Anticancer drug distribution in lymph and blood during adjuvant chemotherapy after surgery for gastric carcinoma. A study with a combined preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil

Previously the authors reported that the fat emulsion of 1-(2-tetrahydrofuryl)-5-fluorouracil, tegafur (FT-207), yielded significantly higher concentrations of tegafur in the lymph and plasma compared to tegafur enteric-coated granules (FT-G). However, the emulsification did not improve the metabolic conversion rate of tegafur to 5-fluorouracil (5-FU). A study was performed to assay the plasma and lymphatic concentrations of tegafur, 5-FU, and uracil in seven patients after radical surgery for gastric carcinoma who were given a combined oral preparation of FT-207 and uracil (UFT). Both lymph and plasma 5-FU levels after UFT were 20 times greater than those after FT-G, although FT-207 levels were not different. Patients given UFT showed significantly greater 5-FU and uracil concentrations in the lymph compared with the plasma. The results of this study suggest a potential use of UFT as an adjuvant postoperative chemotherapeutic agent for gastric carcinoma.     

Antineoplastic effect of UFT therapy (uracil-FT-207 combination therapy) on experimental pancreatic cancer transplanted in the pancreas and subcutaneous region

The pancreatic duct cell adenocarcinoma induced by di-isopropanol nitrosamine could be easily and repeatedly transplanted into the subcutaneous or pancreatic tissues of the homologous animals. We established a tumor bearing animal design in which tumor tissues were transplanted simultaneously into subcutaneous and pancreatic tissues. At the first week after the transplantation, the animals were divided into three groups: In FT group FT-207 was given at a dose of 15 mg/kg/day, in UFT group FT-207 and uracil were given at a dose of 3 mg/kg/day and; 6.7 mg/kg/day (molar ratio; 1:4), respectively and in control group a solvent of FT-207 was given. In all groups the drugs were administrated orally for ten days. The size of tumors transplanted in subcutaneous and pancreatic tissues increased more slowly in FT and UFT groups, as compared with that of control group. The inhibitory effect on tumor growth observed in UFT group was more striking than that in FT group. No major side effects were observed in all groups. At the fourth weeks after subcutaneous and intrapancreatic transplantation, the animals were divided into two groups: In FT group FT-207 was given at a dose of 30 mg/kg and in UFT group FT-207 and uracil were given at a dose of 30 mg/kg and 67.2 mg/kg, respectively. In both groups the drugs were given orally, and at one hour after the administration all the animals were killed to determine 5-FU concentration in various tissues. The 5-FU concentrations of subcutaneous and intrapancreatic transplanted tumor tissues were significantly higher in UFT group than those in FT group. UFT therapy, therefore, seems to be hopeful for the treatment of human pancreatic cancer.     

Long-term administration of tegafur in postoperative adjuvant chemotherapy in gastric cancer patients. Serial analysis of serum tegafur and 5-fluorouracil concentrations, and influence from PSK combination

We investigated the pharmacokinetics of long-term (2-year) daily oral administration of FT-207-E or UFT for postoperative adjuvant chemotherapy in 85 gastric cancer patients by measuring serum FT-207 and 5-FU concentration serially. There were no significant changes in serum FT-207.5-FU concentration during observation period between FT-207-E and UFT groups. There was different operative modality between partial gastrectomy (Billroth I) and total gastrectomy, but no significant difference in serum FT-207.5-FU concentration between the two groups, and no significant serial changes in serum FT-207.5-FU concentrations were observed in both groups. Conversion from FT-207 to 5-FU measured by serum concentration was not suppressed by combination with the biological response modifier PSK.     

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.     

Comparative pharmacokinetic study between UFT and FT-207 suppo and phase II studies in gynecological malignancies

Plasma pharmacokinetics and accumulation into tissues were comparatively examined between UFT and FT-207 suppo and 7 gynecological malignancies were treated by UFT in a phase-II study. FT-207 suppo, the maximum level was attained. After administration, UFT plasma FT reached its maximum level at 2-3 hr, but for 0.5-1 hr after administration. On the other hand, plasma 5-FU concentration reached its peak 1-2 hr or 3-4 hr after UFT administration and revealed very low levels after FT-207 suppo administration. 5-FU accumulation in normal tissue (NT) was not proportional to administered doses of UFT, but in cancerous tissue (CT) it was dependent on total UFT dose. The CT/NT ratio with respect to 5-FU concentration was 5.36 after UFT administration. The same ratio after FT-207 suppo administration was 2.63. The specificity of 5-FU accumulation into cancerous tissue after UFT administration was significantly demonstrated. According to the Evaluating Criteria for cancer chemotherapy in solid tumors by the Japanese Society for Cancer Therapy, we obtained results of PR 2, NC 2 and PD 3 using a 600 mg/day administration of UFT for 7 gynecological malignancies consisting of 6 cervical carcinomas and 1 endometrial carcinoma.     

Serum and tissue concentrations of UFT in patients with lung cancer

Postoperative serum and tissue concentrations of 5-FU, FT-207 and uracil were measured in 36 patients with lung cancer who were administered UFT for seven days preoperatively. The concentration of 5-FU was high in tumor tissue and lymph nodes, but very low in serum. Such differences were not observed in the FT-207 levels. Tumor concentration of 5-FU in patients administered daily doses of 600 mg was 0.151 +/- 0.099 microgram/g which was three times higher than the minimum inhibitory concentration, and higher than that seen with other doses. The histological type and T factor were not related to the tissue concentration of 5-FU. Lymph node metastasis was not related to the concentration of 5-FU in the lymph nodes. The optimal daily dose of UFT for patients with lung cancer was considered to be 600 mg.     

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.     

N1-(2 tetrahydrofuryl)-5-fluorouracil (FT-207) in the postoperative adjuvant chemotherapy of gastric cancer. Delivery of a fat-emulsified agent to the lymph

The influence of fat emulsification of N1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) on lymphatic transport was studied in seven postoperative gastric cancer patients. The water-in-oil-type of emulsion of FT-207 (FT-w/o), the oil-in-water-type emulsion of FT-207 (FT-o/w) and an enteric-coated granule of FT-207 (FT-G) each in 1-g doses, calculated in terms of FT-207, were administered orally. Lymph from a thoracic duct fistula, prepared in advance, and from the blood of a peripheral vein was collected simultaneously along a time course after administration to measure the concentrations of FT-207 and 5-fluorouracil (5-FU). For FT-w/o, FT-207, and 5-FU, concentrations were significantly higher, both in the lymph and in the blood, than those for FT-G and FT-o/w. However, no significant differences in FT-207 and 5-FU concentrations were observed between FT-o/w and FT-G. It was concluded that FT-w/o can be useful as an adjuvant chemotherapeutic drug in the postoperative treatment of gastric cancer.     

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.     

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.     

Randomized trial comparing UFT and FT-207 in the treatment of advanced hepatocellular carcinoma (first report: well controlled study on the patients for whom transcatheter arterial embolization could not be applied) Osaka Research Society for Liver, Gallbladder and Pancreas

In a randomized trial, Tegafur (FT-207) or Tegafur-Uracil (UFT) was administrated to 76 patients with advanced hepatocellular carcinoma for whom transcatheter arterial embolization could not be applied. Efficacy on the reduction of tumor size, subjective symptoms and clinical laboratory findings were comparable in both groups. However, survival rate in the UFT group was significantly higher than in the FT-207 group in only 3 limited subgroups of patients: with nodular type tumor, with main nodule of less than 5 cm in maximum diameter, and without prior chemotherapy. Incidence of adverse effects were higher in UFT group than FT-207 group, but not significantly.     

A sensitivity test of UFT and FT-207 against human pulmonary cancer using nude mice

Transplanted tumors of human pulmonary adenocarcinoma subcutaneously into nude mice were used, to investigate the effect UFT and FT-207. Concentration of 5-FU and uracil in tumors, measured by the gas chromatographic-mass fragment graphic method, was followed. 5-FU concentration in UFT group were higher than other group, and uracil concentration show no significant difference. In one of the lines, tumor growth was stopped in UFT group and regression rate was 68% in comparison with control group, pathologically revealed grade II b in classification of Simosato-Oohoshi. It was also indicated in this experiment, anticancer effect is related with specific anticancer drug sensitivity.     

Dependence of chemotherapy response on p53 mutation status in a panel of human cancer lines maintained in nude mice

In contrast to findings in vitro, the clinical response to anticancer chemotherapy is not simply associated with the p53 mutation status. To analyze the relationship between the actual response of solid tumors with p53 mutation and other biological characteristics, we used a human cancer-nude mouse panel of 21 lines derived from stomach, colorectal, breast, lung, and liver cancers for experimental chemotherapy. We examined the tumor growth rates of the cancer lines and the effects of nine drugs in clinical use, namely, mitomycin C (MMC), cisplatin (CDDP), nimustine hydrochloride (ACNU), irinotecan (CPT-11), cyclophosphamide (CPA), 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), a 4:1 mixture of uracil and FT-207 (UFT), 5'-deoxy-5-fluorouridine (5'-DFUR), and adriamycin (ADM), on these tumors. The chemotherapy response was expressed as the tumor growth inhibition rate (IR). The genomic DNA sequences of the p53 gene in exons 5 through 8 were analyzed in these cancer tissues, and p53 mutations were detected in 10 of the 21 cancer lines (48%). Resistance to MMC was observed in p53 mutant tumors with smaller IRs than those for wild-type tumors (57.7% vs. 79.9%, P < 0.03). No significant differences were noted with the other eight drugs. To explore the role of the p53 function in the chemotherapy response, we calculated the correlation coefficients between chemosensitivity and tumor growth rate separately in p53 mutant and wild-type groups. In the p53 wild-type group, we found a positive correlation for the following drugs: ADM (P < 0.02), ACNU (P < 0.007), CPA (P < 0.011), UFT (P < 0.012), and FT-207 (P < 0.02). In the p53 mutant group, only CPA (P < 0.003) showed a positive correlation. The kinetics suggests that in the wild-type tumors, DNA damage caused by anticancer drugs occurs proportionally to the rate of DNA synthesis, and p53-mediated apoptosis is subsequently induced. The low frequency of positive correlation in the p53 mutant tumors is compatible with the loss of function or malfunction of mutant p53. The present results provide kinetic evidence that p53 function affects the response to anticancer drugs. Preserved p53 function tended to confer good chemosensitivity on rapidly growing tumors. However, the p53 mutation status did not seem to be suitable for use as an exclusive indicator to predict the chemotherapy response of human cancer xenografts.     

Evidence produced in Japan: tegafur-based preparations for postoperative chemotherapy in breast cancer

Oral fluoropyrimidine anticancer agents (oral 5-fluorouracil [5-FU]) able to be used as chemotherapy for breast cancer include tegafur–uracil (UFT), tegafur–gimeracil–oteracil potassium (S-1), doxifluridine, and capecitabine. Since the 1980s, UFT has been most widely used for postoperative chemotherapy in breast cancer. UFT is an oral preparation that was designed to achieve and maintain high concentrations of 5-FU in plasma by combining tegafur, a prodrug of 5-FU, with uracil. UFT is characterized by mild adverse events, allowing long-term treatment. The prolonged maintenance of high plasma 5-FU concentrations has been suggested to inhibit micrometastases after surgery. Recently, large clinical trials conducted in Japan have shown that UFT-based postoperative chemotherapy is therapeutically useful in patients with node-negative (n0), high-risk breast cancer. We review the results of clinical trials of postoperative chemotherapy with UFT in Japan and discuss its roles and future prospects.     

Effect of N1-(2'-tetrahydrofuryl)-5-fluorouracil and 5-fluorouracil on nucleic acid and protein biosyntheses in Ehrlich ascites cells.

N1-(2'-Tetrahydrofuryl)-5-fluorouracil (FT-207) is a derivative of 5-fluorouracil (5-FU) and has been accepted as a new chemotherapeutic drug. The inhibitory effects of FT-207 and 5-FU on nucleic acid and protein biosyntheses in Ehrlich ascites cells were compared. Both drugs markedly inhibited the incorporation in vivo of the labeled precursors into nucleic acid and protein. The inhibitory effect of FT-207 on DNA and RNA synthesis lasted for a long period of time. Two hr after administration of 5-FU (250 mug/g body weight), the absolute size of uracil pool of liver increased by at least 50%. However, in an in vitro study, FT-207 at a concentration of 60 mug/ml produced no effect on the incorporation of precursors into DNA and RNA of Ehrlich ascites cells 3 hr incubation. If 5-FU was added to Ehrlich ascites cell suspension simultaneously with [5-3H]uridine, the incorporation of the labeled precursor into RNA increased by 30 to 50%.     

Effect of UFT on urinary bladder tumors in rats induced by N-butyl-N-(4-hydroxybutyl)nitrosamine

The effect of combined tegafur and uracil (UFT) on the development of rat urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was studied. Two hundred F344 male rats were divided into 10 groups. Groups 1 to 5 were given 0.05% BBN in drinking water for the initial 8 weeks of the experiment, and Groups 6 to 10 were the controls of the prior 5 groups treated with BBN. UFT in commercial diet was administered at daily doses of 100mg (30.9 mg as FT-207) per kg of body weight in Groups 2 and 4 and 200 mg (61.7 mg as FT-207) per kg of body weight in Groups 3 and 5. Groups 2 and 3 received UFT throughout the period of the experiment, and Groups 4 and 5 for 12 weeks after 8 week treatment with BBN. All animals were sacrificed at 20 weeks, and studied histopathologically. In Groups 1 to 5, urinary bladder tumors developed in 20 of 20, 13 of 20, 6 of 20, 14 of 20 and 6 of 20, respectively. Incidences of tumors in the 4 groups treated with UFT were significantly lower than that in Group 1 treated with BBN alone. This result shows that UFT inhibits the development of urinary bladder tumors in rats induced by BBN.     

UFT concentration in various tissues from cancer patients

UFT, an antitumor drug combined of Tegafur 1 and Uracil 4, was administered preoperatively to 23 cancer patients including 11 cases of breast, 8 of gastric, 2 of colon and 2 of other cancers. Tissue specimens of different sites and serum samples were collected during the operation: cancer tissues, normal breast, normal gastric, colon or rectal wall, lymph nodes and subcutaneous fatty tissues, etc., and concentrations of tegafur (FT), 5-fluorouracil (5-FU) and uracil were studied using HCLP or GC-MF methods. In most cases, 5-FU and uracil concentrations detected in cancer tissues from the patients were higher than those found in non cancer sites. FT and 5-FU fractions in cancer tissues were found to be higher than those of the patients receiving only 800 mg of Tegafur fine granules as previously reported. Patients with benign tumor having mastopathy or were reported to show very low 5-FU concentration in tissue which was almost undetectable. From the above results, it has been suggested that UFT is a useful drug in cancer chemotherapy.     

Metabolism of 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil in mice.

1,3-Bis(tetrahydro-2-furanyl)-5-fluorouracil (FD-1) is a new masked compound of fluorinated pyrimidine and a derivative of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT-207). The pharmacokinetics of FD-1 and FT-207 were compared in the livers and kidneys of control mice and in mice (DD males) pretreated with phenobarbital. The half-time in the liver of FD-1 orally administered was about 40 minutes, whereas that of FT-207 in the liver was about 3 hours. Hepatic concentrations of 5-fluorouracil (FUra) originating from FD-1 were three to five times as much as those originating from FT-207. FD-1 formed 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-T-F-FU) and FT-207 by a ratio of about 3 to 10, respectively. Although FD-1 had a short period of half reduction, FT-207 and 3-T-F-FU had a half-time lasting for 3--4 hours. In contrast, the renal concentration of FD-1 was one-third that of FT-207. Oral administration of FD-1 to the mice pretreated with phenobarbital elevated the FT-207 and 3-T-F-FU levels in the livers to twice the levels in the control mice and further elevated the FUra levels in the livers to twice the levels in the controls. These results indicate that FD-1 is catabolized in the liver by microsomal enzymes (including cytochrome P450) faster than is FT-207, which consequently enlarges the hepatic pool of the intermediates on the way to FUra formation.     

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.     

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.