5-FU concentration in tissues of gastric cancer patients with preoperative administration of UFT--especially in comparison with FT-207

FT-207 or UFT was administered preoperatively to 74 patients with gastric cancer. The 5-FU and FT-207 concentrations in the serum and various tissues were investigated. The 5-FU concentration in various tissues was higher than in the serum after the administration of FT-207 or UFT. Especially it showed that 5-FU concentration in tumor was highest in other normal tissues. The 5-FU concentration in the tumor for the UFT group was higher than for the FT-207 group. There was a significant difference between the UFT and FT-207 groups (P less than 0.05). Levamisole had no influence on the concentration of 5-FU.     

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.     

Clinical study of serum and tissue concentrations of FT-207 and 5-FU in patients with cancer of the large intestine following preoperative application of FT-207 suppositories

1.5 g/day of FT-207 suppository was administered for two weeks prior to operation to twenty patients with large bowel carcinoma of familiar poliposis coli. The level of FT-207 and 5-FU in serum, lymph node, tumor and normal colonic mucosa were determined by bioassay. The levels of FT-207 in the rectum, sigmoid colon and tumor were higher than that in serum. The levels of 5-FU in the rectum, sigmoid colon, tumor and lymph node were also higher than that in serum. The levels of FT-207 and 5-FU in carcinoma of the rectum was higher than those in serum. Compared with the level in normal rectal mucosa, only the level of 5-FU in rectal carcinoma was higher. From the histological point of view, the highest levels of FT-207 and 5-FU was observed in well-differentiated adenocarcinoma. There was no side effect experienced in our series, therefore, FT-207 suppository seems to be one of the safe promising preoperative chemotherapies.     

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.     

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.     

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.     

Serum concentration of 5-FU and tegafur (FT-207) after administration of tegafur (FT-207) suppository with the colostomy

Tegafur (FT-207) suppositories were administered at a rate of 750 mg via the artificial anus (ST Group) following surgery of rectal cancer. Comparative studies were conducted of changes in blood concentrations of 5-FU and tegafur at the time of initial administration and following one week of continuous use for the low-anterior resection cases (LA Group) and the rectal administration cases (RE Group). FT-207 concentration at initial administration was low in the ST group compared to those for both LA and RE groups which received anal administration of the drug, but only little changes were noted. Blood concentration one hour after administration was 11.1 micrograms/ml, elevated to 14.3 micrograms/ml at two hours, and remained at 10 micrograms/ml and above for six hours following administration. The ST group 5-FU concentrations at two, four and six hours after administration were significantly lower than those in the RE group but the changes were little. Blood concentrations were 0.015 microgram/ml at one hour after administration, 0.017 micrograms/ml at two hours and maintained virtually the same level thereafter. An effective concentration of 0.012 microgram/ml was maintained even at ten hours following administration. After one week of administration of the suppositories, the ST group showed the lowest concentration among three groups, but it was approximately double compared to the initial concentration; FT-207 showed nearly the same concentration in the LA group and 5-FU blood concentration was 0.025 microgram/ml at one hour after administration, reached to a maximum of 0.030 microgram/ml at two hours and maintained 0.020 microgram/ml and higher at ten hours. 5-FU concentration in the LA and RE groups after one week of continuous administration showed a dual-peaked pattern. No patient with an abnormal artificial anus was involved in this study. The artificial anus is thought to be an adequate and effective administration route of FT-207 suppositories.     

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.     

Clinical study on concentration of FT-207 and 5-FU in serum, lymph nodes and tissues after rectal administration of FT-207 suppositories for malignant diseases of the liver, biliary tract and pancreas

