Abstract
Abstract At present, most of the anticancer drugs are given parenterally, showing drug concentration above the maximum tolerable concentration (MTC) followed by rapid elimination from the plasma that causes enhanced side effects and lower efficacy. In contrast, low dose oral maintenance therapy may increase therapeutic efficacy by increasing the exposure time to cancer cells and also reduce the side effects by maintaining the drug concentration below MTC level. Pemetrexed is a folate antagonist approved for maintenance chemotherapy in lung cancer. However, a major limitation of Pemetrexed is the poor oral bioavailability which imposes IV administration. In this context, we have developed a physical complex of Pemetrexed with lysine conjugated deoxycholic acid (DCK) in water (mole ratio 1:2) for the purpose of oral delivery. The DSC thermogram of Pemetrexed/DCK complex showed the complex formation due to disappearance of exothermic and endothermic peaks from Pemetrexed. The pharmacokinetic studies of Pemetrexed/DCK were done in SD rats and analyzed by HPLC method. In antitumor study, low dose continuous oral therapy from 2.5 mg/kg to 20 mg/kg showed substantial tumor inhibition in SCC7 tumor bearing C3H mice. We also evaluated maintenance chemotherapy as oral Pemetrexed/DCK administration in A549 tumor bearing nude mice. We found that 5 mg/kg dose of oral Pemetrexed successfully inhibited tumor progression and also showed additional antitumor effects when given with Cisplatin as maintenance chemotherapy. In the context of oral anticancer drugs, we need to consider the toxicities in GI tracts (GIT). For this purpose, apoptosis in GI tracts and morphology of different organs were assessed by TUNEL and H&E staining. One month toxicity studies have been conducted in nude mice and we found that 5 mg/kg oral dose did not produce any abnormalities in hematological and serological parameters in mice having intact morphology of GI tracts. Our studies offer safe and effective oral maintenance chemotherapy of pemetrexed for cancer patients at home. Citation Format: Foyez Mahmud, Seho Kweon, Hyo Won Chang, Hae Yoon Nam, Mi Ra Kim, Jung Je Park, Sang Yoon Kim, Youngro Byun. Metronomic maintenance chemotherapy of orally active pemetrexed for effective treatment of lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4390. doi:10.1158/1538-7445.AM2015-4390
Published Version
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