Pharmacokinetics and biodistribution of Erufosine in nude mice--implications for combination with radiotherapy.
BACKGROUND
Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice.


METHODS
NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity.


RESULTS
Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (<10%) in a dose dependent manner. Subcutaneous injections of high-dose Erufosine caused local reactions at the injection site. Therefore, this regimen at 40 mg/kg body weight Erufosine was stopped after 14 days. No gross changes were observed in organ weight, clinical chemistry and white blood cell count in treated compared to untreated controls except for a moderate increase in lactate dehydrogenase and aspartate-aminotransferase after intensive treatment. Repeated Erufosine injections resulted in drug-accumulation in different organs with maximum concentrations of about 1000 nmol/g in spleen, kidney and lungs.


CONCLUSIONS
Erufosine was well tolerated and organ-concentrations surpassed the cytotoxic drug concentrations in vitro. Our investigations establish the basis for a future efficacy testing of Erufosine in xenograft tumor models in nude mice alone and in combination with chemo- or radiotherapy.
Henke
Guido
G
Department of Radiooncology, University Hospital Tübingen, Hoppe-Seyler-Str 3, 72076 Tübingen, Germany.
Lindner
Lars H
LH
Vogeser
Michael
M
Eibl
Hans-Jörg
HJ
Wörner
Jürgen
J
Müller
Arndt C
AC
Bamberg
Michael
M
Wachholz
Kirsten
K
Belka
Claus
C
Jendrossek
Verena
V
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003131:Combined Modality Therapy; D051379:Mice; D008819:Mice, Nude; D010755:Organophosphates / Q000493:pharmacokinetics*; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D011878:Radiotherapy; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D010755:Organophosphates; D000644:Quaternary Ammonium Compounds; D011838:Radiation-Sensitizing Agents; C472787:erucylphospho-N,N,N-trimethylpropylammonium