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

Article

Author: Grosman, N

The ether phospholipid AMG-PC (1-O-hexadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-16-OCH3) affects rat mast cell responses in a dual manner. A powerful synergistic interaction with the ionophore A23187 and the phorbol ester TPA indicated an involvement of mechanisms relating to activation of protein kinase C. In contrast, the related hexadecylphosphocholine (miltefosine) only causes inhibition. Here, the investigation is extended to include the antineoplastic ether phospholipids ET-18-OCH3 (edelfosine) and BM 41.440 (ilmofosine) as well as the heterocyclic hexadecylphosphocholine analogues D-20133 and D-21266. The four test drugs had an influence very similar to that of AMG-PC on mast cell responses to selected secretagogues, i.e., they both enhanced and inhibited antigen-induced histamine release whereas only inhibition was observed with compound 48/80. They significantly amplified the response to A23187 alone as well as in combination with TPA and, under certain conditions, inhibitory effects were observed with ET-18-OCH3, D-20133 and D-21266 but not with BM 41.440. The latter was more effective in enhancing A23187 mediated responses and had a wider concentration range of activity than the other three drugs. D-20133 and D-21266 influenced mast cells in a manner distinct from that of hexadecylphosphocholine and may share cellular targets with the ether phospholipids. The results raise speculation of an involvement of mast cells in the immunomodulatory action of these drugs.

01 Apr 1999·Inflammation ResearchQ3 · MEDICINE

On the use of ionophores as probes for calcium signalling. Observations with rat mast cells

Q3 · MEDICINE

Article

Author: Grosman, N

The unexpected histamine release of rat mast cells to ionophores was examinedThe mast cell response to A23187 (DMSO stock solution) decreased after sequential addition of A23187 to a series of test tubes with mast cells (tube number 1 being the 1st in the series, number 5 the 5th, etc.; cells and ionophore are thus added to tube number 7 1 min later than to tube number1).The decrease showed a day to day variation and occasionally exceeded 70%.A similar decline was observed with ionomycin and with very low concentration of A23187 used in combination with TPA.Using A23187 from the aqueous stock solution reduced the day to day variation and increased reactivity in the presence of D-20133 and D-21266.

01 Jan 1993·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

Antineoplastic activity and tolerability of a novel heterocyclic alkylphospholipid, D-20133

Q4 · MEDICINE

Article

Author: Jürgen Engel ; Gerhard Nößner ; H. Rainer Maurer ; Jurij Stekar ; Bernhard Kutscher ; Wolfgang Schumacher ; Peter Hilgard ; Rainer Voegeli

Octadecyl-[2-(N-methylpiperidinio)ethyl]-phosphate (OMPEP, D-20133), a heterocyclic analogue of hexadecylphosphocholine (MIL), has been synthesized in an attempt to increase the therapeutic range of the parent compound. The antineoplastic activity of the novel alkylphospholipid was compared with that of MIL in dimethylbenz(a)anthracene-induced mammary carcinoma of the rat. Using tumors of different sizes and repeated daily doses as well as high single doses, we achieved marked remissions with either compound. However, the therapeutic range of OMPEP was broader than that of the parent drug. Furthermore, the emetic potential of OMPEP tested on ferrets was distinctly less pronounced than that of MIL. In vitro the new alkylphospholipid proved to be more active than MIL in all cell lines tested, and its differentiation-inducing capacity turned out to be superior to that of MIL. No hematological toxicity was observed at various OMPEP doses during a 3-week treatment period.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	-	Asta Medica Ltda	-

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