| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Department of Surgery I, Sapporo Medical University, Sapporo 060-8556 [K. H., M. O., R. D., K. S.]; Chemotherapy Cancer Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 170-8455 [N. H., K. A., Y. N., H. I., Y. Y., S. U.]; Japan Society for Cancer Chemotherapy, Osaka 550-0002 [T. T.]; and Institute for Pathogenic Biochemistry in Medicine, Taiho Pharmaceutical Co., Ltd., Tokyo 101-0054 [T. S.], Japan
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7–39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 ± 41.5 ng/ml; Tmax, 3.5 ± 1.7 h; AUC0–14, 723.9 ± 272.7 ng · h/ml; and T1/2, 1.9 ± 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients’ quality of life. |
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
90% of dosed 5-FU is metabolized mainly to 
-fluoro-ß-alanine, preventing exertion of its antitumor effect (9)
. In addition, the circadian rhythm of DPD activity within a 24-h period may influence the catabolism of 5-FU (10
, 11)
. Furthermore, DPD activity varies up to 100-fold, depending on the particular human cancer cells, and it might be one of the main factors that affect the sensitivity of tumors to 5-FU (12)
. The dose-limiting toxicities in the 5-FU/CVI method are mucositis and diarrhea (3)
. Animal experiments have indicated that these toxicities are induced by phosphoribosylation of 5-FU by orotate phosphoribosyltransferase (EC2.4.2.10) in the digestive tract (13)
, which may be a factor affecting safety in the 5-FU/CVI method. Development of oral fluorouracil antitumor drugs started in Japan in 1971, paying attention to the fact that 5-FU acts in a time-dependent manner (14) . Oral drugs enable patients to receive treatment as outpatients, and they are suitable for maintaining patients’ quality of life. Presently, such medicines as UFT and 5'-deoxy-5-fluorouridine are widely used in Japan for the treatment of various cancers, such as gastrointestinal and breast cancers (15 , 16) . Recently, studies of UFT + leucovorin and Capecitabine have been reported in the United States (17 , 18) . Thus, treatment by oral administration has been highlighted (19 , 20) .
S-1 is a novel oral fluorouracil formulation, consisting of FT, CDHP, and Oxo, in a molar ratio of 1:0.4:1 (21
, 22)
. As shown in Fig. 1
, this drug was developed to improve the tumor-selective toxicity of 5-FU by means of modulating the action by CDHP, which is a DPD inhibitor, and Oxo, which is an orotate phosphoribosyltransferase inhibitor, maintaining prolonged efficacious 5-FU concentrations in the blood and reducing the toxicity to the gastrointestinal tract (23)
. CDHP has 180-fold higher DPD inhibitory activity than that of Ura in vitro (24)
. It has been confirmed that a high blood level of 5-FU is retained when CDHP is combined with FT, a prodrug of 5-FU (22)
. As for Oxo, animal experiments revealed that the output of FUMP and 5-FU incorporated into RNA decreased by 70% only in the small intestine, whereas the output decreased by 0–20% in bone marrow and tumor regions (25)
. This suggests that Oxo is distributed at high levels in the digestive tract after oral administration, leading to relief of gastrointestinal toxicity induced by 5-FU.
|
The early Phase II study was conducted with the regimen of 50 or 75 mg/body, twice daily for 28 consecutive days, followed by a 14-day rest (27) . The response rate was 53.6% (15 of 28) for recurrent gastric cancer and 16.7% (5 of 30) for advanced colorectal cancer. Main adverse reactions were gastrointestinal symptoms and bone marrow suppression, and the incidence of adverse reactions of grades 3 or severer was 35.7% (10 of 28). The incidence of drug discontinuation due to the occurrence of adverse reactions was obviously lower in patients at 90 mg/m2/day or less. Therefore, the recommended dose for the late Phase II study is determined to be 80 mg/m2/day.
We carried out a pharmacokinetic study of 5-FU, intact FT, CDHP, and Oxo, obtained after administration of S-1 at 40 and 80 mg/m2/day for one dose, and we also investigated Ura to confirm the inhibitory effect of CDHP on DPD and its reversibility.
|
PATIENTS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Patients.
