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-beta-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-beta-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 [(3)H]
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.