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Effect of combination of TS-1 and low-dose cisplatin on sarcoma-180 mouse sarcoma
Yoshimasa Suzuki1, Yoshiro Ishibiki, Ken Kawai
1Department of Coloproctological Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Abstract:
TS-1 contains tegaful (FT), 5-chloro-2,4-dihydroxypyridine (CDHP; an inhibitor of 5-fluorouracil (5-FU) degradation) and potassium oxonate (Oxo; an inhibitor of 5-FU assimilation mainly in the digestive tract) in a molar ratio of 1:0.4:1. We evaluated the combination of TS-1 and low-dose cisplatin on mouse sarcoma. Male ddy strain mice at 6 weeks of age were s.c. transplanted with 5 x 106 sarcoma-180 (S-1800) cells and divided into groups of seven animals each: Group A, no treatment; Group B, 5-FU alone by continuous i.p. infusion of 10 mg/kg with a minipump (Alzet); Group C, TS-1 10 mg/kg p.o. alone; Group D, cisplatin 0.2 mg/kg i.p. alone; Group E, B+D; Group F, C+D. Treatment was given for 5 days. Antitumor activity was evaluated on the basis of the tumor weight on day 8, and white blood cell count, red blood cell count, platelet count, BUN, GOT and GPT were determined to detect adverse effects. Tumor weights (g, mean+/-SD) were 0.54+/-0.15 in Group A, 0.52+/-0.17 in Group B, 0.34+/-0.05 in Group C, 0.46+/-0.12 in Group D, 0.34+/-0.07 in Group E and 0.16+/-0.03 in Group F. There were no noticeable adverse effects. The combined TS-1+cisplatin regimen showed considerably enhanced antitumor activities since sarcomas were significantly (p<0.05) decreased as compared with tissue. Mean AUC(0-12) (ng/ml.h) estimated in the groups receiving 5-FU+cisplatin or TS-1 alone was measured to calculate AUC(0-12) by the trapezoidal rule. 5-FU concentrations in blood and tumor from blood concentration data were 435 in Group B, 2651 in Group C, 343 in Group E and 1538 in Group F, while mean AUC(0-12) (ng/g.h) estimated from tumor tissue concentration data were 345 in Group B, 3548 in Group C, 324 in Group E and 2020 in Group F. Cisplatin acted as a modulator of 5-FU, suggesting clinical benefits of the combination of TS-1 and low-dose daily cisplatin.
Insights
The combination of TS-1 (tegaful, CDHP, and potassium oxonate) with low-dose cisplatin significantly enhanced antitumor activity against mouse sarcoma. This novel combination therapy demonstrated improved efficacy with no noticeable adverse effects, suggesting potential clinical benefits.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- TS-1 is an oral anticancer drug composed of tegaful (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo).
- CDHP inhibits 5-fluorouracil (5-FU) degradation, while Oxo inhibits its assimilation in the digestive tract.
- Low-dose cisplatin is being investigated as a potential modulator for chemotherapy.
Purpose of the Study:
- To evaluate the combined antitumor activity of TS-1 and low-dose cisplatin on mouse sarcoma.
- To assess the pharmacokinetic profile and potential synergistic effects of the combination therapy.
- To determine the safety and adverse effects of the combined regimen.
Main Methods:
- Sarcoma-180 cells were implanted in mice, which were then divided into treatment groups.
- Treatments included no treatment, 5-FU alone, TS-1 alone, cisplatin alone, 5-FU + cisplatin, and TS-1 + cisplatin.
- Antitumor activity was assessed by tumor weight, and adverse effects were monitored through blood cell counts and liver/kidney function tests.
Main Results:
- TS-1 alone and TS-1 + cisplatin significantly reduced tumor weight compared to control and 5-FU alone.
- The combination of TS-1 and cisplatin demonstrated the most significant reduction in tumor weight (0.16+/-0.03 g) compared to all other groups (p<0.05).
- Elevated 5-FU concentrations in blood and tumor tissue were observed with TS-1, and cisplatin further modulated these levels, indicating enhanced drug exposure.
Conclusions:
- The combination of TS-1 and low-dose cisplatin exhibits significantly enhanced antitumor activity against mouse sarcoma.
- Cisplatin acts as a modulator, increasing the efficacy of 5-FU delivered via TS-1.
- This combination therapy holds promise for clinical application due to its enhanced efficacy and lack of significant adverse effects.