title: 1-beta-D-arabinofuranosylcytosine conjugates of ether and thioether phospholipids. A new class of ara-C prodrug with improved antitumor activity.
abstract: The 1-beta-D-arabinofuranosylcytosine (ara-C) conjugates 1-O-alkyl (ether) and 1-S-alkyl (thioether) phospholipids, being analogues of ara-CDP-sn-1,2-O-dipalmitoylglycerol (1), showed significant antitumor activity against L1210 and P388 leukemia in vivo. The more active conjugates include the 1-O-alkyl analogues, ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (2) and ara-CDP-rac-1-O-octa-decyl-2-O-palmitoylglycerol (3), and the corresponding 1-S-alkyl analogues, ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (4) and ara-CDP-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (5, Cytoros). The conjugates were formulated by sonication, in which the conjugates existed as discs (size 0.01-0.04 microns). Among the conjugates of the three different phospholipids, the 1-S-alkyl analogues 4 and 5 displayed the strongest antitumor activity against L1210 leukemia in mice, followed by the 1-O-alkyl (2 and 3) and the 1-O-acyl (1) analogues. The 1-S-alkyl analogue 5 was considerably more effective than the 1-O-acyl analogue 1 against myelomonocytic WEHI-3B leukemia in mice. Conjugate 5 (Cytoros) showed a significant therapeutic activity in mice with colon 26 carcinoma, M5076 sarcoma, and C-1300 neuroblastoma. Furthermore, this agent inhibited liver metastases of M5076 sarcoma. Conjugates 3 and 5 also inhibited the metastasis of 3-Lewis lung carcinoma to the lungs of mice. Cytoros (5) and its analogues, with other ether and thioether phospholipids, appear to offer increased therapeutic benefit to mice with tumors.
authors.affiliation: Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: C I
authors.initials: CI
authors.lastname: Hong
authors.forename: C R
authors.initials: CR
authors.lastname: West
authors.forename: R J
authors.initials: RJ
authors.lastname: Bernacki
authors.forename: C K
authors.initials: CK
authors.lastname: Tebbi
authors.forename: W E
authors.initials: WE
authors.lastname: Berdel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D010742:Phospholipid Ethers / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D010742:Phospholipid Ethers; D011355:Prodrugs; D003561:Cytarabine