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.     

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.     

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.     

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.     

Drug concentration in lymph nodes after preoperative administration of UFT (a blend of Tegafur and uracil) for non-small-cell lung cancer

Background. UFT a blend of uracil and Tegafur (1-[2-tetrahydrofuryl]-5 fluorouracil), molar ratio, 4 : 1 is an anti-tumor agent for oral administration that is presumed to maintain the concentration of 5-fluorouracil (5-FU) in tumor tissue. The concentration of 5-FU achieved with UFT in lymph node metastases has, however, not yet been examined; in this study we aimed to clarify the transfer of 5-FU to lymph node metastases in patients treated with UFT. Methods. The subjects were 21 patients with primary non-small-cell lung cancer (NSCLC). Tegafur (600 mg per day), in the form of UFT-E (UFT enteric-coated granules), was administered for 7 days prior to surgery. At the time of lobectomy and lymphadenectomy, 0.3-g tissue specimens were collected from the primary lung tumor, normal lung, lymph node metastases, and normal lymph nodes. The concentrations of Tegafur and 5-FU in each sample were measured. Results. The concentration of 5-FU in lymph node metastases was 63.5 ± 11.6 ng/g, which was greater than the minimum effective tissue concentration (50 ng/g), and was significantly higher than the concentration in normal lymph nodes (P = 0.0053). The concentration of 5-FU in the tumor (50.7 ± 9.7 ng/g) was also greater than the minimum effective tissue concentration, and was significantly higher than the concentration in normal lung tissue (P = 0.0193). No serious side effects were observed during the administration of UFT-E. Conclusions. We concluded that UFT would be useful as a postoperative adjuvant chemotherapeutic agent in patients with NSCLC and lymph node metastases, considering the excellent transfer of 5-FU to lymph node metastases during treatment with UFT. Received: January 5, 2000 / Accepted: April 6, 2000     

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.     

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, 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 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.     

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.     

5-fluorouracil concentration in gastroenterological tumor tissues, in adjacent normal tissues, and in serum after preoperative oral administration of 5'-deoxy-5-fluorouridine (5'-DFUR)

The 5-fluorouracil (5-FU)-concentration in resected tumor tissues was compared with that in the adjacent normal tissues or that in serum. Twenty-three patients with cancer of the digestive organs [(carcinoma of the stomach (12), colon (6), gallbladder (1), liver (1), ampulla of Vater (1), bile duct (1) and pancreas (1)] were administered orally 600-1, 200 mg/day of 5'-deoxy-5-fluorouridine (5'-DFUR) for 3 to 5 consecutive preoperative days. The average 5-FU-concentration in tumor tissues of 14 patients with 16 specimens measured 5 hours after final administration of 5'-DFUR was 62 ng/g. This level was significantly higher than that in adjacent normal tissues (21 ng/g, p less than 0.01). With 10 out of these 14 patients, the 5-FU-concentration in the serum was also measured. Among these 10 patients, the concentration of 5-FU in tumors (54 ng/g) was significantly higher than in adjacent normal tissues (19 ng/g) and in serum (12 ng/ml). At 6 to 9 hours after final administration, the mean concentration of 5-FU was 33 ng/g (n = 4) in tumor tissues, 30 ng/g (n = 5) in adjacent normal tissues and 24 ng/ml in serum. There was no significant difference among these mean values. For 4 patients whose specimens were taken at 17 to 18 hours after the last 5-FU administration, the mean concentration of 5-FU was 29 ng/g (n = 4) in tumor tissues, 14 ng/g (n = 3) in adjacent normal tissues and 4 ng/ml (n = 2) in serum.     

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.     

Study on the concentrations of 5-fluorouracil (5-FU), tegafur (ET) and uracil in bile: comparison of UFT or FT

The serum and bile tegafur (FT), 5-fluorouracil (5-FU) and uracil levels after administration of UFT were assessed in 13 cases of malignant biliary tumor accompanied by biliary obstruction in comparison with FT alone. The serum and bile FT and 5-FU levels showed almost the same transition pattern in both groups, reaching to the plateau in 1-2 weeks and revealing cumulative effect by continual administration. Correlation was obtained between serum and bile levels except for 5-FU level in UFT group (p less than 0.05). Correlation between 5-FU and uracil was obtained in the serum in both groups (p less than 0.05), but no effect of uracil was observed. In bile, correlation was seen only in UFT group (p less than 0.05), and the effect of uracil was observed in bile 5-FU level.     

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.     

前哨淋巴结活检在乳腺癌中的应用

Objective： To discuss if the sentinel lymph node （SLN） biopsy is able to reflect the status of the axillary lymph node and the application of this technic in clinic. Methods： Using^ 99mTc-signed dextran, SLN-biopsy （SLNB） was carried out in 182 cases with breast cancer during May 1999 to September 2006. During the operation, y-detector was used for orientation. After the SLNB, a modified radical mastectomy or breast conserving surgery were carried out to the patients, then a particular separate pathological examination of the SLN was made. Results： 178 cases of SLNB were carried out successfully, and the success rate was 97.8%, the out-checked SLN of each case ranged from 1 to 4, with an average of 2.5. All SLN was located at the first level of axilla, sensitivity of the SLN B was 93.4%, specificity was 100%, false negative rate was 6.6%, false positive rate was 0, accuracy was 97.8%, positive predictive value was 100.0%, negative predictive value was 96.7%, and Youden＇s index was 0.934. Immunohistochemical examination was carried out in 59 cases of SLN, and 14 cases showed the existences of micro-metastasis, however, metastasis had not been found in non-SLN of these cases. Conclusion： SLN is able to reflect the metastasis of the axillary lymph node, and this can suggest the necessity of the axillary dissection in clinic. The SLNB using the isotope-tracer technic is simple and accurate.     

