Journal article
Formulation, stability, and antitumor activity of 1-β-D-arabinofuranosylcytosine conjugate of thioether phospholipid
Cancer research (Chicago, Ill.), Vol.50(14), pp.4401-4406
1990
PMID: 2364392
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.
Details
- Title: Subtitle
- Formulation, stability, and antitumor activity of 1-β-D-arabinofuranosylcytosine conjugate of thioether phospholipid
- Creators
- C. I Hong - Roswell Park Cancer InstituteR. J Bernacki - Roswell Park Cancer InstituteSEK-WEN Hui - Roswell Park Cancer InstituteY Rustum - Roswell Park Cancer InstituteC. R West - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.50(14), pp.4401-4406
- Publisher
- American Association for Cancer Research
- PMID
- 2364392
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 1990
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359958802771
Metrics
23 Record Views