期刊
CLINICAL CANCER RESEARCH
卷 15, 期 1, 页码 131-139出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-08-1691
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资金
- NIH [RO1 CA90696, RO1 CA102792-06]
- Department of Defense [W81XWH-04-1-0164, W81XWH-08-1-0344, W81XWH-05-1-0258]
- NATIONAL CANCER INSTITUTE [R01CA090696, R01CA102792, P30CA142543] Funding Source: NIH RePORTER
Purpose: beta-Lapachone (ARQ 501, a formulation of [A-lapachone complexed with hydroxypropyl-beta-cyclodextrin) is a novel anticancer agent with selectivity against prostate cancer cells overexpressing the NAD(P)H:quinone oxidoreductase-1 enzyme. Lack of solubility and an efficient drug delivery strategy limits this compound in clinical applications. In this study, we aimed to develop beta-lapachone-containing polymer implants (millirods) for direct implantation into prostate tumors to test the hypothesis that the combination of a tumor-specific anticancer agent with site-specific release of the agent will lead to significant antitumor efficacy. Experimental Design: Survival assays in vitro were used to test the killing effect of p-lapachone in different prostate cancer cells. beta-Lapachone release kinetics from millirods was determined in vitro and in vivo. PC-3 prostate tumor xenografts in athymic nude mice were used for antitumor efficacy studies in vivo. Results: beta-Lapachone killed three different prostate cancer cell lines in an NAD(P)H:quinone oxidoreductase-1-dependent manner. Upon incorporation of solid-state inclusion complexes of beta-lapachone with hydroxypropyl-beta-cyclodextrin into poly (D, L-lactide-co-glycolide) millirods, beta-lapachone release kinetics in vivo showed a burst release of similar to 0.5 mg within 12 hours and a subsequently sustained release of the drug (similar to 0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by beta-lapachone millirods compared with controls (P < 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with beta-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity. Conclusions: Intratumoral delivery of beta-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors.
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