TY - JOUR
T1 - Lipid-complexed camptothecin
T2 - Formulation and initial biodistribution and antitumor activity studies
AU - Sugarman, Steven M.
AU - Zou, Yiyu
AU - Wasan, Kishor
AU - Poirot, Ken
AU - Kumi, Robert
AU - Reddy, Sara
AU - Perez-Soler, Roman
PY - 1996
Y1 - 1996
N2 - Water-soluble derivatives of camptothecin, an active topoisomerase I inhibitor, have shown a broad spectrum of activity against human tumors. Early clinical trials with the water-soluble sodium salt of camptothecin were hindered by significant cystitis, gastroenteritis, and leukopenia. Furthermore, the sodium salt of camptothecin has been shown to have significantly less activity than the water-insoluble lactone form of the compound. We describe a formulation of lipid-complexed CPT (LC-CPT; particle size range 20.8-208.1 nm) that is very easy to prepare and allows for intravenous administration in vivo in clinically relevant lipid-drug ratios (12.5:1 w/w). The lipid formulation had in vitro antitumor activity similar to that of CPT formulated without lipids and displayed similar cytotoxicity against MDR-1-negative and -positive tumor cells. The biodistribution of CPT was profoundly affected by lipid complexation; free CPT achieved the greatest concentration in the pulmonary parenchyma while LC-CPT achieved the highest concentration in the gastrointestinal tract. LC-CPT had significant antitumor activity in vivo against intraperitoneal L1210 and P388 leukemia and appeared to be more potent than free CPT.
AB - Water-soluble derivatives of camptothecin, an active topoisomerase I inhibitor, have shown a broad spectrum of activity against human tumors. Early clinical trials with the water-soluble sodium salt of camptothecin were hindered by significant cystitis, gastroenteritis, and leukopenia. Furthermore, the sodium salt of camptothecin has been shown to have significantly less activity than the water-insoluble lactone form of the compound. We describe a formulation of lipid-complexed CPT (LC-CPT; particle size range 20.8-208.1 nm) that is very easy to prepare and allows for intravenous administration in vivo in clinically relevant lipid-drug ratios (12.5:1 w/w). The lipid formulation had in vitro antitumor activity similar to that of CPT formulated without lipids and displayed similar cytotoxicity against MDR-1-negative and -positive tumor cells. The biodistribution of CPT was profoundly affected by lipid complexation; free CPT achieved the greatest concentration in the pulmonary parenchyma while LC-CPT achieved the highest concentration in the gastrointestinal tract. LC-CPT had significant antitumor activity in vivo against intraperitoneal L1210 and P388 leukemia and appeared to be more potent than free CPT.
KW - Lipid-complexed camptothecin
UR - http://www.scopus.com/inward/record.url?scp=0029873920&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029873920&partnerID=8YFLogxK
U2 - 10.1007/s002800050425
DO - 10.1007/s002800050425
M3 - Article
C2 - 8612306
AN - SCOPUS:0029873920
SN - 0344-5704
VL - 37
SP - 531
EP - 538
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -