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.     

Effect of fluoropyrimidine, drugs of tegafur and UFT on transplanted tumor in liver-damaged mice

1-(2-Tetrahydrofuryl)-5-fluorouracil (FT) and UFT are masked compounds of 5-fluorouracil (5-FU) and considered to be gradually metabolized and converted to 5-FU in the liver. Therefore, it is important clinically to classify whether or not these anti-cancer drugs are effective in individuals with liver diseases. BALB/c mice were injected 4 ml/kg of 10% CCl4 intraperitoneally twice a week for two months to induce liver damage. On the 49th day after starting of giving CCl4, mouse sarcoma 180 was transplanted to the right thigh of mice and from the next day 5-FU (10, 20, 30 mg/kg/day), FT (50, 100, 200 mg/kg/day), UFT (10, 20, 30 mg/kg/day) or physiological saline solution for control were orally administered daily for 7 days. On the 61st day, all mice were sacrificed and the weight of excised tumor was measured to judge the effect of anti-cancer drugs. Dose-dependent effect of 5-FU was observed in the liver-damaged mice. FT was more effective in liver-damaged mice than control. It was assumed that the suppression of 5-FU decomposition was due to the insufficient liver function. Effect of UFT was similar in liver-damaged mice to control. These data show that the effects of FT and UFT were not reduced in tumor-bearing mice by liver damage.     

Inhibitory effect of UFT on postoperative lung metastasis of mammary adenocarcinoma in SHR rats

It is well known that UFT has significant therapeutic effects against experimental and clinical cancers at the primary sites. In this experiment, we studied the inhibitory effect of UFT on the lung metastasis of spontaneously developed rat mammary carcinoma (SST-2) after surgical excision of the primary site. In comparison of UFT-treated (15 or 30 mg/kg/day) with 5-FU-treated (9.7 or 19.5 mg/kg/day) groups, UFT was more effective than 5-FU in the antitumor activity and the inhibitory effect of lung metastasis with/without surgical excision of the primary sites. Rats (5-10 rats per group) were inoculated s.c. with 1 x 10(6) SST-2 cells and administered with UFT orally (15, 30 or 60 mg/kg/day) starting the day after tumor inoculation for 30 days. The therapeutic effect of UFT was studied by the growth rate of primary tumor and the numbers of metastatic colonies in the lung 35 days after tumor inoculation, comparing the UFT-treated with control groups. UFT administration at the doses of 30 or 60 mg/kg/day markedly inhibited the growth of the primary tumors and the number of metastatic lung colonies decreased, compared with that of the control group. However, in the group of rats treated at the dose of 60 mg/kg/day, 60% of rats died from the side effects of UFT such as weight loss, hemorrhage etc. In all groups in which the primary tumors were surgically excised 20 days after tumor inoculation and then treated with UFT (15, 20 or 30 mg/kg/day), we observed marked prolongation of survival period and inhibition of lung metastasis as well. Furthermore, we studied the effect of combination therapy of UFT and lentinan (1 mg/kg/day i.p.) on the metastasis of SST-2 cells after surgical excision of the primary sites. It was more effective than UFT alone. Thus, it is clear that UFT is an effective anticancer drug to inhibit metastasis of tumors in the lung after surgical excision of primary tumor.     

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.     

Effect of UFT by oral administration using a murine hepatic metastasis model

We examined the antitumor effect of UFT, a 5-FU derivative using a hepatic metastasis model in mice. BALB/c and CDF1 mice were given orally UFT (30 mg/kg, 50 mg/kg daily or 120 mg/kg every other day) for 20 days after inoculation of colon-26 tumor cells into the portal vein. The number of metastatic nodules and the weight of the liver decreased significantly in all groups of UFT treatment. The therapeutic effect with 50 mg/kg UFT was better than those with the other doses. NK and LAK activities of spleen cells obtained from UFT-treated tumor bearing mice were not significantly different from the untreated control. IL-1 and IL-2 production of the spleen cells were also not significantly changed by the treatment with UFT. These results suggested that the oral administration of UFT represents an antitumor effect against hepatic metastasis in mice without sever suppression of the host immune system.     

