Antitumor activity of synthetic alkylphospholipids with or without PAF activity.
1-O-Octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OMe) has been reported to possess definite antitumor activity in vivo. Twenty-two alkyl lysophospholipid analogs were chemically synthesized, and their antitumor activity against mouse experimental tumors (Sarcoma 180, MM46, P388) was examined. Among them, 1-O-octadecyl-2-O-acetoacetyl-rac-glycero-3-phosphocholine was found to show antitumor activity similar to ET-18-OMe with less acute toxicity. Intravenous injection of the ET-18-OMe with sn-3 configuration retarded the subcutaneous growth of Sarcoma 180 cells effectively, while the growth inhibition by the sn-1 isomer was much less effective. This stereospecificity was similar to that observed in their activities as platelet-activating factor (PAF) agonists. The acetoacetyl compound, another PAF agonist, showed similar stereospecific antitumor action in vivo. These findings suggest that some alkyl lysophospholipids may activate host cells to a cytostatic stage against tumor cells in vivo through binding to a PAF receptor. Our preliminary results indicated that the responsible cells under these conditions might be primarily immature macrophages present in the bone marrow. No appreciable or even adverse stereospecificity was observed in the different sets of experiments where the activity of ET-18-OMe against MM46 tumor cells in vivo or the direct cytotoxicity against human promyelocytic leukemia HL-60 cells in vitro was examined. Under some conditions, the antitumor activity of ET-18-OMe in vivo may be revealed through direct cytotoxicity and/or modulation of the host defense system by "nonspecific" mechanisms. Some alkylphospholipids without PAF activity may also show antitumor activity through similar "nonspecific" mechanisms.
Kudo
I
I
Department of Health Chemistry, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Nojima
S
S
Chang
H W
HW
Yanoshita
R
R
Hayashi
H
H
Kondo
E
E
Nomura
H
H
Inoue
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D005260:Female; D007275:Injections, Intravenous; D051379:Mice; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D008968:Molecular Conformation; D010742:Phospholipid Ethers / Q000008:administration & dosage / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; C026659:edelfosine