Twelve patients, 5 males and 7 females, were recruited to this study. Ages were between 44 and 69 years (median, 54 years). All patients had advanced solid tumors: 5 patients had gastric cancer, 3 had breast cancer, and 4 had colorectal cancer. All of the subjects had cancers with evaluable lesions. Each patient gave informed consent prior to participation in the study. Patients who were thought to have carry-over effects of prior surgery, chemotherapy, or radiation therapy were excluded. Additional criteria included adequate marrow; liver, heart, lung, and renal functions (hemoglobin 
9.0 g/dl; WBCs 4000/mm3 but <12,000/mm3; platelets 10 x 104/mm3; total bilirubin <1.5 mg/dl; GOT · GPT < 40 units; Al-P < 2x the upper limit of normal range adopted by the institute; creatinine less than or equal to the upper limit of normal range); and performance status of 0–2.
Study Plan.
Single administration was carried out and then 28-day consecutive administration was carried out after a 7-day rest to collect blood and urine samples. Twelve patients were selected for single administration, and 10 patients were selected for 28-day consecutive regimen. The doses were determined according to BSA; a standard dose was 80 mg/m2/day, and one dose was 40 mg/m2. In the single administration study, the drug was administered within 30 min after breakfast, at a dose of 40 mg (20 mg x two capsules) for BSA <1.25 m2 50 mg (25 mg x two capsules) for 1.25 m2 BSA < 1.50 m2, and 60 mg (20 mg x three capsules) for BSA >1.50 m2. In the consecutive day administration, the same daily dose used in single administration was administered twice daily (divided into two portions), given after breakfast and after the evening meal, for 28 consecutive days. On Day 28, the drug was administered only once, after breakfast. The times of drug administration were 8:00–9:00 a.m. in the morning and 5:30–7:00 p.m. in the evening. The average single dose per BSA was 35.9 mg/m2 (31.7–39.7 mg/m2), not exceeding 40 mg/m2.
Sample Collection.
In the single administration, the blood samples were drawn on day 1, before administration, and at 1, 2, 4, 6, 8, 10, 14, 24, and 48 h after administration. In the 28-day consecutive administration, blood was drawn on days 1, 7, and 14, before administration, and at 4 h after administration in the morning and in the evening and on Day 28, before administration in the morning and at 1, 2, 4, 6, 8, 10, 14, 24, and 48 h after the last administration. Peripheral blood samples were collected into a heparinized tube at a volume of 6 ml at each sampling time and centrifuged at 3000 rpm for 15 min at 5°C; plasma was stored at -20°C. Urine was collected and pooled during the period of 12 h on the day before administration and on days 1, 2, and 3; the total volume of each sample was measured. Each of 8 ml of mixed pooled urine was stored at -20°C.
Drug Assay.
Analysis of FT, 5-FU, CDHP, Oxo, and Uracil was conducted according to the method by Matsushima et al. (28)
. FT was extracted with dichloromethane from each sample and analyzed using HPLC equipped with a UV absorption spectrometer. 5-FU, CDHP, and Ura were extracted with ethyl acetate from the residue obtained after dichloromethane extraction, and pentafluorobenzyl derivatives were prepared. 5-FU and CDHP were analyzed using a negative ion chemical ionization-gas chromatograph/mass spectrometer, and Ura was assayed using electron impact ionization gas chromatography/mass spectrometry. Oxo was separately extracted from the samples using a solid extraction column; then it was decarbonated, prepared into a pentafluorobenzyl derivative, and assayed using negative ion chemical ionization-gas chromatograph/mass spectrometry. For the analysis of CDHP, Oxo, 5-FU, and Ura by gas chromatography/mass spectrometry, a stable isotope for each compound was used as an internal reference. The measurable ranges of plasma levels were 10–4000 ng/ml for FT, 1–400 ng/ml for 5-FU, 2–800 ng/ml for CDHP, 1–200 ng/ml for Oxo, and 5–2000 ng/ml for Ura; and the measurable region of urine levels was 10-fold wider than that of plasma in each compound. The samples at high concentrations, exceeding the assay range, were appropriately diluted before analysis.
PK Parameters.