In order to study the antitumor effect of FT-207 in a solid tumor, it is necessary to determine the concentration of 5-FU and FT-207 in a tissue. This has only been done so far for gastric cancer and colon cancer, but these has been practically no research carried out regarding cancers of the liver, biliary tract and pancreas. A study was therefore made of lymph nodes and tissues after rectal administration of FT-207 suppositories to 12 patients with cancers of the liver, biliary tract and pancreas. These included 7 cases of pancreatic cancer, 2 cases of gall bladder cancer with infiltration to the liver, and 3 cases of hepatoma. In serum, the concentration of 5-FU reached 0.018 +/- 0.006 micrograms/ml at one hour after administration, 0.019 +/- 0.004 micrograms/ml at three hours after administration, and 0.023 +/- 0.008 micrograms/ml at six hours after administration. These concentrations would be expected to maintain a clinically sufficient dose. The concentration of 5-FU in metastatic lymph nodes was high compared with normal lymph nodes (p less than 0.05), its concentration in liver tumors was high while compared with normal liver tissues (p less than 0.05).     

Blood concentrations of futraful, uracil and 5-fluorouracil (5-FU) after UFT administration in the various reconstructions after gastrectomy. Saitama UFT Research Group]

The study was undertaken in the total of 58 gastric cancer patients among which 17 of Billroth (BI), 14 of Billroth II (B II) anastomosis after subtotal gastrectomy, and 7 of jejunal interposition, 9 of double tract and 11 of Roux en Y anastomosis after total gastrectomy were included. Blood samples were taken before 200 mg of per oral UFT administration and after 1, 2, 3, 5 and 7hrs. consecutively. The blood Futraful (FT) level in the total gastrectomy groups reached peak concentration within 1hr and kept in relatively high level during the observation period of 7hrs. The time to maximum FT concentration delayed in almost of B I and a few of B II patients. The concentration curves of uracil (URA) and 5-FU were similar in shape, revealing steep increase and decrease except B I anastomosis which showed gentle course. The plotted maximum concentrations of URA and 5-FU in the every type of reconstruction showed a significant correlation in the regression line. In the analysis of AUC, URA/FT was under 10%, suggesting the longer retention of the unmetabolite type of FT and early disappearance of URA. The ratio of 5-FU/FT was indifferent in each reconstruction. 5-FU/URA was higher in subtotal rather than total gastrectomy groups. From the data obtained, blood concentration of 5-FU after UFT administration was considered to depend on the emptying status in the gastrectomies. And moreover, it depended on blood URA level, since FT from which 5-FU was derived, was kept still sufficiently remained during observation period.     

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.     

Study on the concentration of FT-207 and 5-FU in serum and tissues of bladder tumor and prostatic carcinoma

Serum and tissue concentrations of 5-FU and FT-207 were estimated in 26 patients with bladder tumor or prostatic carcinoma after administration of FT-207 suppositories. The 5-FU concentration in bladder tumor was higher than in normal mucosal bladder tissue. The 5-FU concentration of prostatic cancer was almost equal to that of normal prostatic tissue. Relatively higher concentrations of 5-FU were recognized in bladder tumor of a high stage than of a low stage. There were no differences of serum and tissue 5-FU concentration in bladder tumor between patients more than 65 years old and those under 65 years old. No side-effects occurred in any case during suppository administration.     

A study of urinary tegafur, 5-fluorouracil (5-FU) and uracil concentrations in the cases of gastric carcinoma for the confirmation of drug-taking compliance after UFT oral administration]

We have measured urinary tegafur (FT), 5-FU and uracil concentrations after UFT oral administration (300 mg daily for 7 days) to confirm drug-taking compliance in the 17 cases undergone gastrectomy. Urinary FT and 5-FU concentrations reached to the plateau 2 and 3 days after administration, respectively, and were maintained until the day after termination of administration. Subsequently, FT and 5-FU concentrations also decreased about 50% at 2 day, 20% at 3 day, 10% of the plateau values at 4 day after termination, respectively. The mean plateau value of urinary FT was 12.9 +/- 6.8 micrograms/dl, and that of urinary 5-FU was 0.67 +/- 0.50 microgram/dl. On the other hand, uracil concentration, was not different before and after administration because of the uracil being present endogenously. Therefore, it was suggested that measurement of urinary FT and 5-FU concentrations is useful for confirmation of UFT-taking compliance.     

