5-FU concentration in tumor tissue and the antitumor effect in patients with gastric cancer after oral administration of UFT

Serum and tumor tissue concentration of FT, 5-FU and uracil were measured in 23 patients with gastric cancer who were administered UFT preoperatively. The degeneration of cancer cells was evaluated histologically and the correlation between 5-FU concentration in the tumor tissue and the antitumor effect was assessed. The average concentration of 5-FU in tumor tissue (0.122 microgram/g) was significantly higher than that in normal gastric tissues. Serum 5-FU concentration was very low, suggesting no accumulation of 5-FU in blood. A positive correlation between the concentration of 5-FU and uracil in tumor tissues was found. A 5-FU level higher than 0.05 microgram/g was frequently demonstrated in tumor tissue, resulting in moderate degeneration of cancer cells in many cases. When tumors were classified according to histological type, intratumoral 5-FU concentration was not always correlated with degeneration of cancer cells. The above results suggested that UFT was a very effective drug for stomach cancer because of high tumor affinity for 5-FU, but that it is necessary to consider the sensitivity of tumor cells to antitumor drugs in order to obtain an excellent antitumor effect.     

Level of 5-FU in uterine cervical cancer tissue after oral administration of UFT

We measured concentrations of 5-FU in cancerous and normal cervical tissues in 16 patients with cervical cancer to whom UFT or tegafur had been administered. The results were as follows: Concentrations of 5-FU in cancerous tissues measured 30 minutes and 2 hours after UFT administration were 0.181 +/- 0.034 microgram/g and 0.562 +/- 0.145 micrograms/g respectively, while in patients to whom tegafur had been administered, they were 0.105 +/- 0.030 microgram/g and 0.126 +/- 0.015 microgram/g respectively. The comparison of 5-FU concentrations in cancerous tissues within each individual patient indicated that the value was higher after UFT administration than after tegafur administration in 13 cases (81.3%). When classified by histological typing, cases of non-keratinizing carcinoma showed the highest value, followed by keratinizing cases and adenocarcinomas, which indicated the lowest value with administration of UFT. However, there were no differences among these three types when tegafur was administered. Based on the above findings, it was indicated that UFT is an antitumor agent with a higher tumor specificity, especially in non-keratinizing carcinoma.     

5-FU concentration in blood and tissue of patients with renal cell carcinoma after administration of UFT

UFT (3 capsules; 300mg FT) was administered to five of 10 patients with renal cell carcinoma, and concentrations of FT, 5-FU and uracil in the serum and tissues (normal renal tissues, renal tumor tissues and liver) were determined 5.2 hours on average, after administration. The levels were also compared with these in the five patients administered 300 mg of FT. There was no difference in FT concentration between the serum and the tissues in the group administered UFT, but the concentration of 5-FU in tumor tissues was significantly higher (25.6 times) than that in the serum. The level was also higher (3.2 times) than that in normal renal tissues. There was a positive correlation between the concentration of 5-FU in the tissues and the concentration of uracil in the tissues. Although there was no difference in the concentration of FT between serum and tissues in patients administered UFT or FT, the concentration of 5-FU in patients administered UFT was definitely higher than that in patients administered FT; the concentration of 5-FU in the tumor tissues of patients given UFT was 3.9 times higher than in those given FT. Thus, UFT induced a concentration of 5-FU in tumor tissues that was maintained at a high level, suggesting that an excellent antitumor effect on renal cell carcinoma can be expected with UFT.     

5-FU concentration in the blood and tissue of patients with gastric and colorectal cancer after administration of UFT or tegafur

UFT or tegafur (5, 7.5 and 15 mg/kg, respectively) were given to Donryu rats with AH-130 cancer twice a day for 3 days, and 5-FU concentrations in the blood, tumor, normal stomach and large bowel tissues were measured by chemical assay and compared. The 5-FU concentrations in the tumor were higher than those of normal tissues and still remained 12 hours after the final dosage. According to increased UFT dosage, there were significantly higher levels of 5-FU concentration in tumor tissues but blood levels of 5-FU were low. The peak of concentration occurred at one to two hours after the final dosage. However, increase in tegafur dosage volume did not correlate with 5-FU levels. Clinical cases (74 patients) of gastric and colorectal cancer were orally administered UFT or tegafur at 300 mg twice a day for 3 days preoperatively. Materials were obtained at surgery at 5.5 hours on average after the final dosage and 5-FU levels in tissues were measured by chemical assay. Concentrations of 5-FU in cancerous tissues after UFT administration were 0.177 +/- 0.131 micrograms/g in gastric cancer and 0.130 +/- 0.051 micrograms/g in colorectal cancer, while in patients to whom tegafur had been administered, the concentrations were 0.194 +/- 0.124 micrograms/g and 0.119 +/- 0.075 micrograms/g, respectively. There was no significant difference in 5-FU levels between the UFT-administered group and the tegafur group.     

