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Int J Cancer. 2017 Nov 1;141(9):1912-1920. doi: 10.1002/ijc.30842. Epub 2017 Aug 2.

Radiotherapy-assisted tumor selective metronomic oral chemotherapy.

Author information

1
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
2
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, South Korea.
3
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea.
4
Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
5
Pharosgen Co, Seoul, South Korea.
6
Department of Biochemistry and Molecular Biology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.
7
KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea.

Abstract

Chemotherapy have commonly been used in maximum tolerated dose to completely eradicate the cancer. However, such treatments often failed due to the complex and dynamic nature of cancer. Therefore, it has been suggested that cancer should be treated as a chronic disease, controlling its growth by providing continuous therapeutic pressure for long-term. Such an approach, however, requires a therapy that is non-toxic and orally available with sufficient potency. Herein, we propose a radiotherapy-assisted orally available metronomic apoptosis-targeted chemotherapy, which delivers doxorubicin continuously to the irradiated tumor with high selectivity while causing minimal toxicities to the normal tissues. DEVD-S-DOX/DCK complex is the anticancer prodrug for our strategy that could selectively release doxorubicin in the irradiated tumor tissue with sufficient oral bioavailability. The prodrug was completely inactive by itself, but displayed potent anticancer activity when coupled with radiotherapy. Consequently, the daily oral administration of DEVD-S-DOX/DCK in combination with the low-dose radiotherapy effectively suppressed the growth of tumor in vivo with no significant systemic toxicities despite that the accumulated dose of doxorubicin exceeded 150 mg/kg. Therefore, the our novel therapy using DEVD-S-DOX/DCK complex is considered as an outstanding treatment option for treating cancer for long-term attributed to its oral availability and low-toxicity profile as well as the potent anticancer effect.

KEYWORDS:

drug delivery system; metronomic therapy; oral chemotherapy; radiation-induced apoptosis-targeted chemotherapy; targeted therapy

PMID:
28635011
DOI:
10.1002/ijc.30842
[Indexed for MEDLINE]
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