This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pan, C. Articles by Bebbington, C. R. Search for Related Content PubMed PubMed Citation Articles by Pan, C. Articles by Bebbington, C. R.

CD10 Is a Key Enzyme Involved in the Activation of Tumor-activated Peptide Prodrug CPI-0004Na and Novel Analogues: Implications for the Design of Novel Peptide Prodrugs for the Therapy of CD10⁺ Tumors

Corixa Corp., South San Francisco, California 94080

Traditional chemotherapeutic drugs are often restricted by severe side effects and lack of tumor specificity. Peptide prodrugs cleavable by peptidases present in the tumor environment have been explored to improve the therapeutic index of cytotoxic drugs. One such prodrug of doxorubicin (Dox), CPI-0004Na [N-succinyl-ß-alanyl-L-leucyl-L-alanyl-L-leucyl-Dox (sALAL-Dox)] has been shown to have an improved antitumor efficacy profile with reduced toxicity compared with Dox in tumor xenograft models (V. Dubois et al., Cancer Res., 62: 2327–2331, 2002). In this study, we demonstrate that CD10, a cell surface metalloprotease expressed on a variety of tumor cell types, is capable of cleaving CPI-0004Na and related peptide prodrugs such as N-succinyl-ß-alanyl-L-isoleucyl-L-alanyl-L-leucyl-Dox (sAIAL-Dox). This proteolytic cleavage generates leucyl-Dox, which is capable of entering cells and generating intracellular Dox. In a [³H]thymidine proliferation assay, analogues of CPI-0004Na showed a 100–300-fold increase in potency on CD10⁺ cells compared with CD10^- cells. Cytotoxicity of CPI-0004Na was inhibited by phosphoramidon, a known inhibitor of CD10 enzymatic activity. Furthermore, Chinese hamster ovary CHO-S cells, which are resistant to CPI-0004Na, could be sensitized to the cytotoxic effect of the prodrug by transfection of a CD10 cDNA. Tumor xenograft studies using LNCaP prostate tumor cells support the important role of CD10 in the antitumor efficacy of these prodrugs against tumors expressing CD10. CPI-0004Na and sAIAL-Dox achieved statistically significant 70% tumor growth inhibition at day 22. CD10 is expressed on many types of human tumors including B-cell lymphoma, leukemia, and prostate, breast, colorectal, and lung carcinomas; therefore, CD10-cleavable prodrugs may be effective in a range of different tumor types.

This article has been cited by other articles:

				A. Fleischmann, T. Schlomm, H. Huland, J. Kollermann, P. Simon, M. Mirlacher, G. Salomon, F. H.K. Chun, T. Steuber, R. Simon, et al. Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients Clin. Cancer Res., December 1, 2008; 14(23): 7838 - 7842. [Abstract] [Full Text] [PDF]

				D. Ravel, V. Dubois, J. Quinonero, F. Meyer-Losic, J. Delord, P. Rochaix, C. Nicolazzi, F. Ribes, C. Mazerolles, E. Assouly, et al. Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin Clin. Cancer Res., February 15, 2008; 14(4): 1258 - 1265. [Abstract] [Full Text] [PDF]

				W.-B. Huang, X.-J. Zhou, J.-Y. Chen, L.-H. Zhang, K. Meng, H.-H. Ma, and Z.-F. Lu CD10-positive Stromal Cells in Gastric Carcinoma: Correlation with Invasion and Metastasis Jpn. J. Clin. Oncol., May 1, 2005; 35(5): 245 - 250. [Abstract] [Full Text] [PDF]

				C. F. Albright, N. Graciani, W. Han, E. Yue, R. Stein, Z. Lai, M. Diamond, R. Dowling, L. Grimminger, S.-Y. Zhang, et al. Matrix metalloproteinase-activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity Mol. Cancer Ther., May 1, 2005; 4(5): 751 - 760. [Abstract] [Full Text] [PDF]