5-FU, FT-207 and uracil concentrations in the serum and tissues of patients with cervical cancer after UFT oral administration

The concentrations of 5-FU, FT-207 and uracil were estimated in blood serum, cancer tissue and normal tissue of patients with uterine cervical cancer. A daily dose of 600 mg of UFT was administrated for 7 days to cervical cancer patients, and they received radical hysterectomy and pelvic lymphadenectomy. After single administration of UFT, the serum concentration of 5-FU was highest at 60 minutes (0.094 micrograms/ml) and became reduced with time. On the other hand, when UFT was administered for 7 consecutive days, the serum concentration of 5-FU was found to reach a plateau between 60 minutes (0.215 micrograms/ml) and 120 minutes (0.222 micrograms/ml) with gradual decline thereafter. Significantly higher levels of 5-FU were achieved at 60 min. and 120 min. and apparent accumulation of 5-FU in serum was observed following continuous administration of UFT. Similar results were observed regarding the change of serum concentration of uracil, while FT-207 was observed to remain in serum for a longer time than 5-FU. In the uterine cervix, the concentration of 5-FU cancer tissue was 0.087 micrograms/ml, approximately 3 times that of normal tissue, and approximately 5.1 times that of the preoperative serum concentration of 5-FU, indicating a tendency to accumulate in cancer tissue. Although a higher concentration of 5-FU was detected in pelvic lymph nodes and ovaries, no significant differences were recognized between metastatic nodes and metastasis-free nodes.     

5-FU concentration in the tissues (tumor and lymph node) of breast cancer patients given preoperative administration of UFT and FT

In 16 patients with breast cancer who were administered UFT or FT-207 (UFT: 9 cases, FT-207: 7 cases) for a were prior to surgery, we studied the concentrations of 5-FU in the blood and tumor tissues, and in normal and metastatic lymph nodes sampled during surgery. As a result, a high level of 5-FU was found in tumors, especially in metastatic lymph nodes, in the patients who were administered UFT. On the other hand, no significant difference was found between the 5-FU levels of blood in UFT- and FT-treated patients. These facts suggest that UFT can be expected to increase antitumor activity without side effects, especially in cases of metastatic lymph nodes.     

Serum concentration of HCFU and 5-FU after oral administration of HCFU in postoperative digestive cancer patients]

In an attempt to establish the optimum dose of HCFU, the effect of the presence of stomach on the absorption of HCFU and both the rise and maintenance of blood HCFU levels was evaluated in patients with gastric cancer (total gastrectomy group) and with colorectal cancer (non-gastrectomy group). The blood concentrations of HCFU fractions and 5-FU were determined in terms of pharmacokinetic parameters in these groups. The Tmax was significantly different between the two groups, with HCFU fraction and 5-FU levels that were significantly higher in the total gastrectomy group 30 minutes after administration. No differences were found in Cmax or AUC. There were no significant differences in Cmax or AUC among the various subgroups given different doses of HCFU (100, 150 and 200 mg) in either group, although dose-dependency was observed. Similar results were obtained in crossover tests. The 5-FU remained at an effective concentration of 0.05 microgram/ml, 4 hours after a single dose of 100 mg HCFU.     

FT, 5-FU and uracil concentrations of the blood, bile and tissue of hepatoma with liver cirrhosis after oral administration of UFT

UFT was orally administered to eight patients with hepatocellular carcinoma (HCC) combined with liver cirrhosis and to five patients with normal liver. The concentrations of FT-207 (FT), 5-FU, and uracil in blood, tissue and bile were then respectively determined. The FT level in cancer tissue and non-cancer tissue was almost identical in patients with HCC. On the other hand, the 5-FU level in normal liver tissue was significantly higher (P less than 0.05) than that in cancer tissue, and the uracil level in normal liver tissue was lower than that in cancer tissue (P less than 0.05). Transportation of FT from blood to liver was significantly correlated with clearance of indocyanine green from the blood (ICGK). These results suggested that transportation of FT from blood to liver and activation of FT were impaired in HCC with liver cirrhosis. However, the 5-FU level in the cancer tissue of HCC tended to be higher than that in non-cancer tissue. The 5-FU level in the tissue had a significant correlation with the FT level in the tissue. In addition, it was presumed that cancer tissue was able to produce 5-FU from FT more quickly than non-cancer tissue.     