PK parameters, the maximum plasma concentration (Cmax), the maximum plasma concentration time (Tmax), the area under the curve (AUC), and the half-life (T1/2) were calculated, using plasma levels obtained from 10 samples in the single administration study or the last 10 samples in the consecutive day administration study in each patient. PK parameters were calculated according to the noncompartment method, using a program renewed in FORTRAN based on the program by Yamaoka and Tanigawa (29)
, validated by comparison with the Nonlin results. The values were expressed as the mean ± SD for 12 cases of single administration and for 10 cases of consecutive day administration. Measured values of plasma levels of consecutive day administration were plotted on a simulation curve, prepared based on the single administration results. The estimated number of days required to reach steady state, the number of days when the plasma level reached >95% of the estimated steady state obtained by simulation, is indicated.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
shows changes in the plasma 5-FU level in a log scale, and Fig. 3
shows those of 12 patients in a normal scale. The mean plasma levels of 5-FU at 2, 4, 6, 8, and 10 h are 104.0 ± 46.7, 115.7 ± 39.6, 69.9 ± 32.2, 37.0 ± 33.4, and 17.9 ± 22.1 ng/ml, respectively. PK parameters of 5-FU in plasma are shown in Table 1
. The ranges and CVs for Cmax and AUC were 72.5–199.8 ng/ml, 32.3% and 356.6–1145.9 ng · h/ml, 37.7%, respectively.
|
|
|
shows changes in the plasma level of FT, CDHP, and Oxo. PK parameters of FT, CDHP and Oxo are shown in Table 1
. The CVs for Cmax and AUC were 13.6 and 27.5% for FT, 41.0 and 41.8% for CDHP, and 74.6 and 68.0% for Oxo, respectively.
Pharmacokinetics of Ura after Single Administration.
Fig. 2
shows changes in the plasma level of Ura. Although Ura is not a metabolite of S-1, the plasma level of Ura before administration is 13.8 ± 10.3 ng/ml. It increases after administration; however, at 48 h, it returns to 16.0 ± 8.5 ng/ml. PK parameters of Ura are shown in Table 1
.
Pharmacokinetics after Consecutive Day Administration.
Fig. 4
shows plasma 5-FU levels measured on days 1, 7, 14, and 28 and a simulation curve prepared based on the results of the single administration study. The values of FT, CDHP, Oxo, or Ura nearly coincide with the values based on the results of the single administration study. PK parameters obtained after the final administration are shown in Table 1
. Excluding FT, which has a long half-life, each parameter nearly coincides with that obtained after single administration. It was estimated that 4 days would be required to reach the steady state for FT, 2 days for 5-FU, CDHP, and Oxo, and 3 days for Ura.
|
Influence of Gastrectomy.
In the single administration study, we compared the PK parameters of 5-FU between the patients who underwent total gastrectomy (PK-2, PK-5, and PK-10 in Fig. 3
) and those who did not. In the gastrectomy group, Cmax, Tmax, AUC0–14, and T1/2 are 139.5 ± 43.0 ng/ml, 2.0 ± 0.0 h, 822.8 ± 246.0 ng · h/ml and 2.1 ± 0.6 h, respectively. In the nongastrectomy group, they are 124.9 ± 43.0 ng/ml, 4.0 ± 1.7 h, 691.0 ± 286.8 ng · h/ml, and 1.8 ± 0.4 h, respectively.
Toxicity and Antitumor Effect.
Three patients (PK-1, PK-2, and PK-7 in Fig. 3
) encountered grade 3–4 adverse drug reactions. Two patients encountered grade 3 and 4 anemia, and one patient encountered grade 3 neutropenia. Tumor regression >50% were observed in four patients (PK-4, PK-6, PK-7, and PK-12 in Fig. 3
). Both toxicity and antitumor effect have no correlation with Cmax and AUC of 5-FU.
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The plasma 5-FU level in 5-FU/CVI varies by report (6, 7, 8 , 34) . Thus, when the dose range of 5-FU was 190–600 mg/m2/day, Css of 5-FU was 10–25000 ng/ml and AUC0–24 of 5-FU was 217–6600 ng · h/ml, whereas these are derived from the action of DPD, a catabolizing enzyme for 5-FU (9 , 10) . Cmax of 5-FU in single administration of S-1 was 128.5 ± 41.5 ng/ml (72.5–199.8 ng/ml), and AUC0–14 was 723.9 ± 272.7 ng · h/ml (356.6–1145.9 ng · h/ml). When S-1 was administered twice daily, AUC corresponding to a daily dose of S-1 was calculated to be 1447.8 ng · h/m. It is suggested that the Cmax and AUC of S-1 correspond to that of 5-FU administered at 300 mg/m2/day, and that the range of the plasma 5-FU level after administration of S-1 is narrower than that of CVI treatment, although S-1 is administered orally. We concluded that exactly the combination of a DPD inhibitor makes the width of variation of the plasma 5-FU level narrower.
