Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse.

PURPOSE: Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated. METHODS: Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay. RESULTS: TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner. CONCLUSIONS: A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.

Duodenal lymphangitis carcinomatosa: endoscopic characteristics and clinical significance.

BACKGROUND AND AIM: Duodenal lymphangitis carcinomatosa has been sporadically described, but so far little attention has been paid to duodenal lymphangitis carcinomatosa. METHODS: Four cases with duodenal lymphangitis carcinomatosa were endoscopically and histologically examined. RESULTS: The four cases exhibited multiple polypoid lesions along the Kerckring's folds and/or were covered by characteristically granular, non-ulcerated mucosa upon thickening. The granularity seems to been caused by dilated lymph vessels containing the carcinoma cells. The lesions were microscopically characterized by: (i) involvement of lymph vessels located in the upper portion of the lamina propria; (ii) no inflammatory changes; and (iii) no desmoplastic changes. Primary sites were thought to be the stomach in case 1, the pancreas in cases 2 and 4, and unknown in case 3. All patients died within 6 months after admission or endoscopic examination. CONCLUSIONS: As duodenal lymphangitis carcinomatosis shows characteristic endoscopic appearance, endoscopic diagnosis is not difficult. We should realize that the lesion represents extremely poor prognosis, and it should be distinguished from ordinary metastatic duodenal carcinoma.