title: Camptothecin-20-PEG ester transport forms: the effect of spacer groups on antitumor activity.
abstract: An improved synthesis of the hindered PEG-camptothecin diester transport form has been achieved using the Mukaiyama reagent. We have also assessed the effect of changing the electronic configuration of the (d-position of PEG-camptothecin transport forms on the rates of hydrolysis of the pro-moiety, and attempted to correlate these differences to efficacy in two animal models. In addition to the simple substitution of N for O, other synthetic modifications of these atoms were accomplished by employing heterobifunctional linker groups. The half lives by disappearance (rates of hydrolysis) of the transport forms in buffer and rat plasma were determined. It was established that anchimeric assistance to hydrolytic breakdown of the pro-moiety occurs in a predictable manner for some of these compounds. Results for the new derivatives in a P388 murine leukemic model and HT-29 human colorectal xenograft study are also presented. The use of a glycine linker group was found to provide similar efficacy in rodent models to that of simple camptothecin 20-PEG ester, and displayed enhanced pharmacokinetics.
authors.affiliation: Enzon, Inc., Piscataway, New Jersey 08854-3969, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Greenwald
authors.forename: A
authors.initials: A
authors.lastname: Pendri
authors.forename: C D
authors.initials: CD
authors.lastname: Conover
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.forename: Y H
authors.initials: YH
authors.lastname: Choe
authors.forename: C
authors.initials: C
authors.lastname: Gilbert
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.forename: J
authors.initials: J
authors.lastname: Xia
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Hsue
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001692:Biological Transport; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007941:Leukemia P388 / Q000378:metabolism / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009368:Neoplasm Transplantation; D051381:Rats; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin