Low density lipoprotein for delivery of a water-insoluble alkylating agent to malignant cells. In vitro and in vivo studies of a drug-lipoprotein complex.
Previous studies have shown that human leukaemic cells and certain tumour tissues have a higher receptor-mediated uptake of low density lipoprotein (LDL) than the corresponding normal cells or tissues. LDL has therefore been proposed as a carrier for anti-cancer agents. In the current study, a water-insoluble mitoclomine derivative (WB 4291) was incorporated into LDL. The WB 4291-LDL complex contained about 1,500 drug molecules per LDL particle and showed receptor-mediated toxicity in vitro as judged from the difference in growth inhibitory effect on normal and mutant (LDL-receptor-negative) cultured Chinese hamster ovary cells. However, cellular drug uptake did not exclusively occur by the receptor pathway since mutant cells were also affected to some extent. The LDL part of the complex had the same plasma clearance and organ distribution as native LDL after i.v. injection in mice and rabbits. Therapeutic effects were observed when Balb-C mice with experimental leukaemia were treated with the complex. After i.p. administration to mice with i.p. leukaemia median survival time was prolonged 2.5-fold and 40% became long time survivors. The effect was weaker (42% increase in life span) after i.v. injections of the complex to mice with i.v. leukaemia.
Vitols
S
S
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Söderberg-Reid
K
K
Masquelier
M
M
Sjöström
B
B
Peterson
C
C
D000477:Alkylating Agents / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004337:Drug Carriers; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy; D008077:Lipoproteins, LDL / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage*; D011817:Rabbits; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008077:Lipoproteins, LDL; D009588:Nitrogen Mustard Compounds; C066486:WB 4291