Oral pemetrexed facilitates low-dose metronomic therapy and enhances antitumor efficacy in lung cancer
| Autor: | Jeong Uk Choi, Sojung Lee, Dong Soo Lee, Jooho Park, Youngro Byun, Ok-Cheol Jeon, Farzana Alam, Jin Woo Park, Foyez Mahmud, Ruby Maharjan |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Drug Lung Neoplasms media_common.quotation_subject Administration Oral Mice Nude Pharmaceutical Science Antineoplastic Agents Apoptosis Pemetrexed Pharmacology Bile Acids and Salts Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Oral administration Animals Humans Medicine Lung cancer Cell Proliferation media_common Cisplatin Mice Inbred BALB C Neovascularization Pathologic business.industry medicine.disease Metronomic Chemotherapy stomatognathic diseases 030104 developmental biology A549 Cells 030220 oncology & carcinogenesis Administration Metronomic Toxicity Caco-2 Cells Pharmaceutical Vehicles business medicine.drug |
| Zdroj: | Journal of Controlled Release. 284:160-170 |
| ISSN: | 0168-3659 |
| DOI: | 10.1016/j.jconrel.2018.06.018 |
| Popis: | There is a growing interest in preclinical research to consider low-dose metronomic chemotherapy as antiangiogenic cancer treatment. Oral metronomic therapy, in particular, has shown much promise with its ease of daily administration and higher therapeutics window. In that regard, we developed oral pemetrexed using the physical complex with the bile acid enhancers (DCK). In a caco-2 permeability study, the oral pemetrexed/DCK complex had significantly higher drug uptake, and inhibited efflux transporter activity as well. We further observed that the mechanism of oral drug uptake was related to transcellular along with bile acid transporter mediated pathways. The oral administration of drug complex in rats revealed high bioavailability (22.37%) and extended mean residence time. Using SCC7 and A549 xenograft models, we demonstrated that antitumor effects from daily oral metronomic pemetrexed significantly reduced tumor in a dose-dependent manner. The antitumor activity of oral pemetrexed/DCK complex plus cisplatin was superior to both monotherapies. The xenograft study also revealed that oral metronomic therapy markedly reduced microvessel density, proliferation and increased apoptosis in the tumor tissues. Oral metronomic doses were significantly correlated with the elevation of plasma deoxyuridine level, an essential biomarker for pemetrexed therapy. One-month toxicity study confirmed that daily dosing of oral pemetrexed is safe by investigating apoptosis in the gut tissues from mice. Moreover, we analyzed different biochemical parameters and enzymes from the blood to prove that our newly developed oral pemetrexed complex is well tolerated. |
| Databáze: | OpenAIRE |
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