D-21266, a new heterocyclic alkylphospholipid with antitumour activity

• Published in: European journal of cancer (1990) Vol. 33; no. 3; pp. 442 - 446
• Main Authors: Hilgard, P., Klenner, T., Stekar, J., Nössner, G., Kutscher, B., Engel, J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.1997; Elsevier
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic agents; Antineoplastic Agents - therapeutic use; antitumour activity; Biological and medical sciences; Body Weight - drug effects; Chemotherapy; Dose-Response Relationship, Drug; Female; heterocyclic alkylphospholipid; in vitro tumour cell lines; in vivo DMBA-induced mammary tumour; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; Medical sciences; Pharmacology. Drug treatments; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacology; Phosphorylcholine - therapeutic use; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured - drug effects; in vitro tumour cell lines; heterocyclic alkylphospholipid; in vivo DMBA-induced mammary tumour; antitumour activity; Antineoplastic agent; Animal model; Rat; Rodentia; Pharmacology; Experimental study; Miltefosine; Vertebrata; Chemotherapy; Mammalia; Cell line; Animal; Tumor cell
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(97)89020-X

The aim of this study was to determine the antitumour effects of D-21266 in a rodent tumour model. Hexadecylphosphocholine (INN: Miltefosine) represents the first anticancer agent which was specifically formulated for topical use in cancer patients. The development as an oral drug was hampered by the gastrointestinal toxicity. Hexadecylphosphocholine derivatives were sought with a better therapeutic index. Octadecyl-(1,1-dimethyl-4-piperidylio)phosphate (D-21266) was identified as a suitable candidate. This compound is highly active in vitro inhibiting the growth of a number of human cancer cell lines. Mammary carcinomas were induced in Sprague-Dawley rats using DMBA, and oral doses of D-21266, in various schedules, were given to the animals. A high antineoplastic potency was observed without inducing loss of body weight at highly effective doses. The antitumour effect could be enhanced by introducing a dose schedule consisting of a high loading dose followed by a low maintenance dose, both of which are only marginally active when given alone. Therefore, D-21266 with its favourable pharmacological and toxicological profile, warrants evaluation in the clinic. However, the concept of clinical trials requires new approaches to dose finding and response evaluation, because the dose-response relationship of this compound is distinctly different from that of classical cytostatic agents.