Reproducibility of fluorine-18-6-fluorodopa positron emission tomography in normal human subjects

We calculated the mean energy required to produce an ion pair (W) in methane-, propane- and butane-based tissue-equivalent (TE) gas mixtures from W values in pure constituent gases according to various models for energy partition among gas components. We found an agreement between the experimental and calculated W values in the methane-based TE gas regardless of the model concept. In contrast, only those models which take into account differences in the stopping powers, total ionization cross sections and model constants of gas components give acceptable results for the propane-based TE gas. The calculated W value for high-energy electrons in the isobutane-based TE gas mixture is 25.2 eV for high-energy electrons and 28.0 eV for approximately 5 MeV alpha particles.     

Changes in neurotransmitters in multiple sclerosis

PURPOSE: The aim of this study was to identify the route of administration of 5-FU with the greatest pharmacological advantage in a rat model using non-invasive in vivo 19F nuclear magnetic resonance (NMR) spectroscopy. METHODS: 5-FU (50 mg/kg) was administered to anesthetized Wistar rats cannulated into the hepatic artery, portal vein or tail vein and 11 NMR spectra were acquired from the liver region to 60.5 min every 5.5 min. RESULTS: With systemic i.v. (tail vein) infusion, the 19F-NMR signal for 5-FU from the liver region peaked in the first spectrum (0-5.5 min), and then gradually decreased. The signal for the 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) gradually increased to the sixth spectrum (0-33.0 min) and then plateaued. Following portal vein infusion the intensity of the first 5-FU spectrum was twice as high as that following i.v. infusion, but the intensity decreased and the FBAL signal increased gradually in the sixth spectrum as systemic i.v. infusion. In contrast, the intensity of the 5-FU signal following hepatic artery infusion was the same as that following portal vein infusion in the first spectrum, and maintained a strong intensity to the final spectrum (60.5 min). The FBAL signal was detected from the second spectrum following hepatic artery infusion, but its intensity was significantly weaker than that following i.v. or portal vein infusion. CONCLUSIONS: Hepatic arterial infusion resulted in the active form of 5-FU being present for a longer time and its degradation in the liver being suppressed compared with the results following portal vein infusion. This catabolic advantage of hepatic arterial infusion could lead to a more potent anti-tumor activity against liver metastases, but could also lead to significant host toxicity including biliary toxicity. We recommend that the dose/schedule of 5-FU administered via the hepatic artery should be adjusted carefully.     

Calculation of activation energies for defect movement during coincidence boundary migration in nickel oxide using computer simulation techniques

Two possible atomistic mechanisms of grain boundary migration in nickel oxide are examined for two coincidence boundaries using computer simulation techniques. In mechanism I, the boundary migrates by anion vacancy diffusion across it (calculated activation energy 0.64 eV in a (21̄1)/[011] boundary). In mechanism II, ions migrate across the boundary to add onto the opposite crystal lattice without the need for vacancies (activation energy 0.78 eV in a (12̄2)/[011] boundary and control by cation migration). The activation energy for an anion diffusion jump down a (21̄1)/[011] boundary is calculated as 1.57 eV. Anion vacancy supply down the boundary is therefore expected to be rate controlling for any migration mechanism requiring anion vacancies (i.e. mechanism I). There are few literature values for the grain growth activation energy in bulk NiO but values of ~0.9 eV are deduced from published data on grain sizes in NiO scales. 0.9 eV is low in comparison with literature values for a variety of ceramics. Comparison between 0.9 eV and the computer predicted activation energies for defect migration suggests that, unless the effective anion vacancy formation energy at a general grain boundary is considerably lower than expected, it is likely that anion vacancy formation is not required for boundary migration in NiO.     

