title: Lipid-complexed camptothecin: formulation and initial biodistribution and antitumor activity studies.
abstract: Water-soluble derivatives of camptothecin, and 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 P338 leukemia and appeared to be more potent then free CPT.
authors.affiliation: Department of Gastrointestinal Oncology and Digestive Diseases, University of Texas, M.D. Anderson Cancer Center, Houston TX 77030, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Sugarman
authors.forename: Y
authors.initials: Y
authors.lastname: Zou
authors.forename: K
authors.initials: K
authors.lastname: Wasan
authors.forename: K
authors.initials: K
authors.lastname: Poirot
authors.forename: R
authors.initials: R
authors.lastname: Kumi
authors.forename: S
authors.initials: S
authors.lastname: Reddy
authors.forename: R
authors.initials: R
authors.lastname: Perez-Soler
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008055:Lipids / Q000737:chemistry; D008657:Metabolic Clearance Rate; D051379:Mice; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008055:Lipids; D002166:Camptothecin