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PubMed1991

Concentration of 5-fluorouracil in renal cells from cancer patients administered a mixture of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil.

The concentrations of 5-fluorouracil (5-FU) and related compounds were studied in tissues including renal cells removed from 27 cancer patients, to whom UFT (a mixture of uracil and tegafur in a molecular ratio of 4:1) was administered orally over 5 days. The level of 5-FU in cancer tissue was two-fold that of the normal kidney (87 +/- 79 ng/g vs. 38 +/- 29 ng/g, p less than 0.005), with almost the same level of tegafur. The serum 5-FU level was as low as 4 ng/ml. These results confirm the high efficiency of UFT with minimal side-effects compared to tegafur.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

[Mechanism for synergistic antitumor effect in the combination of 5-fluorouracil with cisplatin in vivo tumor models: from the view of biochemical modulation of 5-fluorouracil].

The mechanism for 5-fluorouracil (5-FU) and cisplatin (CDDP) synergism was investigated in experimental tumor models in rodents in vivo. The reduced folates such as 5, 10-methylenetetrahydrofolate (CH2FH4) and tetrahydrofolate (FH4) which play a significant role in the metabolism of 5-FU were increased about 2 to 3 fold 5 in P388 and Yoshida sarcoma cells of rodents at 24 hours following intraperitoneal administration of CDDP (5 mg/kg), and tritiated 2'-deoxyuridine incorporation into DNA fraction of the CDDP-treated cells was more strongly inhibited than that of non-treated cells after incubation with 5-FU, which indicated the increased formation of a tight ternary complex between thymidylate synthase, FdUMP derived from 5-FU and elevated CH2FH4. The combination of single intraperitoneal CDDP and 6 day-continuous infusion of 5-FU and/or 7 consecutive oral administration 5-FU derivative, BOF-A2, enhanced synergistically the antitumor activity against solid Yoshida sarcomas in rats as compared to each drug alone. These data suggest that CDDP play an important role as not only an effector but also a modulator in biochemical modulation of 5-FU in cellular methionine metabolism and by resultant elevation of intracellular reduced folates.

Animals↗
PubMed1991

Advanced colorectal carcinoma. A prospective randomized trial of sequential methotrexate, 5-fluorouracil, and leucovorin versus 5-fluorouracil alone.

One hundred and twenty-five previously untreated patients bearing metastatic or advanced recurrent (inoperable) colorectal carcinoma and measurable disease were prospectively randomized. Those in arm A received 5-fluorouracil (5-FU), 1,200 mg/m2 i.v. infusion over 2 h, while those in arm B received methotrexate (MTX), 200 mg/m2 i.v. (push injection), followed 20 h later by 5-FU, 1,200 mg/m2 i.v. infusion over 2 h, plus calcium leucovorin (LV), 25 mg i.m. every 6 h for eight doses beginning 24 h after MTX administration. Cycles were repeated every 15 days. All patients receiving treatment were evaluable for toxicity and survival, and 118 patients were evaluable for response. The objective regression rate (complete plus partial response) was 12% (7 of 58) in arm A and 28% (17 of 60) in arm B (p = 0.049). No change was observed in 24% (14 of 58) in arm A and in 35% (21 of 60) in arm B (p = 0.28), while progressive disease was registered in 64% (37 of 58) and 37% (22 of 60) in arms A and B, respectively (p = 0.006). Median duration of response was 3 months in arm A and 5 months in arm B (p = 0.39). The median survival was 8.3 months in arm A and 11.2 months in arm B (p = 0.25). No statistically significant differences were found when objective regression and survival were related to site of primary tumor, performance status, and number of involved organs. There were two drug-related deaths in arm B due to severe myelosuppression followed by mucositis and sepsis. Of nonhematologic toxicities, diarrhea was more frequently observed in arm B, as were mucositis and infectious complications. Our results indicate that the sequential schedule MTX-5-FU-LV with 20-h intervals between MTX and 5-FU is superior in terms of objective regression to 5-FU alone given at the dose and schedule used in the present study. However, MTX-5-FU-LV did not have a significant impact on survival.

