Stomach- and Site-Selective Delivery of 5-Fluorouracil Following Its Application on the Gastric Serosal Surface in Rats

Abstract

Advanced gastric cancer with serosal invasion is usually unresectable, so anticancer drugs are infused intravenously as a palliative treatment; however, patients with unresectable gastric cancer die within a few months after exploration, with or without palliative surgery. 5-Fluorouracil (5-FU) is the cornerstone chemotherapy regimen for gastric cancer, having mild to moderate toxicity and response rate.1) However, the activity of single agents, including 5-FU, against gastric cancer is approximately 20% or less.2) To improve the therapeutic effect of anticancer drugs on gastric cancer, intraarterial administration has been studied. 3,4) When the anticancer drugs are administered via the vasculature route, however, they are distributed through the whole body via the blood stream, leading to inadequate delivery to target sites in the stomach, as well as potential toxicity in other organs. These circumstances underscore the need for novel and more effective strategies for the treatment of gastric cancer.Thus, stomach-and site-selective drug delivery is a very important strategy for the optimization of chemotherapy in terms of efficacy and safety. We originally elucidated that phenol red, bromphenol blue, and bromosulphonphthalein as model drugs are adequately absorbed from the gastric serosal surface and accumulate site-selectively in the stomach in rats. 5,6) Although the gastric serosal surface application of anticancer drugs holds promise for site-selective delivery in the stomach, little is known about the gastric and systemic distribution characteristics of anticancer drugs following application on the gastric serosal surface. In the present study, we examined the detailed absorption and distribution characteristics of 5-FU following application on the gastric serosal surface for the site-selective delivery of 5-FU in the stomach in rats. MATERIALS AND METHODSChemicals 5-FU was purchased from Nacalai Tesque, Inc. (Kyoto, Japan). All other chemicals were of reagent grade.Absorption and Distribution Experiments All experiments in the present study were carried out in accordance with the Guidelines for Animal Experimentation of Nagasaki University. Male Wistar rats (250-270 g) were anesthetized with sodium pentobarbital (50 mg/kg i.p.). After the peritoneum was dissected about 5 cm, a cylindrical diffusion cell (i.d. 9 mm, effective area 0.64 cm 2 ) was attached to the gastric serosal surface with surgical adhesive (Aron Alpha A, Sankyo Co. Ltd., Tokyo, Japan), and 5-FU (0.2, 2, and 10 mg/mlϫ0.5 ml, isotonic phosphate-buffered saline, pH 7.4) was added directly to the cylindrical diffusion cell (Chart 1). The body temperature of the rats was maintained at 37°C with a heat lamp during the experiment. As a control experiment, 5-FU (10 mg/mlϫ0.5 ml, isotonic phosphatebuffered saline, pH 7.4) was administered intravenously using a syringe with a needle (26Gϫ1/2Љ) and orally by gastric intubation. After application on the gastric serosal surface, the solution in the diffusion cell and the blood was sampled at appropr...

Highly stomach-selective gene transfer following gastric serosal surface instillation of naked plasmid DNA in rats

“…In fact, transgene expression was not observed in the stomach following oral administration with nanoparticles-in-microsphere in rats. 17 We previously developed a method to apply drugs onto the surface of intraperitoneal organs such as the liver , 18 kidney 19 and stomach, [20][21][22] and found it to be a useful method for site-selective drug delivery to these organs. Furthermore, we reported on site-selective gene expression following instillation of naked pDNA onto the liver surface, 23 kidney surface 24 and gastric serosal surface 25 in mice.…”

Effect of Metabolic Inhibitors on the Hepatic Disposition of 5-Fluorouracil after Application to the Rat Liver Surface

“…19,20) We have also investigated other organs as an administration route of 5-FU. 21,22) Although viscous additives to 5-FU solution improved site-selective accumulation of 5-FU, 23) the increase in 5-FU concentration at the application site was not large enough.5-FU has been widely used in chemotherapy regimens against a variety of cancers such as liver, 24) colon, 25) stomach 26) and pancreatic cancer. 27) However, approximately 85% of administered 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD).…”

“…19,20) We have also investigated other organs as an administration route of 5-FU. 21,22) Although viscous additives to 5-FU solution improved site-selective accumulation of 5-FU, 23) the increase in 5-FU concentration at the application site was not large enough.…”

Spleen-Selective Gene Transfer Following the Administration of Naked Plasmid DNA onto the Spleen Surface in Mice

“…We previously developed a method for the application of drugs onto the surface of the intraperitoneal organs such as the liver, [14][15][16][17][18][19][20][21][22][23][24] kidney, [25][26][27][28][29] and stomach [30][31][32] in rats and found it to be a useful method for site-selective drug delivery to these organs. Furthermore, we reported on site-selective gene expression following the instillation of naked pDNA onto the liver surface [33][34][35][36] and kidney surface 37) in mice.…”