Identification of antidotes against the gastrointestinal toxicity of alkylphosphocholines

Miltefosine (D-18506; hexadecylphosphocholine) and perifosine [D-21266; oct adecyl-(1-1-dimethyl-piperidino-4-yl)phosphate], two alkylphosphocholine de rivatives, display high antitumor activity in vitro and in vivo. Miltefosin e, the prototype of this class of compounds, induced loss of appetite and d ecrease in body weight as major clinical side effects after oral administra tion. The aim of the present studies was to investigate the influence of mi ltefosine and perifosine on the body weight of tumor-bearing or healthy rat s. Furthermore, the effect of dopamine or serotonin receptor antagonists in combination with perifosine or miltefosine was studied. The aim of these e xperimental investigations was to identify drugs which could antagonize the weight loss induced by the alkylphosphocholines. In addition, it was a pre requisite that the antitumor activity remained unchanged. Consequently, two approaches were selected for this study: the autochthonous dimethylbenzant hracene (DMBA)-induced mammary carcinoma of the rat and healthy nontumor-be aring rats were treated orally with miltefosine or perifosine alone or in c ombination with different dopamine or serotonin antagonists (domperidone, p imozide, metoclopramide or cyproheptadine). It was found that the D-2 dopam ine receptor antagonists domperidone and pimozide injected intraperitoneall y antagonized miltefosine-induced weight loss in healthy rats. Similarly, i n DMBA-tumor bearing animals the weight reduction was significantly inhibit ed by the dopamine antagonists without abolishing the antitumor activity of the alkylphosphocholines. Metoclopramide and cyproheptadine, both serotoni n receptor antagonists, were ineffective. in contrast to miltefosine after oral administration, perifosine only slightly decreased the body weight of healthy rats and this effect could be significantly antagonized by domperid one or pimozide. Similarly, in DMBA-tumor bearing rats, perifosine caused n o body weight reduction, however, in combination with domperidone the weigh t increase was more pronounced, whereas the antitumor activity was not infl uenced. in conclusion, domperidone is a potential candidate antagonist for the gastrointestinal side effects induced by alkyl-phosphocholines in patie nts. (C) 1998 Prous Science. All rights reserved.