Metmyoglobin/fluoride: effect of distal histidine protonation on the association and dissociation rate constants

The kinetics of formation and dissociation of the horse metmyoglobin/fluoride complex has been investigated between pH 3.4 and 11. The ionic strength dependence of the reaction has been measured at integral pH values between pH 5 and 10. Hydrofluoric acid, HF, binds to metmyoglobin with a rate constant of (4.7 +/- 0. 7) x 10(4) M-1 s-1. An apparent ionization in metmyoglobin with a pKa of 4.4 +/- 0.5 influences the rate of HF binding and is attributed to the distal histidine, His-64. Protonation of His-64 increases the HF binding rate by a factor of 2.6. The fluoride anion, F-, binds to metmyoglobin with a rate constant of (5.6 +/- 1.4) x 10(-2) M-1 s-1, about 10(6) times slower than HF. Binding of either HF or F- to hydroxymetmyoglobin cannot be detected. Protonation of the distal histidine facilitates HF dissociation from the metmyoglobin/fluoride complex. HF dissociates with a rate constant of 1.9 +/- 0.3 s-1. The fluoride anion dissociates 2000 times more slowly, with a rate constant of (8.7 +/- 1.6) x 10(-4) s-1. The apparent pKa for His-64 ionization in the fluorometmyoglobin complex is 5.7 +/- 0.1. The association and dissociation rate constants are relatively independent of ionic strength with secondary kinetic salt effects sufficient to account for the ionic strength variation of both, consistent with the idea that association and dissociation of neutral HF dominate the kinetics of fluoride binding to metmyoglobin.     

Hybridized valence electrons of 4f~(0-14)5d~(0-1)6s~2: the chemical bonding nature of rare earth elements

The chemical bonding nature of rare earth(RE) elements can be studied by a quantitative analysis of electron domain of an atom. The outer electrons of RE elements are within the valence shell 4f~(0-14)5d~(0-1)6s~2, which are involved in all chemical bonding features. We in this work found that the chemical bonding characteristics of 4f electrons are a kind of hybridizations, and classified them into three types of chemical bonding of 4f~(0-14)5d~(0-1)6s~2, furthermore, the coordination number ranging from 2 to 16 could thus be determined. We selected Y(NO_3)_3, La(NO_3)_3, Ce(NO_3)_3, YCl_3, LaCl_3, and CeCl_3 as examples to in-situ observe their IR spectra of chemical bonding behaviors of Y~(3+), La~(3+) and Ce~(3+) cations, which could show different chemical bonding modes of 4f and 5d electrons. In the present study, we obtained the direct criterion to confirm whether 4f electrons can participate in chemical bonding, that is, only when the coordination number of RE cations is larger than 9.     

A pilot study of gamma-1b-interferon in combination with fluorouracil, leucovorin, and alpha-2a-interferon

The combination of IFN-alpha-2a (IFN-alpha) and IFN-gamma-1b (IFN-gamma) has been found to produce more than additive cytotoxicity with fluorouracil (5-FU) in HT 29 colon cancer cells due to enhanced DNA-directed effects. We therefore studied the combination of IFN-gamma with IFN-alpha, 5-FU, and leucovorin (LV) in a clinical trial. Fifty-three patients received an initial cycle of 5 million units (MU)/m2 IFN-alpha s.c. on days 1-7 with 500 mg/m2 LV and 370 mg/m2 5-FU i.v. on days 2-6. IFN-gamma was then added once tolerable doses of 5-FU and IFN-alpha were established for each patient. IFN-gamma was administered at one of six dose levels between 0.3-4.8 MU/m2 s.c. on days 1-7. This design permitted comparison of the clinical toxicity and pharmacokinetics of 5-FU in two consecutive cycles in an individual treated with the same doses of 5-FU/LV/IFN-alpha in the absence and presence of IFN-gamma. In 43 matched patient cycles, the addition of IFN-gamma did not seem to worsen gastrointestinal toxicity, and skin toxicity tended to be milder. 5-FU clearance was higher in 14 cycles with IFN-gamma compared to the patient's prior cycle with the same doses of 5-FU/LV/IFN-alpha: 798 +/- 309 versus 601 +/- 250 ml/min/m2 (mean +/- SD; P = 0.04). In these 28 cycles, the median 5-FU clearance was significantly lower in 11 cycles that were complicated by more severe diarrhea: 524 versus 798 ml/min/m2 (grade 2 versus 0-1; P = 0. 0032). Overall, 38% and 26% of patients had grade 3-4 diarrhea and mucositis. Dose reductions of IFN-gamma for chronic fatigue, malaise, or anorexia were ultimately required more frequently with >/=2.4 MU/m2 (P = 0.018), and the maximum tolerated dose of IFN-gamma was considered to be 1.2 MU/m2/ day. Objective responses were seen in 41% of 29 measurable colorectal cancer patients. Compared to our previous experience with 5-FU/LV/IFN-alpha, IFN-gamma and IFN-alpha appeared to have opposite effects on 5-FU clearance. These results suggest that any potential benefit of adding IFN-alpha to 5-FU/LV on this schedule may not depend solely on alterations in 5-FU clearance.     

Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05

BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy. Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated. METHODS: Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994. Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months. All statistical tests were two-sided. RESULTS: There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%). CONCLUSION: The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity.     

Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.     

Response of Bitot's spots to a single oral 100,000- or 200,000-IU dose of vitamin A

PURPOSE: A randomized, controlled clinical trial was conducted in Indonesia to study the response of Bitot's spots to a 100,000-IU dose of vitamin A, which is known to be associated with fewer acute side effects than the currently recommended 200,000-IU dose. METHODS: A total of 114 children (ages 13 to 59 months) with Bitot's spots were given an ocular examination; serum retinol concentration was measured, and the relative dose response test carried out. After administering one 100,000- or 200,000-IU oral dose of vitamin A, ocular examinations were repeated weekly for seven weeks and then biweekly for 20 more weeks, or until lesions were healed on two consecutive examinations. RESULTS: Either dose of vitamin A was similarly effective in healing Bitot's spots. The most important factor in predicting responsiveness to treatment was baseline serum retinol concentration: children with lower pretreatment concentrations were more likely to have responsive lesions. No child had a relapse within the first three months after treatment. However, by six months, children who had received the higher dose were 82% less likely to have a relapse compared with children who had received the lower dose. CONCLUSIONS: Although either a 100,000- or 200,000-IU dose of vitamin A is similarly effective in healing Bitot's spots, a 200,000-IU dose provides longer protection. This benefit justifies the higher rates of transient mild side effects associated with the 200,000-IU dose. The current 200,000-IU dose of vitamin A recommended by the World Health Organization for prophylactic dosing should not be reduced.     

Arterial infusion chemotherapy of 5-FU and leucovorin for patients with liver metastases from colorectal cancer

Fifteen patients with liver metastases from colorectal cancer were treated by arterial infusion of 5-FU and leucovorin. Two regimens were performed. One was weekly bolus infusion of leucovorin following bolus infusion of 5-FU (bolus group), the other was 5 days continuous infusion of 5-FU and leucovorin in 3 weeks (continuous group). One PR was obtained both in the bolus group and in the continuous groups. The objective response rate was 11% in the bolus group and 20% in the continuous group. The one- and 2-year survival rates for these patients were 40% and 0% in the bolus group, and 80% and 60% in the continuous group, respectively. These results suggest that continuous arterial infusion of 5-FU and leucovorin was more effective than individual bolus arterial infusion of leucovorin and 5-FU for patients with liver metastases from colorectal cancer.     

Adsorption behaviour of sodium hexametaphosphate on pyrochlore and calcite

Abstract

FTIR, XPS and zeta potential measurements were performed on pyrochlore and calcite to study the adsorption mechanisms of sodium hexametaphosphate (NaHMP). While no hexametaphosphate could be detected on the FTIR spectra of NaHMP treated pyrochlore or calcite, the observed chemical shifts of the binding energies of Ca 2p^5/2 (0·25 eV) and P 2p (0·20 eV) electrons indicated that the hexametaphosphate groups formed a complex with calcium on calcite. The complex seemed soluble in water leaving a low concentration of its residue on calcite surface after water washing, thus undetectable by FTIR. The binding energy shifts of Nb 3d^5/2 (0·13 eV) and Ca 2p^5/2 (0·10 eV) electrons on NaHMP-treated pyrochlore were within instrumental resolution, therefore, NaHMP was not strongly bound to pyrochlore. The zeta potentials of pyrochlore and calcite were both lowered in the presence of NaHMP. However, for pyrochlore, the zeta potential drop occurred mainly in the acidic pH range, while the drop for calcite was independent of pH, indicating possible chemisorption of NaHMP on calcite. The work explained the selective depressive function of NaHMP in the hydroxamic acid flotation of carbonatite niobium ores.