5-FU concentration in the serum and the tumor tissue after administration of UFT 200 mg/day to patients over 80 years of age with oral cancer

UFT was administered orally at a dosage of 200 mg/day, 2 times a day, to patients over 80 years of age with oral cancer. The concentration of 5-FU in the serum and tumor tissue, as well as the side effects, were investigated. The results were as follows: 1. The concentration of 5-FU in the serum peaked (0.017 to 0.066 microgram/ml) 1 or 2 hours after UFT administration. The concentration 8 hours after administration was relatively high (0.016 to 0.041 microgram/ml). 2. The 5-FU concentrations in the tumor tissues in 3 out of 5 cases were greater than 0.05 microgram/g, which is considered to be the effective level. The concentration tended to be higher with increased duration of administration. 3. A minor side effect, bone marrow dysfunction, was observed. No effect on the function of the liver or digestive system was observed.     

Clinical study on the permeability of FT-207 and 5-FU in primary lung cancer

Distribution of the FT-207 and 5-FU between plasma and lung tissue as well as tumor tissue was studied in 28 patients with lung cancer after administration of FT-207 preoperatively. Two methods of administration were employed, one is intravenous drip infusion (IV Group) (800 mg/day for three days) and the other is suppository (Supp Group) (750 mg 2/day for three days). The level of FT-207 was higher in plasma than in normal lung tissue or tumor tissue in IV Group. There was no difference in the level of FT-207 between plasma, normal lung tissue and tumor tissue in Supp Group. The level of 5-FU was higher in tumor tissue than in plasma both in IV Group and Supp Group. Furthermore, intravenous drip infusion was more effective method to give FT-207 because of higher level of 5-FU in tumor tissue than in normal tissue. Comparison of the tissue level in IV Group between two histologic types of tumor, i.e. squamous cell carcinoma and adenocarcinoma, disclosed that there was no significant difference in the concentration of FT-207 and 5-FU both in normal lung tissue and in tumor tissue.     

Preoperative treatment of FT-207 suppository in cervical cancer-- serum and tumor tissue content of FT-207

A 750 mg FT suppository was inserted daily for seven days prior to surgery of uterine cervical carcinoma. The concentrations of FT and 5-FU in the serum, tumor tissue, adjacent normal tissues and regional lymph nodes were then measured. In addition, the concentrations of FT and 5-FU in the serum of patients who had been receiving chemotherapy for long term (an average of 15 months) after the initial remission were measured. The results are as follows: The 5-FU concentration in the serum of patients following short duration of administration was 0.014 +/- 0.006 micrograms/micromilligram. The 5-FU concentration in the tumor tissue was 0.209 +/- 0.132 microgram/g. This was approximately 3.2 times higher than the concentration in the normal tissue which was 0.065 +/- 0.017 microgram/g, and approximately 2.4 times higher than in the regional lymph nodes of 0.088 +/- 0.055 microgram/g. Relatively higher concentrations of 5-FU were seen in the non-keratinizing type than in the keratinizing type suggesting. The correlation between the concentration in the tumor tissue and the histologic findings of the carcinoma tissue. The 5-FU concentration in the serum of patients receiving long-term chemotherapy was 0.019 +/- 0.015 microgram/micromilligram, showing no significant difference from the patients receiving short-term chemotherapy.     

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.     

Long-term chemotherapy in patients with stage IV gastric cancer after surgical treatment--a randomized comparative study of FT-207 and UFT

A prospective randomized and comparative study of FT-207 and UFT was performed for cases of Stage IV gastric cancer involving long-term cancer chemotherapy after surgery. Immediately after the surgery, the subjects were randomly divided into two groups: A group treated by MMC and FT-207: and B group treated by MMC and UFT. From a total of 54 cases, 8 cases were excluded, so that A group consisted of 24 subjects and B group of 22 subjects. There were no differences in background factors between the two groups. In a comparison of all the cases, B group revealed a significantly higher survival rate than A group. These results indicated that the simultaneous use of MMC and UFT was effective as a long-term cancer chemotherapy after surgery for patients with Stage IV gastric cancer.     

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.