Induced Phenotype Targeted Therapy to Overcome Tumor Heterogeneity

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In a study reported in the Journal of the National Cancer Institute, Lee and colleagues designed a caspase-3–specific activated prodrug containing doxorubicin linked to a peptide moiety (DEVD-S-DOX), which is cleaved by caspase-3 at apoptosis. Apoptosis was induced in C3H/HeN mammary tumor-bearing mice via gamma knife radiation.

A single radiation exposure induced apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3, which cleaved DEVD and activated the prodrug. The released doxorubicin further activated DEVD-S-DOX via cytotoxic effects on neighboring tumor or supporting cells, resulting in repetitively induced expression of caspase-3, activation of DEVD-S-DOX, and induction of apoptosis. Tumor growth was significantly reduced vs radiation alone (848 vs 2,511 mm3 at 14 days), and the treatment was associated with low toxicity to normal cells and tissues.

The investigators concluded:

Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects. ■

Lee BS, et al: J Natl Cancer Inst 107(2):dju403, 2015.




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