Disease relevance of NCI60_004534

• 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 [1].
• A phase II trial of ilmofosine in non-small cell bronchogenic carcinoma [2].
• The activity of the alkyllysophospholipids Et-18-OCH3 and BM 41.440 and of the alkylphosphocholine He-PC was investigated in a human glioma xenograft (T 406) [3].
• Cytotoxicity of ether phospholipid BM 41.440 on neuroblastoma cells [4].
• The activity of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET18OMe) and 3-hexadecylmercapto-2-methoxymethyl-propyl-1-phosphocholine (Ilmofosine) (BM 41.440) was tested in variants of B16 murine melanoma, grown in adhesion cultures (B16F1 with low metastatic potential; B16F10 and B16BL6 with high metastatic potential) [5].

Psychiatry related information on NCI60_004534

• 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 [6].

High impact information on NCI60_004534

• Myosin light chain kinase and cAMP-dependent protein kinase were not inhibited by BM 41.440, indicating a specificity of the action of the agent [7].
• BM 41.440 partly blocked the TPA-induced depletion of soluble PKC in HL60 and KG-1 cells (responsive to the differentiating effect of TPA) but not in K562 cells (resistant to the TPA effect) [7].
• Plasma concentrations of ilmofosine and its sulfoxide metabolite were evaluated by high-pressure liquid chromatography [1].
• Enantioselective synthesis and antiproliferative properties of an ilmofosine analog, 2'-(trimethylammonio)ethyl 3-(hexadecyloxy)-2-(methoxymethyl)propyl phosphate, on epithelial cancer cell growth [8].
• No association between the expression of the MDR2-encoded P-gp and resistance to ilmofosine was observed [9].

Biological context of NCI60_004534

• Ilmofosine was found to induce a dose-dependent accumulation of CA46 cells in G2-phase of the cell cycle [10].
• Transcriptional activation of the SRE-FAP-TK-CAT as well as the SRE-TK-CAT constructs by Ha-ras is sensitive to the PKC-inhibitor ilmofosine (BM41440) and blocked by long-term exposure to TPA [11].
• Pharmacokinetics of the thioether phospholipid analogue BM 41.440 in rats [12].

Anatomical context of NCI60_004534

• The thioether lysophospholipid BM 41.440 proved to be toxic against cells of two neuroblastoma cell lines in a dose- and time-dependent manner [4].
• In comparison, hematopoietic progenitor cells (granulocyte/monocyte-colony-forming units) proved to be less sensitive to short-term treatment with BM 41.440 [4].
• This observation makes it unlikely that BM 41.440 can be used for treatment of neoplasia such as neuroblastoma, because only short-term treatment is acceptable considering the high bone marrow toxicity [4].
• The antineoplastic ether phospholipids BM 41.440 (ilmofosine) and ET-18-OCH3 (edelfosine) effectively inhibited the leukocyte membranes whereas the ATPase activity of synaptosomes was significantly increased by 20 microM and slightly inhibited by higher concentrations of these agents [13].
• Effect of the anti-neoplastic agents edelfosine (ET-18-OCH3), ilmofosine (BM 41.440) and the hexadecylphosphocholine analogues D-20133 and D-21266 on histamine release from isolated rat mast cells [14].

Associations of NCI60_004534 with other chemical compounds

• The in-vitro activities of four anticancer alkyllysophospholipids, ET-18-OCH3 (edelfosine), hexadecylphosphocholine (miltefosine), ilmofosine and SRI 62-834, were determined with ED50 values for Leishmania donovani and Trypanosoma cruzi amastigotes between 0.2 and 5.0 microM and for Trypanosoma brucei trypomastigotes between 7.0 and 50.8 microM [15].
• Screening for cytotoxicity in the clonogenic assay in human tumor xenografts and L1210 mouse leukemia revealed comparable dose-dependent effects of the alkyl lysophospholipid ET-18-OCH3 and the thioether lipid BM 41.440 [16].
• Expression of Ha-ras by dexamethasone leads to a transcriptional activation of the fos-CAT construct which was found to be sensitive to the PKC inhibitor ilmofosine (BM41440) and abrogated by PKC depletion following long-term exposure to TPA [11].

Gene context of NCI60_004534

• The protein kinase C inhibitor ilmofosine (BM 41 440) arrests cells in G2 phase and suppresses CDC2 kinase activation through a mechanism different from that of DNA damaging agents [10].
• Indeed, cdc2 became dephosphorylated and cyclin B1 protein levels decreased as ilmofosine treated cells became arrested in G2 [10].
• Long-term treatment of an ilmofosine-resistant Meth A subline with the drug does not induce multidrug resistance, indicating that ilmofosine does not increase the level of P-gp [9].
• In vivo, Meth A sarcoma growth was dose and time dependently reduced in CB6F1 mice under therapeutic IV application of BM 41.440-activated M phi [17].

Analytical, diagnostic and therapeutic context of NCI60_004534

• The thioether phospholipid ilmofosine (BM 41 440) is a new anti-cancer drug presently undergoing phase II clinical trials [9].

References