Effects of preoperative administration of UFT in gastrointestinal cancer

UFT, a combination antitumor drug consisting of 1 part Futraful and 4 parts Uracil, was administered preoperatively to 10 patients with gastric cancer, 9 patients with colo-rectal cancer and 1 patient with hepatocellular carcinoma. A pharmacokinetic study was then carried out after oral administration of 600 mg per day of UFT, measuring Uracil, Futraful and 5-FU levels in serum and tumor tissue. Preoperative total doses of UFT for gastric cancer were 3.0-11.4 g, for colo-rectal cancer 3.6-16.8 g and for hepatocellular carcinoma 8.4 g. Side effects, mainly gastrointestinal symptoms, were observed in 3 cases. Abnormalities of liver function test, depression of serum protein and bone marrow damage were observed in 4 cases. 5-FU concentration in the tumor tissue was higher than 0.05 mu/g in 15 of 19 patients (79%). This suggested that 5-FU was maintained in the tumor tissue for a longer period. However, it also suggested that the concentration of Uracil in the tumor tissue corresponded to the total dose of UFT as did the degree of side effects.     

Predictors of non-sentinel lymph node metastasis in breast cancer patients with positive sentinel lymph node (Pilot study)

Background: Sentinel Lymph Node Biopsy (SLNB) procedure was found to be an accurate method of staging the axilla in patients with early stage breast cancer. The standard of care for breast cancer patients with positive SLN metastasis includes complete Axillary Lymph Node Dissection (ALND). However, in 40–70% of patients, the SLN is the only involved axillary node. Factors predicting non SLN metastasis should be identified in order to define subgroups of patients with positive SLN in whom the axilla may be staged by SLNB alone.Objectives: To identify the factors predicting metastatic involvement of the non-SLNs in breast cancer patients having SLN metastasis.Patients and Methods: Data were collected and analyzed from 80 patients with early stage invasive breast cancer (T1, T2, N0, M0) who underwent SLNB at the Surgical Oncology Department, Kuwait Cancer Control Center (KCCC) between November 2004 and February 2009. SLNB was performed using a combined technique (radioactive colloid, and blue dye) in the majority of cases. In some cases, only one technique was used. Complete ALND was performed in the case of failure of SLN identification and in patients with positive SLN. Multiple variables (patient, tumor, and SLN characteristics) were tested as possible predictors of nonsentinel lymph node metastasis.Results: The mean age of patients at diagnosis was 46.6 years. The median tumor size was 2 cm. The SLN identification rate was 96.2% (77 out of 80 patients). The SLN was positive in 24 patients (31%), and half of these showed evidence of capsular invasion. The median number of SLNs removed was two. The median number of positive SLNs was one. The incidence of non-SLN metastasis associated with positive SLN was 50% (12 out of 24 patients). Lymphovascular invasion was found to be the only factor associated with non-SLN metastases. In addition, two trends were observed, though they did not reach the statistical significance: the first is that the majority of patients having capsular invasion of the SLN (8 out of 12 patients, 67%) had positive non-SLN metastasis, and the second is that the patients having more than one SLN metastasis were more likely to have non-SLN metastasis (4 out of 5, 80%).Conclusion: In the current pilot study, only the lymphovascular invasion in the area of the primary tumor was found to be significantly related to the nonsentinel lymph node metastasis. There was a tendency toward higher incidence of nonsentinel lymph node metastasis associated with the number of positive SLN and capsular invasion of SLN, though this did not reach the statistical significance. This could be attributed to the small number of patients recruited. Further evaluation of the predictors of nonsentinel lymph node metastasis on a larger number of patients is required. The validation of these predictors in prospective studies may enable approximately half of early stage breast cancer patients with positive SLN to be staged with SLNB alone while avoiding the morbidity of unnecessary ALND.     

Thymidylate synthase activity after preoperative administration of 5-FU in patients with gastric or colorectal cancer

Continuous intravenous injection of 5-FU was given at 300 mg/m2 to patients with gastric or colorectal cancer for consecutive 3 days preoperatively, and the relationships between the time until collection of samples (from final administration of 5-FU to excision of tissue samples) and total thymidylate synthase (TS total) activity, free thymidylate synthase (TS free) activity, thymidylate synthase inhibition rate (TSIR), thimidine kinase (TK) activity, and tissue 5-FU and FdUMP concentrations investigated. TS total was shown to gradually reduce with time, but the relationship between time and the other assay items could not be identified due to large variability in the data. TS total and TK also proved to be affected also by the sites at which the samples were collected, and exhibited significantly higher enzyme activity in tumor tissue than that in normal tissue.