1-β-d-Arabinofuranosylcytosine 5′-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (ara-CDP-dl-PTBA) is an effective stable 1-β-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 µm). Analyses on thin-layer and high-pressure liquid chromatography showed that the conjugate was chemically stable upon storage at 3–4°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-β-d-arabinofuranosylcytosine 5′-monophosphate and phosphatidic acid. At 3–4°C, the micellar structure remained generally unchanged for 6 mo (size, <0.1 µm). Samples stored for 4 mo at room temperature formed some larger vesicles (size, 0.1 to 0.4 µm). Antitumor activity against i.p. implanted L1210 leukemia in mice remained relatively constant with samples stored for 6 mo at 3–4°C or 3 mo at room temperature. 1-β-d-Arabinofuranosylcytosine 5′-triphosphate (ara-CTP) levels were elevated (>500 pmol/107 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 (>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 >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.

1

These studies were partially supported by Program Grant CA-13038 and grants CA 21071 and CA 42898 from the National Cancer Institute.

This content is only available via PDF.