Anti-metastatic and anti-angiogenic activity of UFT in a lung spontaneous metastasis model in mice]

We investigated the effect of UFT on a pulmonary metastasis after excision of the primary lesion, which was induced by implantation of murine renal carcinoma cells, RENCA. The cells were implanted into the left kidney of Balb/cA mice, and nephrectomy of the left kidney with a primary tumor was performed on day 10 after implantation. Administration of antitumor drugs, was started on day 13 [UFT (20 mg/kg, p.o., 5'-DFUR (24.6 mg/kg, p.o.), 5-FU (19 mg/kg, i.v.), TNP-470 (30 mg/kg, s.c.)]. In this metastasis model, the estimated mean survival time of the control group was 41.3 +/- 2.9 days. A significant life-prolonging effect was observed for UFT and 5-FU (T/C: 160.8%, 125.7%, respectively). An inhibitory effect on the growth of metastatic tumors in the lung was detected for both UFT and TNP-470 (TWI: 55.5%, 48.7%, respectively), but not 5'-DFUR. In a dorsal air sac (DAS) model, UFT abrogated angiogenesis induced by RENCA in a dose-dependent manner. These data suggest that the life-prolonging effect of UFT results from the continuous exposure of a tumor to its cytotoxic effects and anti-angiogenic activity.     

Relationship of in vivo antitumor activities of fluorinated pyrimidines to thymidylate synthase activity and intratumoral concentrations of 5-fluorouracil and uracil

MOPC-104E plasmacytomas were subcutaneously transplanted into BALB/c mice and after 7 days the mice were administered different fluorinated pyrimidines at 4 times the clinical doses, 5-fluorouracil (5-FU, 15 mg/kg), tegafur (FT, 100 mg/kg) or UFT (FT, 20 mg/kg + uracil, 44.8 mg/kg) daily for 7 days. Tumor growth was most effectively inhibited in the UFT group. The % inhibition of tumor growth on day 14, while not correlating with the concentration of 5-FU in the tumor, negatively correlated with the concentration of uracil, which was lowest in the UFT group. The activity of thymidylate synthase (TS) was measured using a 5-fluoro-deoxyuridine monophosphate (FdUMP) binding assay. The total and free TS activities in the tumor negatively correlated with the % inhibition of tumor growth, and were lowest in the UFT group. However, the % inhibition of TS activity in the tumor, which was about 80% in all 3 groups, did not correlate with the tumor-inhibitory effect. These results suggest that uracil in the tumor may play an important role in the metabolism of fluorinated pyrimidines, and that exogeneously administered uracil may decrease the amounts of uracil and TS in the tumor, and subsequently cause 5-FU accumulation.     

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.     

Therapeutic Effect of 1 M Tegafur-0.4 M 5-Chloro-2,4-dihydroxypyridine-1 M Potassium Oxonate (S-1) on Liver Metastasis of Xenotransplanted Human Colon Carcinoma

S-1 [1 M tegafur (FT)-0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP)-1 M potassium oxonate (Oxo)], was developed as a new oral antineoplastic agent based on biochemical modulation of fluorouracil (5-FU) by CDHP and Oxo. The therapeutic effect of S-1 on human colon cancer xenografts (TK-13) with high metastatic potential to the liver was evaluated. Small pieces of TK-13 were sutured into the cecal wall of 52 nude mice, and the animals were randomly divided into 3 groups [control ( n =17), UFT (combination of 1 M FT and 4 M uracil) ( n =18) and S-1 ( n =17)]. S-1 or UFT was administered orally at an equitoxic dose (S-1, 7.5 mg/kg; UFT, 17.5 mg/kg as FT) for 37 consecutive days beginning 10 days after the transplantation. S-1 showed higher tumor growth inhibition than UFT ( P < 0.05) and also showed a significant anti-metastatic effect on liver metastasis, while UFT did not. Liver metastasis developed in only 2 of the 17 mice (12%) in the S-1 group, whereas it developed in 9 of the 17 (53%) and 7 of the 18 (39%) in the control and UFT group, respectively. Analysis of AUC (area under the curve) revealed that S-1 yielded higher 5-FU levels in both tumor tissue (1.6 times) and plasma (2.5 times) than UFT. These results suggest that S-1 will show a higher clinical therapeutic effect against human colorectal cancer than UFT.     

Therapeutic effect of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) on liver metastasis of xenotransplanted human colon carcinoma.