Pharmacokinetics of 5-FU after S-1 oral administration for adjuvant chemotherapy in gastric cancer patients

We studied the pharmacokinetics of 5-FU after S-1 oral administration at the usual dose (80 mg/m2) for adjuvant chemotherapy in 13 advanced gastric cancer patients (Stage II, III), and at a decreased dose (60 mg/m2) for adjuvant or combined chemotherapy in 13 advanced gastric cancer patients. Pharmacokinetic parameters of 5-FU in the serum were as follows: Cmax, 159 .9 2+/-45.2 ng/mL, Tmax, 2.17+/-0.58 h;T1/2, 3.13+/-2.88 h; and AUC(0-8), 768.0+/-260.8 ng h/mL in the patients with the usual dose, and Cmax, 117.3+/-55.1 ng/mL; Tmax, 2.62+/-0.9 6 h; T1/2, 3.09+/-1.9 5 h and AUC(0-8), 565.9+/-216.8 ng h/mL in the patients with the decreased dose. No difference in AUC was observed between operative methods. Adverse events of more than grade 3 were recognized in 7 patients, and AUC of 6 patients were more than 800 ng h/mL. The plasma concentration of 5-FU was quite different between patients. The difference of Cmax and AUC was 3-4 times. It was concluded that we must pay attention to individual differences in the plasma concentration of 5-FU in postoperative gastric cancer patients when S-1 would be administered.     

5-Fluorouracil, tegafur, and uracil concentrations in serum and tissue of the patients with hepatocellular carcinoma after UFT administration

UFT is a preparation consisting of tegafur and uracil at the molar ratio 1 : 4. In 22 resected patients with hepatocellular carcinoma (HCC), the concentrations of 5-fluorouracil (5-FU), tegafur and uracil were estimated in the serum, liver and cancer tissues after oral administration of UFT (tegafur, 300mg) before operation. The concentrations of 5-FU, tegafur and uracil in the serum were highest at 2 hours, and reduced thereafter. The maximum 5-FU level was 0.040 +/- 0.034 microgram/ml. The concentrations of 5-FU in the cancer tissue were 0.101 +/- 0.070 microgram/g in all patients, 0.085 +/- 0.050 microgram/g in cirrhotic patients and 0.144 +/- 0.105 microgram/g in non-cirrhotic patients. These concentrations were significantly higher than those in the liver tissue. In 10 out of 13 patients, 5-FU concentrations was higher than 0.056 microgram/g which was reported as minimum effective concentration. Conclusion: the concentration of 5-FU after oral administration of UFT prior to resection of HCC was estimated in the serum, liver and cancer tissues. The concentration of 5-FU in cancer tissues was satisfactorily higher regardless of cirrhotic or non-cirrhotic conditions UFT seemed to be a safe and useful drug since tissue 5-FU concentration was higher than those in the serum and liver.     

A study on UFT concentration in tissues and serum of patients with malignant gynecologic tumors following oral administration

UFT was orally given at a dose of 200 mg twice a day to seven female patients with malignant gynecological tumors. Measurements of blood and tissue concentrations of tegafur (TF), fluorouracil (FU) and uracil (U) showed that the concentrations of both FU and U were clearly increased. The ratio of concentration in the tumor to that in peripheral blood was 9.3, while that of the concentration in the internal iliac lymph nodes to that in the internal iliac artery was 11.2. The changes in blood levels of the three compounds were determined one and five days after UFT administration. There was a distinct difference in the blood levels of the drug among TF, FU and U. TF reached its peak concentration two hours after breakfast and four hours after supper; both FU and U reached their peak concentrations two hours after breakfast and one hour after supper. Furthermore, TF showed a tendency to accumulate after continuous administration, but this was not the case with FU or U. These findings suggest that even during continuous administration, the blood level of FU remains low.     

