title: Tumor localization and antitumor efficacy of novel sapphyrin compounds.
abstract: Sapphyrins are pentapyrrolic metal-free expanded porphyrins with potential medical use as anticancer agents. The novel sapphyrin derivative, PCI-2050, functionalized with 2-[2-(2-methoxyethoxy)ethoxy]ethoxy groups to enhance solubility and a modified bipyrrole moiety was found to be more potent in inducing apoptosis than the previously described sapphyrin PCI-2000. Because some sapphyrins may localize to tumors, we took advantage of the intrinsic fluorescence of these compounds to develop a flow cytometry-based assay to track sapphyrin biodistribution in tumor-bearing mice. Ex vivo analysis of sapphyrin-injected animals revealed that PCI-2050 preferentially localized to tumor, whereas PCI-2000 distributed into normal tissues rather than tumor. PCI-2050 uptake in xenograft tumor cells and resultant tumor cell cytotoxicity was dose dependent. To investigate structure-activity relationships, we focused on PCI-2050 and three derivatives that differ by their alkyl substituents on the bipyrrole moiety: PCI-2051, PCI-2052, and PCI-2053. Treatment of Ramos cells in culture or treatment of Ramos xenograft-bearing animals with each of the sapphyrins followed by ex vivo growth of tumor cells revealed the same pattern of cytotoxicity: PCI-2050 > PCI-2052 > PCI-2051 > PCI-2053. Thus, subtle changes in the alkyl substituents on the bipyrrole moiety result in significant changes in antitumor activity. PCI-2050 displayed significant antitumor efficacy in both Ramos and RKO xenograft models without hematologic, hepatic, or renal abnormalities as assessed by complete blood counts and serum chemistries. On the basis of these findings, it is concluded that the sapphyrin PCI-2050 warrants further evaluation as a potential anticancer agent due to its intrinsic proapoptotic activity and tumor localization ability.
authors.affiliation: Cancer Biology, Pharmacyclics, Inc., 995 East Arques Avenue, Sunnyvale, CA 94085, USA. lnaumovski@pcyc.com
authors.forename: Louie
authors.initials: L
authors.lastname: Naumovski
authors.forename: Mint
authors.initials: M
authors.lastname: Sirisawad
authors.forename: Philip
authors.initials: P
authors.lastname: Lecane
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Jason
authors.initials: J
authors.lastname: Ramos
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cortez
authors.forename: Darren
authors.initials: D
authors.lastname: Magda
authors.forename: Patti
authors.initials: P
authors.lastname: Thiemann
authors.forename: Garry
authors.initials: G
authors.lastname: Boswell
authors.forename: Dale
authors.initials: D
authors.lastname: Miles
authors.forename: Dong Gyu
authors.initials: DG
authors.lastname: Cho
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Sessler
authors.forename: Richard
authors.initials: R
authors.lastname: Miller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D009369:Neoplasms / Q000378:metabolism; D011166:Porphyrins / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C504033:PCI 2000; C517053:PCI 2050; D011166:Porphyrins; C440448:sapphyrin