S-1 [1 M tegafur (FT)-0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP)-1 M potassium oxonate (Oxo)], was developed as a new oral antineoplastic agent based on biochemical modulation of fluorouracil (5-FU) by CDHP and Oxo. The therapeutic effect of S-1 on human colon cancer xenografts (TK-13) with high metastatic potential to the liver was evaluated. Small pieces of TK-13 were sutured into the cecal wall of 52 nude mice, and the animals were randomly divided into 3 groups [control (n=17), UFT (combination of 1 M FT and 4 M uracil) (n=18) and S-1 (n=17)]. S-1 or UFT was administered orally at an equitoxic dose (S-1, 7.5 mg/kg; UFT, 17.5 mg/kg as FT) for 37 consecutive days beginning 10 days after the transplantation. S-1 showed higher tumor growth inhibition than UFT (P<0.05) and also showed a significant anti-metastatic effect on liver metastasis, while UFT did not. Liver metastasis developed in only 2 of the 17 mice (12%) in the S-1 group, whereas it developed in 9 of the 17 (53%) and 7 of the 18 (39%) in the control and UFT group, respectively. Analysis of AUC (area under the curve) revealed that S-1 yielded higher 5-FU levels in both tumor tissue (1.6 times) and plasma (2.5 times) than UFT. These results suggest that S-1 will show a higher clinical therapeutic effect against human colorectal cancer than UFT.     

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.     

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.     

Chemosensitivity of micrometastases and circulating tumor cells to uracil and tegafur as evaluated using LacZ gene-tagged Lewis lung carcinoma cell.

The chemosensitivity of the sequence of steps responsible for metastasis formation including circulating tumor cells and micrometastases to a 5-fluorouracil derivative (UFT) was examined with a novel micrometastasis model featuring Lewis lung carcinoma cells tagged with the bacterial LacZ gene and hygromycinR gene (hygR). Metastases in the lung could be specifically detected at the single-cell level by X-Gal staining after inoculation of LacZ-transfected tumor cells. Spontaneous metastasis in mice bearing subcutaneous primary tumors was significantly inhibited by UFT at doses of 15-20 mg/kg when it was orally administered from day 14, during the early stage of micrometastasis formation, but not by late administration from day 22. Experimental pulmonary metastasis was also inhibited without significant toxic side effects by oral administration of UFT at a daily dose of 20 mg/kg from day 4, when the tumor cells start new growth in the lung, but not by daily treatment from 8 days after intravenous injection. Oral administration of UFT had no effect on tumor cell arrest in the lung as detected by X-Gal staining. Furthermore, PCR analysis revealed that circulating tumor cells in the peripheral blood of mice bearing primary tumors after subcutaneous injection of hygR-tagged tumor cells were significantly reduced by the oral administration of UFT for 7 days in a dose-dependent manner. These results indicate that circulating tumor cells in the peripheral blood and micrometastases in the initial growth phase in the lungs are sensitive to this chemotherapeutic agent, and suggest that micrometastasis formation can be effectively inhibited by long-term oral administration of anticancer agents with minimal toxic side effects.     

The inhibitory action of BOF-A2, a 5-fluorouracil derivative, on squamous cell carcinoma.

Inactivation of antineoplastics is a serious problem in cancer therapy, and prevention of the inactivation is a surpassing strategy for enhancement of their therapeutic effects. BOF-A2, which contains both EM-FU, a masked form of 5-fluorouracil (5-FU), and CNDP, an inhibitor of 5-FU degradation, was developed with this aim. We compared the antitumor effects of BOF-A2 and 5-FU in human squamous cell carcinoma cells transplanted to nu/nu mice. Each drug (0.9-7.0 mg/kg of 5-FU and 3.8-30 mg/kg of BOF-A2) was orally administered every day to 5 mice in each dosage group for 4 weeks. Although the maximal tumor growth inhibition by 5-FU (3.5 mg/kg per day) was about 50% of the control value, 15 mg/kg per day of BOF-A2, which is equimolar to 3.5 mg/kg per day of 5-FU, almost completely inhibited the tumor growth. The flow-cytometric analysis revealed that BOF-A2 (15 mg/kg per day) induced more prominent S-phase-accumulation (63 +/- 6%) of tumor cells than did 3.5 mg/kg per day of 5-FU (43 +/- 18%), and immunohistochemical stainings indicated that the decrease of proliferating cell nuclear antigen expression was more prominent in tumor cells in the BOF-A2-treated mice than in the 5-FU-treated mice. Correspondingly, the DNA synthesis was markedly suppressed in tumor cells obtained from BOF-A2-treated mice. Compared with 5-FU, BOF-A2 more strongly induced apoptosis; apoptotic cells detected by nick-end labeling techniques were about 20% of the tumor cells in 5-FU (3.5 mg/kg per day)-treated mice, and nearly 50% in BOF-A2 (15 mg/kg per day)-administered mice. The expressions of involucrin, cytokeratin 10 and protein kinase C eta, which are associated with squamous cell differentiation, were not increased by BOF-A2 or 5-FU, although the expression of transglutaminase was slightly augmented by both drugs. These results indicate that compared with 5-FU, BOF-A2 more strongly suppresses the growth of squamous cell carcinoma by inhibiting DNA synthesis and inducing apoptosis but not cell differentiation.     