On a effectué des mesures de FTIR, de XPS et de potentiel zêta du pyrochlore et de la calcite afin d’étudier les mécanismes d’adsorption de l’hexamétahosphate de sodium (NaHMP). Bien qu’on ne puisse pas détecter d’hexamétaphosphate dans les spectres de FTIR du pyrochlore ou de la calcite traités au NaHMP, les décalages chimiques observés des énergies de liaison des électrons de Ca 2p^5/2 (0·25 eV) et de P 2p (0·20 eV) indiquaient que les groupes d’hexamétaphosphate formaient un complexe avec le calcium sur la calcite. Le complexe semblait soluble dans l’eau, laissant une faible concentration de son résidu à la surface de la calcite après lavage à l’eau, donc indétectable par FTIR. Les décalages de l’énergie de liaison des électrons du Nb 3d^5/2 (0·13 eV) et du Ca 2p^5/2 (0·10 eV) du pyrochlore traité au NaHMP se situaient dans les limites de résolution de l’instrument. Donc, le NaHMP n’était pas fortement lié au pyrochlore. Les potentiels zêta du pyrochlore et de la calcite s’abaissaient tous deux en présence de NaHMP. Cependant, la chute de potentiel zêta du pyrochlore se produisait principalement dans la gamme de pH acide, alors que la chute pour la calcite était indépendante du pH, indiquant la possibilité d’une chemisorption du NaHMP sur la calcite. Ce travail explique la fonction sélective et dépressive du NaHMP lors de la flottation à l’acide hydroxamique des minerais de carbonite de niobium.     

Comparison of 5-fluorouracil pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer

STUDY OBJECTIVE: To compare 5-fluorouracil (5-FU) pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer. DESIGN: Prospective, unblinded observational study in consecutive patients. SETTING: Large regional teaching hospital. PATIENTS: Five patients with colorectal cancer. INTERVENTIONS: Patients received folinic acid 200 mg/m2 intravenously over 2 hours, followed by 5-FU 600 mg/m2 intravenous bolus over 30 minutes, then 5-FU 600 mg/m2 intravenous infusion over 22 hours, administered on days 1 and 2. This 48-hour cycle was repeated every 14 days. MEASUREMENTS AND MAIN RESULTS: Concentrations of 5-FU in whole blood, plasma, and red blood cells were determined by high-performance liquid chromatography. ADAPT II was used for pharmacokinetic computations. The optimum model was determined for each matrix by calculating Akaike's information criteria values. Concentrations of 5-FU in whole blood were 106-115% of simultaneous plasma concentrations (median 112%), and packed red blood cell levels were 5-17% of plasma concentrations (median 11%). The drug's concentration-time profile was similar in the three matrices. The drug is reported to be unstable in whole blood, and red blood cell 5-FU concentrations were near the limit of detection (10 ng/ml), supporting plasma as the preferred matrix for therapeutic drug monitoring studies. Six pharmacokinetic models were fitted to the 5-FU individual data sets to determine the best curve fit. The optimal model for whole blood and plasma data sets was one compartment with both linear and nonlinear elimination models; a one-compartment model with nonlinear elimination provided the best curve fit for 5-FU in red blood cells. A two-compartment model with nonlinear elimination gave a similar degree of curve fit for plasma 5-FU as the one-compartment model with both linear and nonlinear elimination. CONCLUSIONS: These pharmacokinetic results provide the basis for further investigation into the ability to correlate 5-FU systemic exposure with clinical drug activity.     

Gsalpha contains an unidentified covalent modification that increases its affinity for adenylyl cyclase

Many G protein alpha subunits are dually acylated with myristate and palmitate or are palmitoylated on more than one cysteine residue near their N termini. The Galpha protein that activates adenylyl cyclase, alphas, is not myristoylated but can be reversibly palmitoylated. It appears that alphas contains another, as-yet-unidentified covalent modification that decreases its apparent dissociation constant for adenylyl cyclase from 50 nM to <0. 5 nM. This modification is at or near the N terminus of the protein and is hydrophobic. Palmitoylation of native alphas does not account for its high affinity for adenylyl cyclase.     

Analysis of clinical effects of a concurrent CDDP/5-FU therapy on inoperable colon cancer

The mechanisms of synergic effects on cancer cells, the rational dose schedules resulting from these action mechanisms, and actual clinical results for inoperable colon cancer patients by a concurrent CDDP/5-FU therapy, are described. We analyzed the clinical results on the basis on the literature dealing with concurrent CDDP/5-FU therapy for inoperable colon cancer patients. This analysis suggested that some modified dose schedules of CDDP and 5-FU for inoperable colon cancer patients made no difference in response rates, survival times or adverse effects. Concurrent low-dose CDDP/5-FU therapy for inoperable colon cancer patients is now awaited in Japan.     

Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity

5-Fluorouracil (5-FU) is used widely in the treatment of several common neoplasms. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. Several recent studies have described a pharmacogenetic disorder in which cancer patients with decreased DPD activity develop life-threatening toxicity following exposure to 5-FU. We reported recently the first Japanese case of decreased DPD activity accompanied by severe 5-FU toxicity. The present study describes the results of molecular analysis of this patient and her family, in which three novel mutations (Arg21Gln, Val335Leu, and Glu386Ter) of the gene coding for DPD were identified. We also revealed that Arg21Gln and Glu386Ter are on the same allele and that Val335Leu is on the other allele, on the basis of analysis of the family genome. Expression analysis in Escherichia coli showed that Val335Leu and Glu386Ter led to mutant DPD protein with significant loss of enzymatic activity and no activity, respectively. The Arg21Gln mutation, however, resulted in no decrease in enzymatic activity compared with the wild type. The present data represent the first molecular genetic analysis of DPD deficiency accompanied by severe 5-FU toxicity in a Japanese patient.     

Model for inactivation of alpha-amylase in the presence of salts: theoretical and experimental studies

According to a previous report, only the smaller anions, like chlorides,that readily fit into the anion binding site of alpha-amylase can cause an increased stability (relative to enzymes in aqueous solution), and the anions that are too large to fit into the binding site should have no effect on the enzyme. Even though the results on large benzoate ions are consistent with the above postulate, much larger citrate ions from sodium and potassium citrate show stabilization at moderate salt concentrations and follow an expected trend of low stability only at large salt concentrations. The citrate ions from ammonium citrate exhibit very little to almost no stabilization. In addition, low to moderate concentrations of NaCl that provide a large stability to the enzyme show almost no stability in the presence of EDTA. We put forward an inactivation model that involves a reversible dissociation of the anion bound to the protein, followed by a reversible inactivation step of calcium ion dissociation and an irreversible denaturation step of apoenzyme.     

First-pass metabolism of 5-fluorouracil in the perfused rat small intestine

The first-pass intestinal metabolism of 5-fluorouracil (5-FU) was investigated by single-pass perfusion of the rat small intestine. At the low concentration of 0.06 mg/ml, the fraction of 5-FU absorbed into (i.e., appeared in) the mesenteric venous blood (Fa,b) was about 50% smaller than the fraction absorbed (disappeared) from the intestinal lumen (Fa), indicating the first-pass extraction of 5-FU in the intestinal mucosa. By addition of uracil (6 mg/ml), the Fa of 5-FU was reduced presumably by competition for the pyrimidine carrier at the process of intestinal uptake (entry into the mucosa). The Fa,b was also reduced, but to a lesser extent, resulting in insignificant first-pass extraction. These results suggest that the extraction of 5-FU in the absence of uracil is caused by metabolism and that uracil is a competitor for this pathway. When 5-FU concentration was raised from 0.06 to 0.6 mg/ml in the absence of uracil, the Fa was reduced by about 50%, consistent with the suggestion of the involvement of saturable uptake by the pyrimidine carrier, and thereafter remained unchanged at 6 mg/ml. However, since Fa,b was also reduced by a similar extent, the intestinal availability (FI=Fa,b/Fa) was unchanged at about 0.5, indicating that the intestinal first-pass extraction of 5-FU is independent of concentration with the extraction ratio (difference between unity and FI) of about 0.5 over the wide range of concentration from 0.06 to 6 mg/ml. Thus, the present study demonstrates that the significant first-pass metabolic extraction of 5-FU occurs in the mucosa of the small intestine, supporting our previous suggestion that 5-FU undergoes first-pass metabolism not only in the liver but also in the small intestine after oral administration. Considering that the oral bioavailability of 5-FU in the human (28%) is reportedly comparable with that in the rat (28%), it is likely that intestinal first-pass metabolism may be significant also in the human. Intestinal first-pass metabolism should be taken into account to explore more efficient and controlled oral 5-FU therapy.     