Pharmacokinetic studies of UFT, and 5-FU + Eniluracil (5-FU · EU), which contain DPD inhibitors, have already been conducted (34, 35, 36)
. When UFT at 370 mg/m2 (as the amount of FT) was administered orally, Cmax and AUC0–8 of 5-FU were 265 ng/ml and 338 ng · h/ml, respectively (34)
. When 5-FU · EU were orally administered at 20 mg/m2/day (as the amount of 5-FU), Cmax and AUC0–24 of 5-FU were 1037.7 and 7700 ng · h/ml, respectively (35)
. These PK parameters are obviously different from those of S-1. The differences in Cmax and AUC of 5-FU were considered to be due to the difference in the inhibitory effect of DPD. The DPD inhibitory activity increases in the order of Ura, CDHP, and EU. Furthermore, their characteristics are different. CDHP is reversible, and EU is irreversible. The intensity of the DPD inhibitory activity may affect Cmax and AUC. Besides, it may affect the CVs for the AUC of 5-FU. In fact, the CV values of UFT, S-1, and 5-FU · EU were 65, 35, and 20%, respectively. Also, the DPD inhibitory activity is considered to affect the PK parameter of 5-FU, especially T1/2. T1/2 of each compound was 0.22 h for i.v. administration of 5-FU alone, 0.34 h (-phase) for UFT, 1.9 h for S-1, and 6.1 h for 5-FU · EU (9
, 34
, 35)
. On the other hand, Tmax was 1.1 h for UFT, 3.5 h for S-1, and 0.76 h for 5-FU · EU. The varied values suggest that the slow-releasing effect of FT may be involved, besides the DPD inhibition activity. This means that the ratio of duration, in which the 5-FU plasma level is within a certain range (e.g., 50–200 ng/ml), is higher for S-1 in comparison with other drugs, when consecutive oral administration was used, and that the combination of CDHP and FT was successful to allow an effect similar to that of long-term 5-FU/CVI treatment to be obtained. In addition, because the Tmax and T1/2 of CDHP were similar to those of 5-FU or Oxo, it is suggested that the combination of FT, CDHP, and Oxo as an oral drug is an exquisite method, from the viewpoint of PK parameters.
The plasma FT level after single administration of S-1 was 1971 ng/ml or 2.0 µg/ml. In the Phase I/II studies of single administration of UFT alone and FT alone at 300 mg/body, the plasma FT level was 13.7 and 12.3 µg/ml, respectively (37)
, which are 6-fold higher against that of FT after administration of S-1. Because an average dose of S-1 (as FT) was 35.9 mg/m2, or 50 mg/body, was about 6-fold against that of UFT and FT, the value of the plasma FT level after administration of S-1 is appropriate. On the other hand, the AUC of 5-FU after administration of S-1 was larger than that of UFT; however, the plasma FT level of S-1 was one-sixth of that of UFT. This means that S-1 is more effective than UFT, and that the incidence of adverse reactions, induced by decomposition products of FT or 5-FU, becomes smaller.
However, 50% of CDHP is excreted into urine, indicating that renal function may directly affect the activity of S-1. Therefore, CDHP may remain in the body if renal function is impaired, and an increase in the plasma 5-FU level will be induced by a DPD inhibitory effect of CDHP after consecutive-day administration. It may lead to the occurrence of severe adverse events. Considering that S-1 is to be administered to patients with cancer, physical examinations at regular intervals, including examination of renal function, will be necessary.
Ura is present in blood as an in vivo constituent (shown in Fig. 2
). After the administration of S-1, which contains CDHP, the plasma level of Ura attained a Cmax of 0.8 µg/ml at 5 h and disappeared thereafter at T1/2 of 3 h. From this fact, it may be confirmed that there is a DPD inhibitory activity of CDHP; the effect is reversible. In UFT, Ura is combined as a competitive inhibitor of DPD. The Cmax and T1/2 of Ura of UFT were 3.0 µg/ml and 0.5 h, respectively (37)
, showing a large difference from Ura’s behavior after administration of S-1. This suggests that Ura produced by DPD inhibition with CDHP has little influence on the plasma 5-FU level of S-1.