Effects of UFT on experimental liver metastases and on the immunologic capacity of the hosts

An experimental model is introduced for the study on liver metastasis using intrasplenically injected EL-4 and Lewis lung tumor (LLT) cells. The inhibitory effects of UFT, FT and 5-FU on the frequencies of metastatic foci in the liver were compared. All drugs showed inhibitory effect on the frequencies of liver metastasis. However, a high dose of UFT suppressed strongly the frequencies of liver metastasis. In order to compare the immunosuppressive activity of UFT with that of FT and 5-FU at the dose to give 50% inhibition of liver metastasis (MED50), we determined the MED50 values of UFT, FT or 5-FU against liver metastasis of EL-4 and LLT cells. FT and 5-FU were suppressed strongly the humoral response against SRBC, the delayed hypersensitivity against picryl chloride and the phagocytic activity. UFT had no inhibitory effect on immune responses.     

Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer

Bone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. Therefore, intervention of bone metastases is one of the important targets in the management of breast cancer. In the present study, we examined the effects of the orally administrable chemotherapeutic agent UFT (a combination of tegafur and uracil at a molar ratio of 1:4) on bone metastases using an animal model of the 4T1/luc mouse breast cancer. The 4T1/luc cells developed spontaneous metastases to bone following orthotopic cell inoculation. Oral daily administration of UFT (20 mg/kg/day) significantly reduced the orthotopic tumor burden; however, the lower dose (15 mg/kg/day) did not. In contrast, histologic examination showed that both doses of UFT significantly suppressed bone metastases in a dose-dependent manner. Since clinical studies have demonstrated that bisphosphonates (BPs), specific inhibitors of osteoclastic bone resorption, are beneficial for breast cancer patients with bone metastases, we next examined the effects of UFT combined with the BP zoledronic acid (ZOL) on established bone metastases. The combination of UFT (20 mg/kg/day) with ZOL (250 microg/kg) caused an enhanced reduction of bone metastases compared with UFT alone. In vitro studies showed that 5-fluorouracil (5-FU), an active metabolite of UFT, and ZOL increased apoptosis in 4T1/luc cells and inhibited osteoclast-like cell formation in an additive fashion. Our results suggest that oral UFT is an effective chemotherapeutic agent for advanced breast cancer accompanying bone metastases and that the combination with BP increases its benefits for bone metastases.     

A case of liver metastasis of rectal cancer demonstrating complete response to 5-FU + Leucovorin + UFT

Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme that metabolizes 5-fluorouracil (5-FU). We report a patient with metachronous liver metastasis from rectal cancer with low expression of DPD, who demonstrated complete response to chemotherapy comprising 5-FU, Leucovorin, and UFT. A 53-year-old man underwent macroscopically curative proctectomy with coloanal anastomosis for lower rectal cancer (Curability B). The DPD level in the primary tumor determined by an enzyme-linked immunosorbent assay was extremely low (10.3 U/mg.protein). Three months postoperatively, 5-FU (333 mg/m2) + Leucovorin (200 mg/m2) therapy (once a week for 3 weeks with a one-week rest interval, repeatedly) was started as an adjuvant therapy. However, computed tomography demonstrated a solitary liver metastasis 3 cm in size 1 month later. Chemotherapy was continued with dose escalation of 5-FU (500 mg/m2) and with oral administration of UFT-E (400 mg/body, daily). Five months later, computed tomography did not detect the liver metastasis, and this finding was maintained for two months (complete response). This case provides evidence that a low expression of DPD in the primary lesion is related to a favorable response of liver metastasis to 5-FU-based systemic chemotherapy.     

