Journal
CANCER
Volume 118, Issue 11, Pages 2986-2996Publisher
WILEY
DOI: 10.1002/cncr.26596
Keywords
cathepsin B; gastric cancer; peritoneal carcinomatosis; Doxorubicin; prodrug
Categories
Funding
- National Natural Science Foundation of China [20621502, 20921062]
- State Key Project on Innovative Drug Development [2009ZX09301]
- National University Students Innovation Training Project of China [101048639]
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BACKGROUND: Doxorubicin (Adriamycin) is effective in gastric cancer treatment, but with severe dose-dependent toxicities. A novel prodrug of doxorubicin (Ac-Phe-Lys-PABC-ADM) is designed to deliver free doxorubicin relying on cathepsin B and reduce side effects. The authors examined the antitumor effect and toxicities of Ac-Phe-Lys-PABC-ADM against gastric cancer peritoneal carcinomatosis. METHODS: SGC-7901 gastric cancer cell line was used for the study. The in vitro study investigated the effects of doxorubicin and Ac-Phe-Lys-PABC-ADM on cell growth dynamics and cell cycle. The in vivo study investigated the efficacy and toxicity of Ac-Phe-Lys-PABC-ADM on a nude mice model of peritoneal carcinomatosis, with doxorubicin as positive control. RESULTS: In the in vitro study, Ac-Phe-Lys-PABC-ADM had a lower dose-dependent inhibitory effect on SGC-7901 cells. In the in vivo study of control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups, the median experimental peritoneal carcinomatosis indexes were 6, 1.5, and 1, respectively (P = .004); the body weights were 24.32 +/- 1.40 g, 18.40 +/- 2.97 g, and 23.61 +/- 0.80 g, respectively (P = .000). Biochemical studies showed that Ac-Phe-Lys-PABC-ADM had significantly lower toxicities on the bone marrow, liver, kidney, and particularly heart. Histopathological studies of the control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups found significant myocardium toxicities in 3, 7, and 4 animals, respectively. CONCLUSIONS: Ac-Phe-Lys-PABC-ADM could be an effective molecular targeting drug to treat gastric cancer peritoneal carcinomatosis with enhanced efficacy and reduced toxicity. Cancer 2011. (c) 2011 American Cancer Society.
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