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Membrane affinity and metabolism of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine into cultured KB cells.
- Source :
-
Cancer research [Cancer Res] 1981 Nov; Vol. 41 (11 Pt 1), pp. 4484-8. - Publication Year :
- 1981
-
Abstract
- N4-Palmitoyl-1-beta-D-arabinofuranosylcytosine (N4-palmitoyl-ara-C), a lipophilic derivative of 1-beta-D-arabinofuranosylcytosine, possessed an affinity for KB cell plasma membrane. Approximately 15 to 25% of the drug incorporated into KB cells was retained in plasma membrane when the cells were treated with the drug for 1 to 32 hr at 10 microM, the concentration required for 50% inhibition of cell growth. Less than 5.3% of the drug was found in the plasma membrane when the cells were treated with 1-beta-D-arabinofuranosylcytosine. N4-Palmitoyl-ara-C in the membrane fraction cosedimented with plasma membrane in a sucrose density gradient at 4 degrees, indicating a close association between the drug and the membrane. The affinity of N4-palmitoyl-ara-C for plasma membrane probably contributes to the efficient uptake rate and the strong cytotoxic effect of N4-palmitoyl-ara-C reported previously. The metabolites of N4-palmitoyl-ara-C in KB cells, treated with the drug for 32 hr at the concentration required for 50% inhibition of cell growth (10 microM), were analyzed by diethylaminoethyl Sepharose CL-6B column chromatography and thin-layer and paper chromatography. This analysis showed that over 98% of the drug present in the KB cell was N4-palmitoyl-ara-C. The active metabolites, 1-beta-D-arabinofuranosylcytosine, 1-beta-D-arabinofuranosylcytosine 5'-monophosphate, N4-palmitoyl-1-beta-D-arabinofuranosylcytosine 5'-monophosphate, and 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, were found in amounts of 0.41, 0.37, 0.17, and 0.05%, respectively, of the total drug found in the cells. Also found were the inactive metabolites 1-beta-D-arabinofuranosyluracil and 1-beta-D-arabinofuranosylcytosine diphosphate choline in amounts of 0.61 and 0.29%, respectively.
- Subjects :
- Animals
Cell Fractionation
Cell Line
Cell Nucleus metabolism
Centrifugation, Density Gradient
Chromatography, Paper
Chromatography, Thin Layer
Cytarabine metabolism
Cytarabine pharmacology
Cytoplasm metabolism
Palmitates metabolism
Palmitates pharmacology
Cell Membrane metabolism
Cytarabine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 41
- Issue :
- 11 Pt 1
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 7306971