Adult↗
PubMed1990

Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion.

The activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells and plasma concentration of 5-fluorouracil (FUra) were simultaneously determined in cancer patients receiving FUra by protracted continuous infusion (300 mg/m2/day). Blood samples were drawn every 3 h over 24-h period and the resulting DPD and FUra values analyzed for circadian periodicity. In the seven patients studied, a circadian rhythm of DPD activity was observed (P less than 0.00001, Cosinor analysis) with the peak of activity at 1 a.m. (0.197 +/- 0.007 nmol/min/mg) and the trough at a 1 p.m. (0.113 +/- 0.007 nmol/min/mg). In addition, a circadian rhythm was observed for the plasma concentrations of FUra obtained over a 24-h period (P less than 0.00001, Cosinor analysis) with peak values (27.4 +/- 1.3 ng/ml) occurring at 11 a.m. and trough values (5.6 +/- 1.3 ng/ml) occurring at 11 p.m. The ratio of the maximum concentration of FUra to the minimum concentration observed was almost 5-fold. This study demonstrates a circadian variation of DPD activity in human peripheral blood mononuclear cells and a circadian variation of FUra plasma levels in patients receiving FUra by protracted continuous infusion. An inverse relationship between the circadian patterns of DPD activity and FUra plasma levels was also noted, suggesting that an association may exist between DPD activity and FUra plasma concentration. Further evidence of an association between DPD activity in peripheral blood mononuclear cells and plasma FUra concentration was demonstrated by a linear relationship between the two parameters in all patients (r = -0.627) and within individual patients (-0.978 less than r less than -0.742). With the recent advent of programmable pumps, information on the circadian pattern of FUra and/or DPD may be useful in planning continuous infusion schedules in order that optimal plasma drug concentration may be maintained over a 24-h cycle, thereby enhancing the therapeutic efficacy of FUra administered by continuous infusion.

Aged↗
PubMed1990

Resistance of a human ovarian cancer line to 5-fluorouracil associated with decreased levels of 5-fluorouracil in DNA.

Two human ovarian cancer cell lines were established from a patient before (PEO1) and after (PEO4) the onset of resistance to 5-fluorouracil (5-FU)/cisplatin-based chemotherapy. Using growth inhibition assays, we determined that the PEO4 line was almost 5-fold more resistant to 5-FU than the PEO1 line. The addition of either 1 or 20 microM leucovorin did not enhance the growth-inhibitory effects of 5-FU against the resistant PEO4 line. In characterizing the potential mechanisms of 5-FU resistance, we found no differences in thymidylate synthase activity between the two lines using both the 5-fluoro-2'-deoxyuridine-5'-monophosphate-binding and catalytic assays. A 4-hr exposure to 1 microM 5-FU resulted in greater ternary complex formation in the resistant line, and we observed no differences between the two lines in 5-FU incorporation into RNA. However, a 4-hr exposure to 1 microM [3H]5-FU resulted in a 3-fold decrease in 5-FU accumulation in the DNA of the resistant PEO4 line. Cesium sulfate gradient centrifugation was used to more accurately separate and analyze for DNA-incorporated 5-FU metabolites and confirmed that the absolute level of 5-FU in the DNA of the PEO4 cells was markedly decreased (6.5-fold) compared with that of the sensitive PEO1 cell line. Moreover, time course studies demonstrated that the accumulated 5-FU in the DNA of the PEO4 cells was more rapidly removed compared with that in the PEO1 cells. Our findings suggest that decreased 5-FU levels in DNA, in part due to an enhanced removal from DNA, represent a mechanism by which the human ovarian cancer PEO4 line expresses decreased sensitivity to 5-FU.

