D-21266, A NEW HETEROCYCLIC ALKYLPHOSPHOLIPID WITH ANTITUMOR-ACTIVITY

The aim of this study was to determine the antitumour effects of D-212 66 in a rodent tumour model, Hexadecylphosphocholine (INN: Miltefosine ) represents the first anticancer agent which was specifically formula ted for topical use in cancer patients. The development as an oral dru g was hampered by the gastrointestinal toxicity. Hexadecylphosphocholi ne derivatives were sought with a better therapeutic index. Octadecyl- (1,1-dimethyl-4-piperidylio) (D-21266) was identified as a suitable ca ndidate. This compound is highly active in vitro inhibiting the growth of a number of human cancer cell lines. Mammary carcinomas were induc ed in Sprague-Dawley rats using DMBA, and oral doses of D-21266, in va rious schedules, were given to the animals. A high antineoplastic pote ncy was observed without inducing loss of body weight at highly effect ive doses. The antitumour effect could be enhanced by introducing a do se schedule consisting of a high loading dose followed by a law mainte nance dose, both of which are only marginally active when given alone. Therefore, D-21266 with its favourable pharmacological and toxicologi cal profile, warrants evaluation in the clinic. However, the concept o f clinical trials requires new approaches to dose finding and response evaluation, because the dose-response relationship of this compound i s distinctly different from that of classical cytostatic agents. (C) 1 997 Elsevier Science Ltd.