by 9 publications

References 7 publications

Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)

Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)

Effects of etherlipid analogs on cell membrane functions

Hexadecylphosphocholine does not influence phospholipase D and sphingomyelinase activity in human leukemia cells

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