Antitumor effect of UFT on human ovarian cancer grafted to nude mice and 5-FU concentration in tumor and normal tissues

Antitumor effects of UFT, tegafur (FT-207), cisplatin (CDDP) and the combination of UFT with CDDP on a human ovarian cancer xenograft in nude mice and the concentration of 5-FU in the tumor tissue and major organs were studied. UFT (48.6mg/kg/day X 20) or tegafur (15.0mg/kg/day X 20) was daily administrated orally, and CDDP (5mg/kg/day X 3) was administrated intraperitoneally at an 7-day interval. The inhibition rates of the tumor growths were 49.6% with UFT, -2.3% with tegafur and 17.7% with CDDP, respectively. In the combination of UFT with CDDP, severe side effect were observed. The concentration of 5-FU in UFT-treated group was higher than tegafur group: about 2 times in the tumor, 5 times in the liver, 9 times in the kidney and 4 times in the spleen, respectively. In the combination of UFT with CDDP, the concentration of 5-FU in major organs, especially in the kidney, in nude mice that died at 10 day after drug administration were higher than in those of UFT. These findings indicate that UFT increases the intratumoral concentration of 5-FU to elicit better antitumor effect and also the concentration of 5-FU in various normal organs after long time administration.     

Single drug chemotherapy with 5-FU oral administration of bladder cancer

58-year-old male with bladder cancer complicated acute myocardial infarction (aMI) were treated by 5-FU 300 mg/day orally for approximately one and a half months as single drug chemotherapy preoperatively. CT studies showed PR in bladder lesion and an improvement of bilateral hydronephrosis also. Biochemical evaluations as Thymidylate synthase inhibition and FdUMP were made on biopsy and operative specimens of urinary bladder. Clinical trials with 5-FU oral administration in bladder cancer were not held widely. Although its effectiveness and safety has been accepted in several fields. It was useful for a conservative operation case as single drug chemotherapy.     

Studies on 5-FU concentration and thymidine phosphorylase activity in tissues of patients with colorectal cancer after SF-SP administration

5-fluorouracil (5-FU) concentrations in peripheral blood, portal blood, normal and cancer tissues were evaluated in 26 patients with colorectal cancer after SF-SP administration (800 mg/day for 10 days). Thymidine phosphorylase activity in cancer tissues was also evaluated. 5-FU concentration in cancer tissues was significantly higher than that in other three specimens, and much higher than 0.05 microgram/g which was reported to be the minimum effective concentration. 5-FU concentration in portal blood was lower than MEC (0.05 microgram/ml). As for the relationship with the pathological features of cancer, the protruding lesions showed a higher 5-FU concentration than the ulcerative ones, and the lesions invaded only to submucosa or proper muscle showed a higher concentration than others. 5-FU concentration ratio in cancer tissues per in peripheral blood (T/B ratio) was related to thymidine phosphorylase activity. The higher was the thymidine phosphorylase activity, the greater T/B ratio. The results suggest that the tumor with higher thymidine phosphorylase activity might have a more pronounced anticancer efficacy of 5-FU.     

Level of 5-FU in cancerous and normal tissues of nude mice after oral administration of tegafur coadministered with uracil (UFT)

In order to investigate the effect of UFT, a new antitumor agent, 5-fluorouracil (5-FU) levels in serum and various tissues were measured by the gas chromatographic-mass fragmentographic method. The subjects used for the study were nude mice which had received implants of human endometrial carcinoma. The results were as follows: As compared with tegafur, the concentration of 5-FU in serum rose quickly when UFT was administered, and the values were clearly high. The concentration of 5-FU obtained in tumor tissues with the use of UFT were 2.5 times higher than those obtained by the use of tegafur. Even with one third of the dose of UFT, values were still 1.5 times higher. In normal tissues, the administration of UFT against that of tegafur resulted in higher concentrations of 5-FU. On the other hand, when one third of the dose of UFT was used, 5-FU concentrations in major organs, such as the liver or kidney, showed clearly low values. Based on these findings, it became clear that the 5-FU concentration in tumor tissue is specifically raised by tegafur coadministered with Uracil (UFT), while such an effect is prevented from proceeding in normal tissue.     

