Selective uptake of a toxic lipophilic anthracycline derivative by the low-density lipoprotein receptor pathway in cultured fibroblasts
N-(N-Retinoyl)-L-leucyldoxorubicin 14-linoleate (r11-DOX), a new lipophilic derivative of doxorubicin, was synthesized and incorporated into low-density lipoprotein (LDL). The drug-LDL complex contained 100- 200 drug molecules/LDL particle. When cultured normal human fibroblasts were incubated with /sup 125/I-LDL-incorporated drug, there was a perfect correlation between the cellular uptake plus degradation of /sup 125/I-LDL and the cellular drug accumulation. The presence of excess native LDL inhibited the cellular uptake and degradation of /sup 125/I-LDL and the drug accumulation to the same extent. In contrast, methylated LDL, which does not bind to the LDL receptor, did not alter the cellular uptake and degradation of /sup 125/I-LDL nor did it alter the drug accumulation. When LDL receptor negative fibroblasts from a patient with the homozygous form of familial hypercholesterolemia were incubated with the drug-/sup 125/I-LDL complex, cellular drug accumulation was very low. The drug-LDL complex inhibited the growth of cultured normal human fibroblasts. The drug incorporated into methylated LDL was much less toxic. These findings suggest that r11-DOX incorporated into LDL is delivered to cells selectively by the LDL receptor pathway. This might be of value in the treatment of leukemia, since it has been previously found that leukemic cells exhibit higher LDL receptor activity than white blood cells and bone marrow cells from healthy subjects.
- Research Organization:
- Karolinska Institute, Stockholm, Sweden
- OSTI ID:
- 5646374
- Journal Information:
- J. Med. Chem.; (United States), Journal Name: J. Med. Chem.; (United States) Vol. 28:4; ISSN JMCMA
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
ANTINEOPLASTIC DRUGS
BETA DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL PATHWAYS
CELL CULTURES
CONNECTIVE TISSUE CELLS
DAYS LIVING RADIOISOTOPES
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
FIBROBLASTS
HALOGEN COMPOUNDS
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE COMPOUNDS
IODINE ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LIPIDS
LIPOPROTEINS
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
PATIENTS
PROTEINS
RADIOISOTOPES
REACTION KINETICS
RECEPTORS
SOMATIC CELLS
TRACER TECHNIQUES