DNA Repair↗
PubMed1985

Clinical controlled trial in advanced breast cancer: CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus CMF + T (cyclophosphamide, methotrexate, 5-fluorouracil, tamoxifen). CMEA Cooperative Treatment Group.

A controlled study with two arms was performed in 153 evaluable patients with advanced breast cancer. All patients were postmenopausal and untreated. The first combination included cyclophosphamide, methotrexate, 5-fluorouracil (CMF, 82 patients) while the second one contained the same cytostatic combination and tamoxifen (zitazonium) (CMF + T, 71 patients). Patients were prospectively stratified according to the dominant sites of metastases and randomized to the respective treatment schedule. In CMF combination the response rate (CR + PR) was 33/82 (40%) and complete response (CR) 8/82 (10%), respectively. In the CMF + T arm the corresponding values were 29/71 (41%) and 14/71 (20%), respectively. From the analysis of the data the superiority of the CMF + T arm could be established concerning CR in soft tissue and CR + PR in bone localization.

Adult↗
PubMed1987

Preliminary analysis of a randomized comparison of 5-fluorouracil versus 5-fluorouracil and high-dose continuous-infusion folinic acid in disseminated colorectal cancer.

In this study, 50 patients were randomly assigned to treatment with 5-fluorouracil (FUra) or FUra plus high-dose continuous-infusion folinic acid. Five of 27 evaluable patients in the FUra group versus 10 of 21 patients in the FUra plus folinic acid arm of the study had objective partial remissions, P = 0.02. Time to progression was 3.9 months for FUra and 8.0 months for FUra and folinic acid, P = 0.006; however, median survivals (11.9 versus 14.5 months) were not different in this crossover study. Toxicity in both treatment arms was mild, although patients receiving FUra plus folinic acid experienced significantly more stomatitis than patients treated with FUra alone. This study suggests that high-dose, continuous-infusion folinic acid, which produces a steady-state level of biologically active folates of 10 microM, significantly increases the therapeutic activity of FUra.

Adenocarcinoma↗
PubMed1987

Biologic modulation of 5-fluorouracil with high-dose leucovorin and combination chemotherapy of 5-fluorouracil and cisplatin in metastatic colorectal adenocarcinoma.

The data from an ongoing 3-arm prospective study of 72 patients with advanced colorectal carcinoma is presented. The 3 regimens are as follows: Regime 1 (every 4 weeks)--5-fluorouracil (FUra) (450 mg/m2 iv bolus daily for 5 days, then 200 mg/m2 iv bolus every other day for 6 doses); regime 2 (every week for 4 weeks, then every other week)--methotrexate (MTX) (50 mg/m2 in a 4-hour infusion) followed by FUra (600 mg/m2 iv bolus); regime 3 (weekly for 6 weeks followed by a 2-week rest period)--D,L-leucovorin (D,L-CF) (500 mg/m2 in a 2-hour infusion) with FUra (600 mg/m2 iv bolus) 1 hour after the D,L-CF infusion began. All monitoring lesions except lung were documented by tissue biopsy. Thirteen of 18 patients in the FUra + D,L-CF arm were evaluable for response. Six of the 13 patients (46%) have had a partial response. The duration of the 6 responses has been 11, 8, 7, 4, 3 and 3 months. In patients with liver metastases as the monitoring lesion, a dramatic improvement in liver function tests has been seen during the first 2 courses (12 weeks) of treatment, but this was not sustained. The toxicity of FUra + D,L-CF was predominantly gastrointestinal; unlike with FUra alone, myelosuppression was not predominant.

Adenocarcinoma↗
PubMed1978

Chemotherapy for colorectal cancer with 5-fluorouracil, cyclophosphamide, and CCNU: comparison of oral and continuous iv administration of 5-fluorouracil.

