Potentiation of cytotoxicity of Kaposi's sarcoma related to immunodeficiency syndrome (AIDS) by liposome-encapsulated doxorubicin.
Kaposi's sarcoma is an independent criterion for the diagnosis of AIDS and develops in nearly 15% of all cases. Current chemotherapy regimens are associated with substantial toxicity, particularly bone marrow suppression, which limit their long-term use. In an attempt to reduce treatment-related toxicity and enhance uptake of the drug in tumor cells, free and liposome-encapsulated doxorubicin was tested in vitro. The liposomes were prepared with cardiolipin, phosphatidylcholine, and cholesterol. Kaposi's sarcoma (KS)-derived spindle cells were exposed to free doxorubicin (DOX) and liposome-encapsulated doxorubicin (LED) for various time intervals and analyzed for cellular cytotoxicity, thymidine incorporation, and cellular drug uptake. Cytotoxicity studies of KS cells with free DOX and LED showed an IC50 of 288 and 7.5 ng/ml, respectively, hence demonstrating a 38-fold higher cytotoxicity by LED. Thymidine incorporation studies in KS cells demonstrated over one log higher toxicity to LED compared to free DOX. Cellular drug uptake studies showed that free DOX concentration peaked in 1 hr in KS cells whereas LED continued to accumulate up to 4 hr. At 4 hr, anthracycline uptake through LED was fivefold higher than the uptake of free drug. Similarly LED uptake in the cells evaluated by direct fluorescent microscopy was much more intense and more frequent than the uptake of free drug. Thus AIDS-KS cells appear to be exquisitely sensitive to LED, which may provide a higher therapeutic to toxicity index in clinical use.
Masood
R
R
Department of Medicine, Norris Cancer Center, University of Southern California, Los Angeles 90033.
Husain
S R
SR
Rahman
A
A
Gill
P
P
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use* / Q000633:toxicity; D004337:Drug Carriers; D006801:Humans; D008081:Liposomes; D008856:Microscopy, Fluorescence; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000209:etiology; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin; D013936:Thymidine