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Research Articles: Therapeutics, Targets, and Development

Tumor localization and antitumor efficacy of novel sapphyrin compounds

¹ Pharmacyclics, Inc., Sunnyvale, California and ² Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas

Requests for reprints: Louie Naumovski, Cancer Biology, Pharmacyclics, Inc., 995 East Arques Avenue, Sunnyvale, CA 94085. Phone: 650-400-0015; Fax: 408-328-3689. E-mail: lnaumovski{at}pcyc.com

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. [Mol Cancer Ther 2006;5(11):2798–805]

Grant support: NIH grant GM0588907 (J.L. Sessler) and funds from the Texas TD & T program.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ D. Magda, in preparation.

⁴ Unpublished observations.

Received 5/ 4/06; revised 8/16/06; accepted 9/25/06.