Forty-six adult patients with colorectal cancer were treated with cyclophosphamide and CCNU administered orally and 5-fluorouracil (5-FU) administered either orally or by continuous iv infusion (FCC-CIF), depending on the availability of hospital beds. The overall response rate in 37 patients with measurable disease was 25%. The response was greater in patients who had had no prior treatment (seven of 20 versus two of 17) and in patients treated with FCC-CIF (six of 19 versus three of 18). Among patients receiving FCC-CIF, response was also greater in those who had received no prior therapy (five of nine versus one of ten). The overall median survival was 7.5 months, regardless of the route of administration of 5-FU. Further investigations are indicated to study the efficacy of 5-FU administered by continuous iv infusion in combination with other agents in patients who have had no prior treatment.

Administration, Oral↗
PubMed1979

Results of a prospective randomized study of hepatic artery infusion with 5-fluorouracil versus intravenous 5-fluorouracil in patients with hepatic metastases from colorectal cancer: A Central Oncology Group study.

In a controlled, prospectively randomized trial, 74 patients with hepatic metastases from colorectal cancer were randomized to either intra-arterial hepatic artery infusion with 5-fluorouracil (5-FU) or systemic chemotherapy with 5-FU. In 61 acceptable patients, there was no significant difference in terms of response rate, time to progression, duration of the response, and survival rate. Though the response rate for the intra-arterial infusion arm was slightly higher than for the systemic arm, the difference was not significant, and the intra-arterial infusion arm was associated with a greater incidence of nausea, vomiting, diarrhea, in addition to complications of femoral-arterial thrombosis, bleeding, and infection at the catheter site not seen in patients treated by systemic chemotherapy. Patients with an objective response to chemotherapy on either treatment arm survived twice as long as the nonresponders. Long-term survival in one patient, 77 months, can occasionally be achieved in patients with hepatic metastases.

Adenocarcinoma↗
PubMed1985

Modulation of 5-fluorouracil catabolism in isolated rat hepatocytes with enhancement of 5-fluorouracil glucuronide formation.

The catabolism of 5-fluorouracil (FUra), which accounts for 90% of the elimination of this antimetabolite in vivo, has recently been characterized in freshly isolated rat hepatocytes in suspension using a highly specific high-performance liquid chromatographic methodology. The present study evaluates the effect of thymine and uracil, which are thought to be catabolized by the same enzymes as FUra, on the metabolism and transmembrane distribution of FUra in isolated rat hepatocytes. Following simulataneous exposure of cells for 5 min to 30 microM [6-3H]FUra and increasing concentrations of either thymine or uracil, dihydrofluorouracil (FUH2) levels decreased in a concentration-dependent manner, and the concentration determined for 50% inhibition of FUra catabolism was 8.0 +/- 0.3 (S.D.) and 67.8 +/- 15.6 microM for thymine and uracil, respectively. Analysis of intracellular and extracellular 3H from 1 min to 2 hr after simultaneous incubation of the hepatocytes with 30 microM FUra and thymine (or uracil) in a 1:7 molar ratio resulted in a decrease of intracellular and extracellular FUH2 and alpha-fluoro-beta-alanine (FBAL), while alpha-fluoro-beta-ureidopropionic acid (FUPA) was enhanced. Unmetabolized FUra (not detected in the absence of thymine or uracil) was detected intracellularly in the presence of thymine or uracil and was accompanied by the appearance of a novel metabolite, preliminarily identified as a glucuronide of the FUra base which reached intracellular levels of 44 +/- 9.76 and 27.45 +/- 1.35 microM in the presence of thymine or uracil, respectively, within 1 hr. This metabolite, which penetrates the cell membrane only slowly, accounted for approximately 60% of the intracellular 3H in the presence of 300 microM FUra and 2 mM thymine, whereas FUra catabolism was inhibited by more than 99% under these conditions. The formation of FUra anabolites was insignificant in the presence of thymine and uracil, and incorporation of FUra into RNA was not enhanced. The lack of anabolism of FUra in isolated hepatocytes exposed to either high initial concentrations of FUra or high intracellular FUra concentrations resulting from modulation (inhibition) of FUra catabolism is consistent with the clinical observation of minimal hepatotoxicity with FUra, despite exposure of the liver to high blood levels. These studies indicate that thymine is a more potent modulator of FUra catabolism in hepatocytes than is uracil. Further studies are needed to clarify the biological importance of the glucuronide of the base FUra which accumulates intracellularly as the concentration of FUra increases within the hepatocytes.