人参皂苷免疫纳米对人胃癌裸鼠移植瘤生长抑制机制探讨

目的研究人参皂苷免疫纳米（VEGFR3-mediated immune-nanoemulsion of ginsenoside Rg3,VRIN）对胃癌生长及其淋巴管生成的机制。方法通过外科原位移植能表达红色荧光蛋白人胃癌NUGC-4细胞的方法建立裸鼠胃癌模型,将32只Balb/c无胸腺裸鼠随机分为生理盐水组、5-氟尿嘧啶（5-FU）组（20mg/kg）、VRIN高剂量组（1mg/kg）和VRIN低剂量组（0.1mg/kg）4组,每组8只。实验终点处死所有受试裸鼠,在开放荧光系统下观察肿瘤生长及转移情况,切除移植肿瘤测瘤质量和瘤体积。免疫组织化学法检测肿瘤组织中微淋巴管密度（lymphatic microvessel density,LMVD）,Real time-PCR和免疫组织化学法检测VEGF-C蛋白和mRNA表达。结果实验终点开放体内荧光成像显示,胃癌NUGC-4细胞肿瘤生长抑制率VRIN高剂量为72.9%,低剂量组为14.5%,5-FU组为69.2%,VRIN高剂量组和5-FU组较生理盐水组瘤质量明显减轻,P〈0.001。生理盐水组淋巴转移率为87.5%（7/8）,5-FU组为50.0%（4/8）,VRIN高剂量组为12.5%（1/8）,低剂量组为37.5%（3/8）,VRIN高剂量组与生理盐水组差异有统计学意义,P=0.01。LMVD计数结果显示,生理盐水组为9.29±2.06,5-FU组为6.42±1.38,VRIN高剂量组为4.25±1.08,差异有统计学意义,F=20.895,P〈0.001;VRIN高剂量组VEGF-C蛋白表达量为0.190±0.059,与生理盐水组（0.269±0.051）差异有统计学意义,P=0.014;VEGF-C mRNA表达结果显示,生理盐水组为1.05±0.19,5-FU组为0.62±0.25,VRIN高剂量组为0.49±0.19,差异有统计学意义,F=8.190,P=0.002。结论 VRIN可抑制人胃癌细胞祼鼠移植瘤生长及淋巴结转移,并通过下调VEGF-C表达抑制肿瘤淋巴管生成。     

Anti-angiogenic activities of UFT and its metabolites, GHB and GBL, in the dorsal air sac (DAS) model in mice

We investigated the effects of UFT and its metabolites, GHB and GBL, on angiogenesis induced by tumor cells in a dorsal air sac (DAS) assay in mice. Five tumor cell lines (murine renal carcinoma; RENCA, human gastric cancer; 4-1ST, human small-cell lung carcinoma; LX-1, and human colon carcinoma; DLD-1, KM-20C) were used in the DAS assay. In this model, UFT demonstrated a significant anti-angiogenic activity in a dose-dependent manner while 5-FU (19 mg/kg/day) and 5'-DFUR (200 mg/kg/day) were less effective. Moreover, tegafur (FT), a component of UFT, and gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL), in vivo metabolites of UFT, inhibited angiogenesis induced by RENCA cells. The inhibitory effects of 5-FU, GHB, and GBL on angiogenesis were increased with administration by continuous infusion, providing a suitable pharmacokinetic profile. These results suggest that GHB and GBL are involved in the expression of anti-angiogenic activity of UFT.     

Continuous venous infusion of 5-fluorouracil (5-FU) under total parenteral nutrition (TPN) in advanced gastric cancer

Continuous venous infusion of 5-FU was investigated in patients with advanced gastric cancer under TPN. In preliminary research Yoshida Sarcoma-bearing rats were continuously infused with 5-FU at a dose of 20 mg/kg/day under TPN. The 5-FU level in the tumor was 2-5 times higher than that in the kidney, stomach, intestine and liver, and 40-50 times higher than that in serum. Advanced gastric cancer patients were continuously infused with 5-FU at a dose of 500 mg/day under TPN. Serum 5-FU level was constantly maintained at 0.05 mcg/ml during the infusion period. The effects of 5-FU continuously infused with other anticancer agents and TPN were satisfactory with regard to anticancer response and general condition. In conclusion, in advanced cancer, 5-FU is recommended for use in continuous infusion at a dose of 500 mg/day under TPN.