Anticancer activity and toxicity of S-1, an oral combination of tegafur and two biochemical modulators, compared with continuous i.v. infusion of 5-fluorouracil

S-1 is an oral combined form of 1 M tegafur [a prodrug of 5-fluorouracil (5-FU)], 0.4 M 5-chloro-2,4-dihydroxypyridine (a reversible inhibitor of dihydropyrimidine dehydrogenase) and 1 M potassium oxonate (an inhibitor of orotate phosphoribosyltransferase). S-1 has been shown to exert a potent antitumor effect with low gastrointestinal toxicity in experimental tumor models. We have therefore compared the antitumor effect of oral S-1 with that of continuous infusion of 5-FU in rats bearing transplants of human and murine tumors. Almost complete inhibition of the tumor growth was obtained on 7 day schedules in Yoshida sarcoma-bearing rats by consecutive administration of 30 mg/kg/day of oral S-1 and 40 mg/kg/day infusion of 5-FU. However, a significant difference between the incidence of toxicities of S-1 and 5-FU, including body weight loss and diarrhea, was noted. The rats given the 5-FU infusion had marked weight loss and severe diarrhea, while those given oral S-1 had neither. Although about 50% inhibition of the tumor growth was attained with 15 mg/kg/day of oral S-1 and 30 mg/kg/day infusion of 5-FU in nude rats with xenografted human colon cancer (KM12C), the rate of body weight loss in the 5-FU-treated group was distinctly higher than in the S-1-treated group. The ratio of the 5-fluoronucleotide concentrations in gastrointestinal tissue to that in the tumor was lower in the S-1-treated rats than in the 5-FU-treated rats. In conclusion, the results suggest that oral S-1 might be more effective in the treatment of cancer patients than continuous infusion of 5-FU, from the standpoint of antitumor potency and toxicity.     

Direction of predator approach and the decision to flee to a refuge

PURPOSE: We report the local control and survival of two Phase I dose escalation trials of combined preoperative 5-fluorouracil (5-FU), low-dose leucovorin (LV), and radiation therapy followed by postoperative LV/5-FU for the treatment of patients with locally advanced and unresectable rectal cancer. METHODS AND MATERIALS: A total of 36 patients (30 primary and 6 recurrent) received two monthly cycles of LV/5-FU (bolus daily x 5). Radiation therapy (50.40 Gy) began on day 1 in the 25 patients who received concurrent treatment and on day 8 in the 11 patients who received sequential treatment. Postoperatively, patients received a median of four monthly cycles of LV/5-FU. RESULTS: The resectability rate with negative margins was 97%. The complete response rate was 11% pathologic and 14% clinical for a total of 25%. The 4-year actuarial disease-free survival was 67% and the overall survival was 76%. The crude local failure rate was 14% and the 4-year actuarial local failure rate was 30%. Crude local failure was lower in the four patients who had a pathologic complete response (0%) compared with those who either did not have a pathologic complete response (16%) or who had a clinical complete response (20%). CONCLUSION: Our preliminary data with the low-dose LV regimen reveal encouraging downstaging, local control, and survival rates. Additional follow-up is needed to determine the 5-year results. The benefit of downstaging on local control is greatest in patients who achieve a pathologic complete response.     

Adenovirus-mediated transduction of Escherichia coli uracil phosphoribosyltransferase gene sensitizes cancer cells to low concentrations of 5-fluorouracil

5-fluorouracil (5-FU), although a widely used chemotherapeutic agent, has a limited effect in the treatment of human solid tumors due to their resistance to the cytotoxic effects of 5-FU. Escherichia coli uracil phosphoribosyltransferase (UPRT) is a pyrimidine salvage enzyme that catalyzes the synthesis of UMP from uracil and 5-phosphoribosyl-alpha-1-diphosphate. The present study demonstrates that adenovirus-mediated transduction of E. coli UPRT gene results in marked sensitization of colon, gastric, liver, and pancreas cancer cell lines to low concentration of 5-FU in vitro. The in vitro bystander effect was observed when only 10% of the hepatoma Hep3B cells were infected with UPRT-expressing adenovirus. In addition, 5-FU treatment of human hepatoma or gastric cancer xenografts in nude mice transduced with UPRT was demonstrated to result in significant in vivo antitumor effects. The adenovirus vector transduction of the UPRT gene followed by 5-FU administration is representative of a new chemosensitization strategy for cancer gene therapy.