Animals↗
PubMed1984

Chemotherapy of advanced colorectal carcinoma: fluorouracil alone vs. two drug combinations using fluorouracil, hydroxyurea, semustine, dacarbazine, razoxane, and mitomycin. A phase III trial by the Eastern Cooperative Oncology Group (EST: 1278).

Patients with advanced colorectal cancer and no prior chemotherapy were randomized to six treatment regimens: A) fluorouracil (FU) alone; B) FU + hydroxyurea (HU); C) semustine (SE) + dacarbazine (DA); D) FU + HU alternating with SE + DA; E) SE + razoxane (RA); F) mitomycin (MI) + DA. There were no significant treatment differences with respect to response, which ranged from 9-23% (overall 32/207 or 15%) or median survival duration, which ranged from 17 weeks to 32 weeks. Patients treated with FU or FU + HU experienced substantially less toxicity than those on the other treatment arms.

Adenocarcinoma↗
PubMed1983

Antitumor effect of 5-fluorouracil in combination with some additives which stimulate the formation of antineoplastic 5-fluorouracil nucleotides.

Both ribose 1-phosphate and deoxyribose 1-phosphate, which were effective in increasing the formation of antineoplastic fluoronucleotides and fluoro-RNA from 5-fluorouracil (5-FU) in the intact cells of Ehrlich mouse ascites tumor, potentiated the antitumor effect of 5-FU. Ethylenediaminetetraacetate, which stimulates the formation of only fluororibonucleotides from 5-FU in intact Ehrlich tumor cells, was ineffective in the potentiation of 5-FU antitumor activity. The relationship between the increased metabolite formation from 5-FU and the antitumor effect of 5-FU is discussed.

Animals↗
PubMed1983

[Experimental studies on the optimal therapeutic mode of intra-arterial infusion of 5-fluorouracil. (1) Preparation of an animal model for continuous intra-arterial infusion and comparison of the therapeutic and adverse effects of 5-fluorouracil delivered by various modes].

5-Fluorouracil (5-FU) is one of the most popular anticancer drugs, especially in treatment of for adenocarcinoma; however, an optimal therapeutic schedule of 5-FU is not determined even now. An animal model for continuous intraarterial infusion in rats was constructed using retrograde cannulation to aorta via right femoral artery in order to study the intraarterial and systemic effects of 5-FU on Yoshida sarcoma implanted in left fore limb and hind limb subcutaneously. By implanting Yoshida sarcoma in fore and hind limb and cannulating and infusing aorta, the regional and systemic antitumor effects could be compared in the same animal. Antitumor effect and toxicity after intraarterial 5-FU administration was studied at various infusion time and doses. The results revealed that intraarterial infusion of 5-FU was more effective than its systemic administration from view points of the antitumor effect. The antitumor effect after one shot intraarterial injection of 5-FU was ar superior to that after continuous infusion of 5-FU. However, toxicity after one shot injection was much more severe than continuous infusion. Consequently, the desirable administration schedule of 5-FU appears to be an intraarterial infusion as short time as possible within tolerable toxicity.

Animals↗
PubMed1983

[Experimental studies on the optimal therapeutic mode of intra-arterial infusion of 5-fluorouracil. (2) Concentrations within the tumors and normal tissues and therapeutic and adverse effects of 5-fluorouracil delivered by various routes].