Comparison of pharmacokinetics of 5-FU and alpha-fluoro-beta-alanine, a metabolite of 5-FU, in plasma after administration of UFT, tegafur, 5-FU or doxifluridine to rats

Toxic effects (neurotoxicity and cardiotoxicity) of 5-FU and its derivatives have been reported by many investigators. These toxicities are considered to be caused by the inhibition of the TCA cycle by alpha-fluoro-beta-alanine (FBAL), a metabolite of 5-FU, and later metabolites. In this study, we focused on FBAL as an index of the above toxicities. We compared the concentrations of 5-FU and FBAL in plasma after administration of UFT, tegafur (FT), 5-FU or doxifluridine (5'-DFUR) to rats (75 mumol/kg) in order to evaluate which compound has the better balance of efficacy and toxicity. UFT exhibited the lowest FBAL concentration in plasma followed by FT, 5'-DFUR and 5-FU. The ratio of FBAL to 5-FU in Cmax and AUC after dosing of UFT was the lowest among these four test compounds. These data indicate that the lowest ratio of FBAL to 5-FU resulted from the inhibitory effect of uracil, a component of UFT, on the metabolism of 5-FU. In conclusion, the present results suggest that UFT has a better balance of efficacy and toxicity than FT, 5-FU and 5'-DFUR.     

Serum and tissue concentration of tegafur and 5-FU after administration of tegafur suppository in patients with lung cancer--correcting the influence of residual blood in the tissue

Tissue concentration of tegafur and 5-FU was studied in 25 patients with of primary lung cancer, given 2 x 750 mg of tegafur suppository daily preoperatively (total doses 3.75-9.75 g, mean 5.16 g). Furthermore, the influence of blood remaining in the tissue was corrected in the determination of tegafur and 5-FU concentration. The tegafur level in tumor tissue (9.614 +/- 5.739 micrograms/g) was significantly (p less than 0.01) low compared with those in serum and normal lung tissue (13.185 +/- 8.198 micrograms/ml, 12.954 +/- 10.048 micrograms/g). On the other hand, the 5-FU level in tumor tissue (0.124 +/- 0.208) was significantly (p less than 0.01, p less than 0.05) high compared with those in serum and normal lung tissue (0.019 +/- 0.013 micrograms/ml, 0.035 +/- 0.031 micrograms/g) and showed approximately 2.5 times more minimum effective concentration against tumor cells (0.05 micrograms/g). The results show that preoperative administration of 2 x 750 mg of tegafur suppository daily is effective for the transfer of tegafur and 5-FU to lung cancer tissue.     

5-FU and HCFU concentrations in serum and tissues in hepatocellular carcinoma after HCFU oral administration

Before proceeding with a resection of a hepatocellular carcinoma (HCC) in patients, the concentrations of 5-FU and 1-Hexylcarbamoyl-5-fluorouracil (HCFU) have been measured in the serum, the liver, and in the cancer tissue after an oral administration of HCFU (300 mg). The maximum 5-FU value was found to be 3.45 +/- 3.21 micrograms/ml (n = 22) at 2 hours, and this value decreased linearly. The concentrations of 5-FU in the liver tissues were 0.02 +/- 0.01 micrograms/g (n = 16) and the concentrations of 5-FU in cancer tissues were 0.03 +/- 0.01 micrograms/g (n = 16). There were no statistical differences found between cirrhotic patients and non-cirrhotic patients. These results indicate that the concentrations of HCFU in the serum and tissues were not influenced by liver damage.     

Concentration of 5-fluorouracil in the blood and tissues of gastric and colo-rectal cancer patients after oral administration of UFT]

UFT is given to the patients with digestive cancer from the time before operation to prevent intra- and post-operative cancer dissemination and metastases. UFT (400 mg/day in terms of tegafur) was given preoperatively for 1-6 days in 6 patients with gastric cancer and 13 with colorectal cancer. The interval between the last administration and the beginning of the operation was 3.9 +/- 1.5 hours (mean +/- SD). The concentrations of tegafur, 5-FU, and uracil in the blood collected at the time of tumor resection were 9.68, 0.017, and 0.08 microgram/ml, respectively. In the patients with gastric cancer 5-FU concentration was 5.5 times higher in the normal mucosa, 3.3 times in lymph nodes, and 10.7 times in the tumor tissues than in the blood. In colorectal cancer patients, also, the 5-FU concentration was 5.6, 8.3 and 20.8 times higher in the normal mucosa, lymph nodes, and the tumor tissue, respectively, than in the blood. The 5-FU concentration in gastric cancer and colorectal cancer tissues decreased with time after administration of UFT but remained above the effective concentration 1.5-7 hours after administration of 200 mg. The tissue concentrations of FT-207, uracil, and 5-FU were correlated with each other.