If Oxo is present in the plasma, it may reduce the antitumor effect by inhibiting the phosphorylation of 5-FU in tumors. In animal experiments, [14C]Oxo was not detectable in tumors after oral administration at 10 mg/kg, although it was 0.8 nmol/g in plasma (25) . It is suggested that the plasma Oxo level observed in this study has little effect.
We found that the influence of gastrectomy was small, but there were small numbers of patients; therefore, we believe that we do not need to take patients’ prior gastrectomy into account for administration of S-1. Regarding pharmacodynamics, both toxicity and antitumor effect have no correlation with Cmax and Tmax of 5-FU.
From these observations, it was pharmacokinetically demonstrated that S-1 is not only an oral drug that shows a similar effect to that of long-term treatment by 5-FU/CVI but is also a next-generation drug with a self-rescuing character. Additional pharmacokinetic studies on interaction with other antitumor drugs will be necessary in the future.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 To whom requests for reprints should be addressed, at Department of Surgery I, Sapporo Medical University, 16 Nishi, Minami-Ichijyo, Chuo-ku, Sapporo 060-8556, Japan. Phone: 81-11-611-2111; Fax: 81-11-613-1678. 
2 The abbreviations used are: 5-FU, 5-fluorouracil; CVI, continuous i.v.; DPD, dihydropyrimidine dehydrogenase; FT, tegafur; UFT, uracil-tegafur; CDHP, 5-chloro-2,4-dihydroxypyridine; Oxo, potassium oxonate; Ura, uracil; BSA, body surface area; PK, pharmacokinetic; CV, coefficient of variation; EU, Eniluracil.
Received 3/ 2/99; revised 5/11/99; accepted 5/14/99.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Ann. Oncol., 7: 47-53, 1996.This article has been cited by other articles:
|
|
 |
|
  K. Fujita, H. Nakayama, W. Ichikawa, W. Yamamoto, H. Endo, F. Nagashima, R. Tanaka, T. Miya, Y. Sunakawa, K. Yamashita, et al. Pharmacokinetics of 5-Fluorouracil in Elderly Japanese Patients with Cancer Treated with S-1 (a Combination of Tegafur and Dihydropyrimidine Dehydrogenase Inhibitor 5-Chloro-2,4-dihydroxypyridine) Drug Metab. Dispos., July 1, 2009; 37(7): 1375 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Fujita, W. Ichikawa, W. Yamamoto, H. Endo, F. Nagashima, R. Tanaka, T. Miya, K. Araki, K. Kodama, Y. Sunakawa, et al. Fixed dosing and pharmacokinetics of S-1 in Japanese cancer patients with large body surface areas Ann. Onc., May 1, 2009; 20(5): 946 - 949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Inoue, Y. Nagasawa, R. Yamamoto, H. Omori, T. Kimura, K. Tomida, Y. Furumatsu, E. Imai, Y. Isaka, and H. Rakugi Severe adverse effects of 5-fluorouracil in S-1 were lessened by haemodialysis due to elimination of the drug NDT Plus, April 1, 2009; 2(2): 152 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Shirasaka Development History and Concept of an Oral Anticancer Agent S-1 (TS-1(R)): Its Clinical Usefulness and Future Vistas Jpn. J. Clin. Oncol., January 1, 2009; 39(1): 2 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Yen-Revollo, R. M. Goldberg, and H. L. McLeod Can Inhibiting Dihydropyrimidine Dehydrogenase Limit Hand-Foot Syndrome Caused by Fluoropyrimidines? Clin. Cancer Res., January 1, 2008; 14(1): 8 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-C. Jeung, S. Y. Rha, H. K. Kim, H. Y. Lim, S. Kim, S. Y. Kim, S. J. Gong, C. H. Park, J. B. Ahn, S. H. Noh, et al. Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations Oncologist, May 1, 2007; 12(5): 543 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Ajani, J. Faust, K. Ikeda, J. C. Yao, H. Anbe, K. L. Carr, M. Houghton, and P. Urrea Phase I Pharmacokinetic Study of S-1 Plus Cisplatin in Patients With Advanced Gastric Carcinoma J. Clin. Oncol., October 1, 2005; 23(28): 6957 - 6965. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Takiuchi, H. Narahara, T. Tsujinaka, M. Gotoh, S.-i. Kawabe, K.-i. Katsu, H. Iishi, M. Tatsuta, K. Fujitani, H. Furukawa, et al. Phase I Study of S-1 Combined with Irinotecan (CPT-11) in Patients with Advanced Gastric Cancer (OGSG 0002) Jpn. J. Clin. Oncol., September 1, 2005; 35(9): 520 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. S.-C. Chu, L. A. Hammond, G. Schwartz, L. Ochoa, S.-Y. Rha, L. Denis, K. Molpus, B. Roedig, S. P. Letrent, B. Damle, et al. Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine S-1 on a Once-Daily-for-28-Day Schedule in Patients with Advanced Malignancies Clin. Cancer Res., August 1, 2004; 10(15): 4913 - 4921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Peters, P. Noordhuis, C. J. van Groeningen, G. Giaccone, U. Holwerda, D. Voorn, A. Schrijvers, J. H. Schornagel, J. H. Beijnen, P. Fumoleau, et al. The Effect of Food on the Pharmacokinetics of S-1 after Single Oral Administration to Patients with Solid Tumors Clin. Cancer Res., June 15, 2004; 10(12): 4072 - 4076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ueda, H. Yamagishi, T. Yamashita, N. Itoh, H. Itoi, T. Shirasaka, and J. A. Ajani S-1-Induced, Prolonged Complete Regression of Lung Metastasis from Gastric Cancer Refractory to 5'-DFUR: a Case Report with Pharmacokinetic Study Jpn. J. Clin. Oncol., May 1, 2004; 34(5): 282 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Nakata, Y. Mitachi, A. Tsuji, S. Yamamitsu, K. Hirata, T. Shirasaka, and K. Hirakawa Combination Phase I Trial of a Novel Oral Fluorouracil Derivative S-1 with Low-Dose Cisplatin for Unresectable and Recurrent Gastric Cancer (JFMC27-9902) Clin. Cancer Res., March 1, 2004; 10(5): 1664 - 1669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Hoff, E. D. Saad, J. A. Ajani, Y. Lassere, C. Wenske, D. Medgyesy, S. Dwivedy, M. Russo, and R. Pazdur Phase I Study with Pharmacokinetics of S-1 on an Oral Daily Schedule for 28 Days in Patients with Solid Tumors Clin. Cancer Res., January 1, 2003; 9(1): 134 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Malet-Martino and R. Martino Clinical Studies of Three Oral Prodrugs of 5-Fluorouracil (Capecitabine, UFT, S-1): A Review Oncologist, August 1, 2002; 7(4): 288 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Cohen, C. G. Leichman, G. Yeslow, M. Beard, A. Proefrock, B. Roedig, B. Damle, S. P. Letrent, A. P. DeCillis, and N. J. Meropol Phase I and Pharmacokinetic Study of Once Daily Oral Administration of S-1 in Patients with Advanced Cancer Clin. Cancer Res., July 1, 2002; 8(7): 2116 - 2122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Peters, C. J. van Groeningen, G. Giaccone, and R. M. White Jr Fluorouracil (5FU) Pharmacokinetics in 5FU Prodrug Formulations With a Dihydropyrimidine Dehydrogenase Inhibitor J. Clin. Oncol., November 15, 2001; 19(22): 4267 - 4269. [Full Text]
|
|
|
|
|
|
R. M. White Correct Fluorouracil (5-FU) Half-Life Comparator for a 5-FU Prodrug Plus a Dihydropyrimidine Dehydrogenase Inhibitor J. Clin. Oncol., June 1, 2001; 19(11): 2970 - 2970. [Full Text] [PDF]
|
|
|
|
|
|
C. J. van Groeningen, G. J. Peters, J. H. Schornagel, H. Gall, P. Noordhuis, M. J. de Vries, S. L. Turner, M. S. Swart, H. M. Pinedo, A. R. Hanauske, et al. Phase I Clinical and Pharmacokinetic Study of Oral S-1 in Patients With Advanced Solid Tumors J. Clin. Oncol., July 14, 2000; 18(14): 2772 - 2779. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
