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Tsukuba, Japan

Nukatsuka M.,Tokushima Research Center | Saito H.,Optimal Medication Research Laboratory | Sakamoto K.,Tsukuba Research Center | Nakagawa F.,Optimal Medication Research Laboratory | And 3 more authors.
Anticancer Research | Year: 2012

Oxaliplatin is effective when used with 5-fluorouracil (5-FU) and leucovorin, or with capecitabine (COX) for the treatment of colorectal cancer. In this experiment, we investigated the optimal combination schedule and antitumor activity of oral S-1 with oxaliplatin combination therapy (SOX) against human colorectal cancer xenografts in vivo. Using human colon cancer COL-1-bearing nude mice, oxaliplatin was administered at a total dose of 8.3 mg/kg on day 1 alone, on day 8 alone, or in divided doses administered on days 1 and 8 with S-1 (6.9 mg/kg, days 1-14). The antitumor activity of SOX, administered according to the divided schedule was significantly superior to both monotherapies (p<0.01), and the toxicity was tolerable. However, administration on day 8 alone failed to significantly increase the antitumor activity, when compared with that of monotherapy, while administration on day 1 alone was toxic in this model. Next, the efficacy of SOX was compared with that of COX (360 mg/kg, days 1-14). The antitumor effect of SOX was significantly superior to that of COX (p<0.01), with an equivalent toxicity; moreover SOX suppressed COL-1 tumor growth for a longer period of time (2.2 times) than did COX. The antitumor activity of SOX against the 5-FU-resistant colorectal cancer cell line KM12C/5-FU was equivalent to that of COX. The evaluation of intermittent SOX administration in a clinical trial might be of critical value. Source

Takasu T.,Tsukuba Research Center | Hayashizaki Y.,Tsukuba Research Center | Tahara A.,Tsukuba Research Center | Kurosaki E.,Tsukuba Research Center | Takakura S.,Tsukuba Research Center
Clinical and Experimental Pharmacology and Physiology | Year: 2015

Summary: Inhibition of sodium-glucose cotransporter 2 is a novel strategy for glycemic control in type 2 diabetes mellitus patients. As the mechanism of action of sodium-glucose cotransporter 2 inhibitors on plasma glucose levels is distinct from that of existing oral antidiabetic drugs, a combination of the two might provide a therapeutic benefit. Here, we investigated the antihyperglycemic effect of ipragliflozin, a selective sodium-glucose cotransporter 2 inhibitor, alone or in combination with oral antidiabetic drugs in a range of relevant mouse models to analyse the blood glucose-lowering properties of different drug types based on their mechanism of action. Oral glucose tolerance tests in ICR mice were used to evaluate the effect of ipragliflozin in combination with the insulin secretagogues, glibenclamide or nateglinide. Liquid meal tests in ICR mice and diabetic KK-Ay mice were used to investigate the combined effect of ipragliflozin with the dipeptidyl peptidase-4 inhibitor, sitagliptin, and α-glucosidase inhibitor, voglibose, respectively. Four-week repeated administration tests in KK-Ay mice were used to examine the combined effect of ipragliflozin with the insulin sensitizers, pioglitazone and metformin. In all mouse models tested, the combination of ipragliflozin and existing oral antidiabetic drugs lowered blood glucose or glycated hemoglobin levels more than either monotherapy. In conclusion, inhibition of sodium-glucose cotransporter 2 by ipragliflozin, alone or in combination with existing oral antidiabetic drugs, has a robust effect on blood glucose levels in a range of mouse models of hyperglycemia. © 2014 Wiley Publishing Asia Pty Ltd. Source

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