5-Fluorouracil levels in Yoshida sarcoma implanted subcutaneously and some organs of rats were measured following intraarterial or intravenous administration of 5-FU at various infusion time and doses, and the relationship between 5-FU level in tumors and antitumor effect was examined. The antitumor effect following intraarterial infusion of 5-FU was superior to its systemic administration. With intraarterial infusion, higher levels of 5-FU in tumors could be expected during infusion and immediately after injection. One-shot intraarterial injection of 5-FU was much more effective than continuous infusion of 5-FU from view points of the antitumor effect. This reason might be attributed to that, 5-FU level in the tumor after one shot intraarterial injection was maintained higher for many longer period than its level during continuous infusion. 5-FU levels in the liver following and during intraaortic infusion of 5-FU showed interesting change, i.e. if 5-FU levels flowing into the liver was low, 5-FU in the liver was not detected at all, however, if high level of 5-FU was flown into, the liver 5-FU was measured even 24 hours after injection. It was supposed that the low level of 5-FU was degraded by the liver easily, but the high level of 5-FU flown into the liver could not be metabolized. From these experiments it may be concluded that infusion time of intraarterial administration of 5-FU must be as short as possible within tolerable toxicity, and infusion doses must be as high as possible that could be degraded by the liver for reduction of toxicity.

Animals↗
PubMed1983

Relationship between antitumor effect and metabolites of 5-fluorouracil in combination treatment with 5-fluorouracil and guanosine in ascites sarcoma 180 tumor system.

The antitumor activity of 5-fluorouracil (FUra) against ascites Sarcoma 180 was significantly enhanced by coadministration of guanosine, and slightly by adenosine, but not by cytidine or uridine. In advanced ascites Sarcoma 180, guanosine also enhanced the action of FUra, but adenosine, uridine, and cytidine did not. The potentiation of antitumor activity by guanosine was reversed by addition of cytidine. The antitumor activity of FUra was significantly potentiated when guanosine was administered either 0 to 15 min before or 5 min after FUra. Changes in metabolites of FUra after potentiation by guanosine were investigated. Total radioactivity in the plasma was significantly decreased 10 min after the combined administration of [6-14C]FUra (3 mg/kg i.p.) and guanosine (100 mg/kg i.p.) in comparison with that of [6-14C]FUra alone and was slightly decreased by coadministration of [6-14C]FUra and adenosine. Conversely, it was significantly increased by uridine or cytidine. The decrease in total radioactivity in the plasma caused by guanosine was completely reversed by addition of cytidine. FUra, 5-fluorouridine, alpha-fluoro-beta-ureidopropionic acid, and alpha-fluoro-beta-alanine were found in the plasma. Intact FUra accounted for about 55% of the total radioactivity. The proportion of metabolites of [6-14C]FUra was not changed by coadministration of [6-14C]FUra and guanosine, adenosine, or cytidine, but the proportion of FUrd was increased by uridine. In the ascitic fluid, the total radioactivity derived from [6-14C]FUra was decreased by its combined administration with guanosine, and it was reversed by addition of cytidine. This pattern was similar to that in the plasma. The main FUra compound was intact FUra itself (90%), and 5-fluorouridine accounted for 1% of the total radioactivity in the ascitic fluid. On the other hand, total radioactivity of [6-14C]FUra in the tumor cells was significantly and slightly increased by guanosine and adenosine, respectively. Total radioactivity after [6-14C]FUra in combination with uridine or cytidine was less than that after [6-14C]FUra alone. Incorporation of [6-14C]FUra into RNA was increased about 3.7 times by its combination with guanosine in comparison with FUra alone, and it was increased 2.0, 0.6, and 0.7 times by adenosine, uridine, and cytidine, respectively. Moreover, FUra-nucleotides were significantly increased by guanosine. The increased radioactivity in RNA and FUra-nucleotides of tumor cells caused by guanosine was completely reversed by cytidine. These changes in incorporation into tumor cells were comparable to those in antitumor activity against ascites Sarcoma 180. The potentiation of antitumor activity of FUra by guanosine was considered to be due to an increase in incorporation of FUra into FUra-nucleotides and RNA in the tumor cells.

