Significance of the low-density lipoprotein (LDL) receptor pathway for the in vitro accumulation of AD-32 incorporated into LDL in normal and leukemic white blood cells.
The accumulation of the lipophilic cancer chemotherapeutic agent AD-32 as free drug and incorporated into low-density lipoprotein (LDL) (AD-32-LDL) has been studied in wbcs from normal subjects and from patients with acute myelogenous leukemia exhibiting high-affinity uptake and degradation of 125I-LDL. The rate of degradation of 125I-LDL in the leukemic cells was four to 25 times higher than that in normal wbcs. The accumulation of LDL-incorporated AD-32 was greater than that of the free drug and could be reduced by the addition of native LDL in excess. AD-32-LDL was as effective as native LDL in inhibiting the degradation of 125I-LDL. Preincubation of wbcs in a lipoprotein-deficient medium enhanced both the degradation of 125I-LDL and the cellular drug accumulation on incubation with AD-32-LDL. Heparin inhibited both the high-affinity degradation of 125I-LDL and the cellular accumulation of LDL-incorporated drug. However, comparison of the high-affinity degradation rate of 125I-LDL and the accumulation of LDL-incorporated AD-32 showed that the cellular drug accumulation markedly exceeded that which could be explained by high-affinity uptake and degradation of AD-32-LDL. Furthermore, saturation of the cellular uptake of LDL-incorporated drug occurred at higher LDL concentrations than saturation of 125I-LDL degradation. The results indicate that cellular uptake of AD-32-LDL is partly mediated by the LDL receptor pathway and partly by a nonspecific mechanism.
D000368:Aged; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood; D005260:Female; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000097:blood*; D007962:Leukocytes / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011973:Receptors, LDL
D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; C016163:valrubicin; D004317:Doxorubicin