title: Formulation, stability, and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugate of thioether phospholipid.
abstract: 1-beta-D-Arabinofuranosylcytosine 5'-diphosphate-rac-1-S-octadecyl-2-O- palmitoyl-1-thioglycerol (ara-CDP-DL-PTBA) is an effective stable 1-beta-D-arabinofuranosylcytosine (ara-C) conjugate of thioether phospholipid against a variety of transplantable tumors in mice. The conjugate was formulated in a micellar solution by sonication, in which the conjugate exists as micellar discs (size, 0.01 to 0.04 micron). Analyses on thin-layer and high-pressure liquid chromatography showed that the conjugate was chemically stable upon storage at 3-4 degrees C for more than a 6-mo period. However, stored at room temperature for 3 mo it began to degrade (3 to 11%) to 1-beta-D-arabinofuranosylcytosine 5'-monophosphate and phosphatidic acid. At 3-4 degrees C, the micellar structure remained generally unchanged for 6 mo (size, less than 0.1 micron). Samples stored for 4 mo at room temperature formed some larger vesicles (size, 0.1 to 0.4 micron). Antitumor activity against i.p. implanted L1210 leukemia in mice remained relatively constant with samples stored for 6 mo at 3-4 degrees C or 3 mo at room temperature. 1-beta-D-Arabinofuranosylcytosine 5'-triphosphate (ara-CTP) levels were elevated (greater than 500 pmol/10(7) cells) in L1210 leukemia cells within 1 h following i.p. administration of 400 mg/kg of ara-CDP-DL-PTBA to mice. More importantly, retention of cellular ara-CTP was prolonged (greater than 24 h) in these tumor cells as compared with ara-C treatments. Administration of ara-CDP-DL-PTBA to mice with colon 26 carcinoma (s.c.) resulted in both significant antitumor activity with an increased life span greater than 100% and decreased tumor size. The conjugate also demonstrated a dose-dependent therapeutic effect in mice with M5076 sarcoma (s.c.) as demonstrated by decreases in tumor size and liver metastases. Overall, ara-CDP-DL-PTBA, a stable lipid conjugate of ara-C in a micellar solution, appears to offer substantial therapeutic benefit to mice with leukemia and solid tumors warranting its further development and clinical investigation.
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: R J
authors.initials: RJ
authors.lastname: Bernacki
authors.forename: S W
authors.initials: SW
authors.lastname: Hui
authors.forename: Y
authors.initials: Y
authors.lastname: Rustum
authors.forename: C R
authors.initials: CR
authors.lastname: West
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D004355:Drug Stability; D005260:Female; D005614:Freeze Fracturing; D007939:Leukemia L1210 / Q000188:drug therapy*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010742:Phospholipid Ethers / Q000138:chemical synthesis / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; D003561:Cytarabine; C063784:ara-CDP-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol