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).     

Effects of intravenous feeding on adjuvant chemotherapy--an experimental study on the distribution of 5-FU after injection of tegafur (1)

Forty-eight male Donryu rats inoculated with Sato lung cancer were used to experimentally determine the effects of intravenous feeding on the concentrations of the chemotherapeutic agents FT-207 and 5-FU in the blood, as well as in the liver and tumorigenic tissue. Following FT-207 administration, the blood, tumor and liver tissue levels were lower than in the IVH group (oral administration). The liver 5-FU concentration, at 0.10 +/- 0.02 microgram/g, was significantly higher in the intravenous feeding group than in the p.o. group (0.05 +/- 0.01 micrograms/g). The 5-FU blood concentration rose quickly, reaching 0.051 +/- 0.013 micrograms/ml and 0.035 +/- 0.004 micrograms/ml at 9 and 12 hours, respectively, following treatment. This was significantly higher than in the p.o. group, which showed corresponding levels of 0.031 +/- 0.004 microgram/ml and 0.022 +/- 0.002 microgram/ml, respectively. The increase in the 5-FU level within the tumor was markedly high in the IVH group compared to the p.o. group, and it peaked at 9 hours following administration. The concentration in the IVH group was thus higher than in the p.o. group at any given time. At 24 hours after treatment, the IVH group level was 0.35 +/- 0.09 microgram/g, against 0.27 +/- 0.05 microgram/g in the p.o. group. The blood concentration of 5-FU following intravenous feeding maintained a high value for a long time, and the 5-FU tumor concentration also remained at a high level. The intravenous route was therefore considered to be advantageous for antitumor chemotherapy.     

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.     

Pharmacokinetics of FT-207 rectum suppository in squamous cell carcinoma of the uterine cervix. (II) Pharmacokinetics in continuous administration at a daily dose of 1 gram

FT-207 rectum suppository at a daily dose of 1 g was repeatedly administered to patients with squamous cell carcinoma of the uterine cervix. Total doses ranged from 7 to 41 g. The following pharmacokinetic results were obtained in comparison with single administration. The blood level of FT-207 showed its peak of 35 to 37 mcg/ml at 4 hours after administration, of which half-time was 11 to 12 hours. The blood level of 5-FU showed its peak of 0.038 to 0.041 mcg/ml at 2 to 4 hours after administration, of which half time was more than 24 hours. Inter-individual differences were less than those of single administration. The level of FT-207 in tumor tissue was 14.2 mcg/g which was 15 times higher than that single administration. The level in healthy uterine cervix was 18.1 mcg/g which was 12 times higher that of single administration. The level of 5-FU in tumor tissue was 0.359 mcg/g which was 5 times than that of single administration. The level in normal tissue was 0.15 mcg/g which was 3 times higher than that of single administration. The level of 5-FU in tumor tissue was 7.8 to 8.4 times higher than that in blood. There was no difference in concentrations of both FT-207 and 5-FU between metastatic and non-metastatic lymph nodes.     

Pharmacokinetics of FT-207 rectum suppository in squamous cell carcinoma of the uterine cervix. (I) Pharmacokinetics in single administration at a dose of 1 gram

In order to use FT-207 rectum suppository for a long-term maintenance chemotherapy of squamous cell carcinoma of the uterine cervix, we examined its pharmacokinetics by single administration at a dose of 1 g employing chemical assay. The results were as follows: 1. The blood level of FT-207 showed its peak of 30 mcg/ml at 2 hours after administration, of which half-time was 9 hours. Inter-individual differences were few in changes in the curve. 2. The blood level of 5-FU showed two peaks, 0.25 mcg/ml at 4 hours and 0.017 mcg/ml at 36 hours after administration. There were large inter-individual differences in its alteration. 3. At the time of operation, both FT-207 and 5-FU showed low concentrations in blood. 4. The level of 5-FU in cervical focus was 0.068 mcg/g which was the highest among those in all genital organs, and 2.7 times higher than the level of 5-FU in blood. 5. There was a significantly positive correlation at r = 0.174 (p less than 0.1) between the level of 5-FU in the focus of cervical cancer and the level of FT-207 in blood.     

Effect of intravenous administration of FT-207 for gastric cancer

FT-207, 800mg per day, was administered intravenously 2 hours per day for 6 days to 15 patients with gastric cancer. By chemical assay, FT-207 and 5-FU concentrations in the blood and tissues were determined. The FT-207 levels in cancerous tissue, metastatic lymph nodes and normal gastric mucosa were almost equal. The mean 5-FU level in cancerous lesions was 0.110 +/- 0.075mcg/g, and was 0.124 +/- 0.080mcg/g in lymph nodes, and 0.043 +/- 0.021mcg/g in normal mucosa. This showed that 5-FU levels were significantly higher in tumors and lymph nodes than in normal mucosa. (p less than 0.05, p less than 0.01 respectively). The mean blood level of 5-FU was low at 4 hours after FT-207 infusion. In conclusion, intravenous drip administration of FT-207 was considered to be effective for gastric cancer because of the high tumor affinity of 5-FU.     

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.     

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.     

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.     

Pre- and intra-operative chemotherapy using FT-207 suppositories--with special reference to lung cancer

This study was conducted to determine efficacy of FT-207 to prevent hematogenous peri-operative metastasis of lung cancer. A total of 16 patients consisting of 10 with squamous cell cancer, 6 with adenocarcinoma were evaluated in this study. The protocol of this study consisted of the pre-and peri-operative chemotherapy, giving 1000 mg of FT-207 suppository daily for 10 days. 5-FU plasma concentration in the systemic circulation during surgery was 0.01 mcg/ml. 5-FU tissue concentration of the normal lung was 0.07 mcg/g, and cancerous tissue (squamous cell ca 0.11 mcg/g, adenocarcinoma 0.12 mcg/g), and lymph nodes 0.15 mcg/g. It was found in this study that the pre-and peri-operative adjuvant chemotherapy with FT-207 was effective to prevent operation-induced hematogenous metastasis of lung cancer.     

Comparison of continuous venous infusion of 5-FU and FT-207 under total parenteral nutrition

Yoshida sarcoma-bearing rats were continuously infused with 5-FU at a dose of 20 mg/kg/day, and FT-207 at a dose of 40 mg/kg/day, 100 mg/kg/day or 140 mg/kg/day under TPN. After 4 days, rats were sacrificed and the 5-FU and FT-207 concentrations in their organs were measured. The 5-FU level in the tumor was almost the same at when 5-FU was injected at 20 mg/kg/day and FT-207 at 140 mg/kg/day. This 5-FU level in the tumor was twice and four times higher than that of the group injected with FT-207 at 100 mg/kg/day and 40 mg/kg/day. The 5-FU level in the tumor in all four groups was almost twice as high as that in the stomach, intestine and kidney, 7-10 times higher than that in the liver, and 10-30 times higher than that in serum. The FT-207 levels in the alimentary tract, kidney, tumor and serum were almost the same. The conclusion of our preliminary research is that FT-207 is recommended for use in continuous infusion at 7 times the dose of 5-FU when injected under TPN.     

Thermotherapy for cancer of the urinary bladder in combination with tegafur suppository and picibanil--concentrations of tegafur in the serum and tissues in bladder carcinoma

Thermotherapy combined with tegafur (FT-207) and Picibanil was performed in 13 patients with cancer of the urinary bladder. The thermotherapy was performed using a closed circulation type of thermotherapeutic apparatus manufactured for this experiment, by way of a 3-way catheter. The flow rate of the perfusate was 150 ml/min at a constant temperature of 43 degrees C. The temperature was monitored at the inlet and outlet catheter of the urethral meatus. The thermotherapy was performed for a 6-hour period once a week. A tegafur 3000-mg suppository was given 2 hours before the thermotherapy, and Picibanil was added to the perfusate at the time of thermotherapy. No anesthesia was used. Complete disappearance of the tumor was observed in 1 case. The concentrations of tegafur in the serum, tumor and bladder wall were measured simultaneously. The levels obtained at two hours after rectal administration of the tegafur 3000-mg suppository were 19.420 mcg/ml for FT-207 and 0.025 mcg/ml for 5-FU in the serum, 13.170 mcg/g for FT-207 and 0.140 mcg/g for 5-FU in the bladder tumor, and 20.447 mcg/g for FT-207 and 0.252 mcg/g for 5-FU in the bladder wall. Eruption was observed in 1 case. No other side effects were noted.     

A case of remarkable regression of a colonic cancer involving metastasis to the liver as a result of FT-207 treatment

In mid-August, 1986, a 50-year-old man underwent a detailed examination following the finding of a tumor in the upper abdominal region. The tumor was revealed to be a sigmoid colon cancer with multiple metastasis to both halves of the liver. Subsequent administration of FT-207 suppositories (750 mg X 2/day) resulted in a recognizable shrinkage of the metastatic lesions in the liver after one month, and a barium enema a month later indicated a decrease in the size of the original tumor. The pre-operative CEA value was 2,317 ng/ml, but this has reduced to 46.7 ng/ml to date March, 1987. In this report of single chemotherapy treatment with FT-207 of a sigmoid colon cancer involving metastasis to the liver, the prognosis obtained for the original and hepatic lesions has been good, and the patient's course to date healthy.     

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.     

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.     

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.     

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.     

The effect of gastrectomy on serum 5-FU concentrations of patients administered UFT per os

Ten post-total gastrectomy patients and five postsubtotal patients were administered with UFT 3 capsules per os. Then the concentrations of the serums FT-207, 5-FU and Uracil, and that of 5-FU in the lymph-nodes were measured chronologically. The concentration of serum FT-207 reached to its peak one hour after administration of the regimen for both the total and subtotal gastrectomy patients and gradually lowered. The 5-FU serum concentration, on the other hand, showed a rapid drop after reaching a peak one hour after administration of the UFT for both the post-total and subtotal gastrectomy patients. The concentration of 5-FU in the lymph nodes remained five times as high as the serum concentration after four hours for both the post-total and subtotal gastrectomy patients.     

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.