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Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides

Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel

Requests for reprints: Yechiel Shai, Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972-8-9342711; Fax: 972-8-9344112; E-mail: Yechiel.Shai{at}weizmann.ac.il.

Key Words: antimicrobial peptide • host defense peptide • lytic peptide

Previously, we reported that intratumor or systemic inoculation of a cationic 15-mer, innate immunity-like lytic peptide composed of D- and L-amino acids ([D]-K₆L₉) caused growth arrest of 22RV1 prostate carcinoma xenografts in a mouse model. However, despite its therapeutic potential, this peptide has significant systemic toxicity at concentrations slightly higher than the therapeutic one. Here, we used the acidic environment created by solid tumors as a trigger to activate anticancer lytic peptides by making them cationic only at low pH levels. We achieved this selectivity by substituting lysines (pKa, 10.5) for histidines (pKa, 6.1) in the parental peptide [D]-K₆L₉. Histidine is protonated below pH 7. For that purpose, we replaced either three or all six lysines in the parental peptide with histidines to obtain the peptides [D]-K₃H₃L₉ and [D]-H₆L₉. Interestingly, in vitro experiments showed pH-dependent activity only with [D]-H₆L₉ mainly toward cancer cell lines. However, both peptides showed reduced systemic toxicity compared with the parental peptide. Intratumor and systemic inoculation of these peptides resulted in a significant decrease in the 22RV1 prostate cancer tumor volume and systemic secretion of prostate-specific antigen in a xenograft mice model. Moreover, histologic modifications revealed a significant reduction in new blood vessels selectively in tumor tissues after treatment with the peptides compared with the untreated tumors. The lytic mode of action of these new peptides, which makes it difficult for the cancer cells to develop resistance, and their selective and pH-dependent activity make them potential candidates for treatment of solid cancer tumors. [Cancer Res 2009;69(8):3458–63]