Pharmacokinetics and metabolism of a new antitumor semisynthetic ether phospholipid,14C-labeled plasmanyl-(N-acyl)ethanolamine,in mice bearing sarcoma Mc11

New natural and semisynthetic antitumor ether phospholipids PNAE and PNAE(s) [plasmanyl-(N-acyl)ethanolamines] and their selective antitumor activity in vivo have been described previously. We are now presenting the pharmacokinetics, in vivo metabolism and distribution of a [¹⁴C]PNAE(s) preparation (1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-[U-¹⁴C]palmitoyl) ethanolamine in the intact or Mc11-tumor-bearing BDF₁ mice. Only partial degradation (about 50%–60%) of [¹⁴C]PNAE(s) was observed in vivo 24h after i.v. administration, as detected by TLC analysis of phospholipids extracted from the blood, liver, tumor and brain of animals. Pharmacokinetic curves of [¹⁴C]PNAE(s) and its metabolites were fitted with a two-compartment model (t ₁ ^2/ =2.5 h,t ₁ ^2/ =61.6 h). After repeated i.v. doses of [¹⁴C]PNAE(s) (administered on days 1, 2, 3, 4, and 5) accumulation of [¹⁴C]PNAE(s) and lyso-[¹⁴C]PNAE(s) in tumor tissue was detected. High levels of [¹⁴C]PNAE(s) were also detected in the liver, lung and spleen of animals. After i.v. administration of [¹⁴C]PNAE(s) the ether phospholipid was also detected in the brain tissue. The parmacokinetic data indicate that repeated parenteral doses of PNAE(s) are necessary to attain therapeutic concentrations in tumor tissue. The very high accumulation of [¹⁴C]PNAE(s) in the liver of animals after repeated i.v. doses, and the absence of toxic side-effects in vivo indicate a possible clinical therapeutic use of PNAE(s), especially in the treatment of tumor metastases in liver as well as in the prophylaxis of liver metastases after surgical removal of primary tumors.     

[dl-1,2-Bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II), a new compound for the therapy of ovarian cancer

Summary The synthesis of diastereoisomeric [1,2-bis (2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes,dl-3-PtCl₂ andmeso-3-PtCl₂, and their evaluation on the hormone-independent, human MDA-MB231 breast cancer cell line, on the cisplatin-sensitive and -resistant L1210 leukemia cell line, on the cisplatinresistant human NIH:OVCAR 3 ovarian cancer cell line, on the P-388 leukemia of the mouse and on the cisplatinsensitive and -resistant Ehrlich ascites tumor of the mouse are described. On all tumor modelsdl-3-PtCl₂ produces a marked inhibitory effect. The diastereoisomermeso-3-PtCl₂ is less active and more toxic. It is striking thatdl-3-PtCl₂ leads to a pronounced inhibition of all cisplatin-resistant tumors. At non-toxic concentrationsdl-3-PtCl₂ produces cytocidal effects on the NIH:OV-CAR 3 cell line. Thereforedl-3-PtCl₂ is of interest for further evaluation for the therapy of ovarian cancer.     

[1,2-Bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II), a new compound for the therapy of ovarian cancer

Summary The enantiomeric [1,2-bis(2-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II) complexes were synthesized and their configuration assessed. A preliminary test in the cisplatin-resistant human NIH:OVCAR-3 ovarian cancer cell line, which was previously characterized by its sensitivity against several therapeutically used drugs, showed that both enantiomers produce cytocidal effects in a concentration of 2.5 M. A difference between the enantiomers became evident from the faster onset of cytocidal activity of theS,S-configurated compound.Dedicated to Professor J. Knabe on the occasion of his 70th birthdayPart I: Müller et al. (1990)