Adenosine↗
PubMed1984

[5-Fluorouracil concentration in various tissues from cancer patients after oral administration of 5-fluorouracil].

5-Fluorouracil(5-FU)is a widely used antitumor agent for treating patients with adenocarcinoma of gastroenterial tract and breast following intravenous or oral administration. The blood level of 5-FU peaked rapidly after intravenous bolus injection and then decreased in a short time, disappearing 90 minutes after injection. But the blood level of 5-FU peaked from 15 to 30 minutes after oral administration of 5-FU tablets or dry syrup and decreased slowly, frequently showing 0.02 microgram/ml at 120 minutes after oral administration. In cancer chemotherapy, a tissue drug concentration is represented by its serum level in practice, generally because of the difficulty in determining the tissue drug level of the patients. This study was performed to determine the tissue 5-FU level after oral administration of 5-FU. Before surgery, 400 to 600 mg of 5-FU tablets was orally administered to 13 patients including 5 cases of gastric, 5 of breast, 1 of colon and 2 of other types of cancer. Tissue specimens of different sites and serum samples were obtained during the operation: cancer tissues, normal gastric or colon wall, normal breast, lymph nodes and subcutaneous fatty tissues, etc. The materials were frozen immediately at -20 degrees C and sent to Pharmaceutical Research Laboratories, Fuji Plant, Kyowa Hakko Kogyo Co., Ltd. ( Nagaizumimachi , Shuntogun , Shizuoka , Japan). The materials were assayed for 5-FU by bioassay method using Staphylococcus aureus 209P or Micrococcus flavus ATCC 10240 as the test organisms. The 5-FU concentration in mastopathy tissue was traced to all of the agents at 20 to 180 minutes after 400 mg of 5-FU was administered orally in tablet form. 5-FU concentrations in gastric cancer tissues ranged from 0.30 to 1.30 micrograms/g at 163 to 235 minutes after administering 600 mg of 5-FU tablets, whereas in normal gastric wall were much lower than in gastric cancer tissues. That in the breast cancer tissues was 0.042 to 0.12 microgram/g at 100 to 240 minutes after oral administration. 5-FU was maintained at a higher concentration in cancer tissues for a long time, while the serum concentration decreased to trace amounts. 5-FU in non-cancerous tissues was invariably traced in most patients as mastopathy tumors. From the above results, 5-FU tablets proved to be a useful drug in cancer chemotherapy.

Adenocarcinoma↗
PubMed1980

Comparison of pharmacokinetics of 5-fluorouracil and 5-fluorouracil with concurrent thymidine infusions in a Phase I trial.

The serum half-life of 5-fluorouracil (5-FUra) in humans is best described as a biexponential decay function, with t1/2 alpha = 7.8 +/- 2.6 (S.E.) min and t1/2 beta = 36.8 +/- 13.5 min during initial courses of this drug alone. Pharmacokinetics of 5-FUra during courses of daily therapy (for 5 days) revealed prolongation of t1/2 in both components of the decay curve, which has not been previously reported. Despite the efficacy of thymidine (dThd) given as a continous i.v. infusion of 8 g/sq m/day in prevention of high-dose methotrexate toxicity, continuous infusion of dThd at this dose does not prevent the toxicity of 5-FUra orreverse inhibition of DNA and RNA synthesis by 5-fura. On the contrary, continuous infusion of dThd appears to increase the toxicity of 5-FUra during continuous dThd infusion revealed prolongation of the 5-FUra t1/2 which remained stable through the course of 5 days of 5-FUra with dThd. This protracted t1/2 is believed to account at least in part for the increased toxicity of 5-FUra with dThd. Dose-limiting mucositis, myelosuppression, and gastrointestinal toxicity were observed at 5-FUra doses ranging from one-half to two-thirds the customarily tolerated dose of 5-FUra alone in similar courses of daily bolus therapy (for 5 days).

Adult↗