Japanese Journal of Clinical Oncology 31:251-258 (2001)
© 2001 Foundation for Promotion of Cancer Research
Intracavitary Chemotherapy with 5-Fluoro-2'-deoxyuridine (FdUrd) in Malignant Brain Tumors
Department of Neurosurgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Background: After completing basic research on the anti-tumor effects and neurotoxicity of 5-fluoro-2'-deoxyuridine (FdUrd) and the balance of thymidine kinase and thymidine phosphorylase activities and confirming the safety of intrathecal FdUrd administration in a previous clinical study of meningeal carcinomatosis, intracavitary administration of FdUrd was performed as a second trial in patients with malignant glioma and metastatic brain tumors.
Methods: The study population consisted of 13 patients, six with glioblastoma, one with anaplastic astrocytoma and six with metastatic brain tumors. This treatment was applied for cystic, small-volume residual or recurrent tumors. FdUrd (1–10 µg ) was administered every day at least 25 times through an Ommaya device placed in the cyst or closed postoperative cavity reconstructed with a patch of galea aponeurotica. Intracavitary chemotherapy with FdUrd was preceded by radiation therapy in two patients but no other adjuvant therapy was performed.
Results: No side effects such as headache, nuchal pain, convulsive attack, bone marrow suppression or liver dysfunction were observed during the course of chemotherapy. Seven of the 13 patients showed responses: complete response six, minor response one, no change two and progressive disease four after the twenty-fifth intracavitary administration of FdUrd when tumor sizes on CT scans and MRI before and after intracavitary chemotherapy were compared.
Conclusions: Intracavitary FdUrd chemotherapy may be useful for the treatment of small-volume tumors.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The results obtained in basic research on intrathecal 5-fluoro-2'-deoxyuridine (FdUrd) chemotherapy suggested that the intrathecal space provides a favorable environment for FdUrd administration and produces a good therapeutic effect on meningeal dissemination of malignant tumors without exhibiting toxicity (1,2). Based on laboratory results, intrathecal chemotherapy with FdUrd for meningeal carcinomatosis was attempted clinically and proved to be a useful and safe therapeutic procedure. The overall response rate was >70% (3).
Fluoro-2'-deoxyuridine (FdUrd) is a 5-fluorouracil (5-FU) derivative. It is converted to an intracellular monophosphate derivative, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which inhibits thymidylate synthase (EC 2.1.1.45) (a key enzyme in DNA synthesis), by thymidine kinase (TK) (EC 2.7.1.21). On the other hand, FdUrd is converted into 5-FU by thymidine phosphorylase (TPase) (EC 2.4.2.4) and its efficacy is markedly reduced (4). In the present study, the balance of thymidine phosphorylase and thymidine kinase activities in the tissues of malignant glioma, metastatic brain tumors, surrounding and distant brain and cyst fluids were measured to determine whether intracavitary administration of FdUrd is suitable for treatment of malignant tumors. FdUrd was administered as intracavitary chemotherapy for malignant glioma and metastatic brain tumors and its efficacy was evaluated in 13 patients.
This basic research and clinical application were performed with the approval of the Ethics Committee of our institute.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Chemicals
Thymidine was purchased from Sigma Chemical (St. Louis, MO) and [2-14C]thymidine (2.2 GBq/mmol) from DuPont (Wilmington, DE). All other chemicals were commercial products.
Samples of Cyst Fluid of Tumors and Human Brain Tissue
Cyst fluid was obtained during surgery by puncturing the cyst with a needle containing heparin.
Surrounding and distant brain tissues were sampled from patients with resected metastatic brain tumors. Distant tissues were sampled when corticotomy was required to approach deep-seated metastatic brain tumors and samples of the surrounding brain tissue were removed from resected metastatic tumors. Tissue and cyst fluid samples were quickly frozen at –80°C and stored until assay.
Assay of Thymidine Kinase (TK) and Thymidine Phosphorylase (TPase)
All procedures were carried out at 4°C. Tissue samples were minced with scissors and homogenized in 4 volumes of 50 mM Tris–HCl (pH 8.0) containing 10 mM 2-mercaptoethanol, 25 mM KCl and 5 mM MgCl2. The homogenate was centrifuged at 105 000 g for 60 min and the resultant supernatant was used for enzyme assays. TK activity was measured by determining the conversion of labeled thymidine to labeled nucleotides employing the DEAE-cellulose disc method (5,6). The reaction mixture, in a total volume of 0.25 ml, contained 50 mM Tris–HCl buffer (pH 8.0), 5 mM MgCl2, 5 mM ATP, 6 mM glycerophosphate, 0.05 mM [2-14C]thymidine (25 µl; 30 000 c.p.m.) and 0.2 ml of enzyme solution. The mixture was incubated at 37°C for 10 min and the reaction was stopped by heating in a boiling water-bath for 3 min. The mixture was centrifuged at 3000 r.p.m. for 30 min and 100 µl of the supernant were applied to a DEAE-cellulose disc, 3 cm in diameter. The disc was immersed in 1 mM ammonium formate for 20 min. The washing liquid was discarded and the disc was then washed with distilled water. This procedure was repeated once more. Nucleotides were retained on the disc during this procedure. Next, the dried disc was placed in a vial containing 10 ml of toluene–phosphorus mixture and its radioactivity was determined.
TPase activity was measured in the manner described above (7). The reaction mixture, in a total volume of 0.125 ml, consisted of 60 mM potassium phosphate buffer (pH 7.6), 0.6 mM 2-14C-labeled nucleotides (0.025 µCi/tube) and 0.05 ml of enzyme solution. The mixture was incubated for 30 min, 2 M perchloric acid (25 µl) was added and the mixture was centrifuged at 3000 r.p.m. for 10 min. Then 100 µl of the supernatant were added to 30 µl of 2 M KOH solution. The resulting precipitate was removed by centrifugation (3000 r.p.m., 10 min) and 10 µl of the supernatant were applied to a silica gel TLC plate (Merck TLC plates precoated with silica gel 60 F254; 3 x 10 cm; thickness, 0.25 mm) and developed with a mixture of chloroform, methanol and acetic acid (17:3:1, v/v/v). Samples of the bases and nucleotides were applied to the plate before the test sample and were vizualized under UV light (254 nm). The spots of each compound were scraped into vials and extracted with 4 M HCl (50 m1) and their radioactivity was measured as described above.
Patients and Intracavitary Chemotherapy with FdUrd
Patients with primary or recurrent malignant glioma and those with metastatic brain tumors were enrolled in this study (Table 1). When most of the malignant glioma or metastatic brain tumor was cystic or resected without opening the ventricle but a small volume of tumor remained because the tumor was composed of a thin wall or was close to an eloquent zone, the cyst was punctured and the Ommaya device was placed or the post-removal cavity was closed using a patch of galea aponeurotica after an Ommaya device had been placed at the center of the closed cavity (Fig. 1). In patient 1, recurrent tumor was not removed because it was located in a region adjacent to the motor area. The Ommaya device was placed in the closed cavity after removal of the pseudo-membrane overlying the cyst wall. In two patients (patients 2 and 3), the Ommaya device was placed in the cyst under local anesthesia without tumor removal. In patient 4, the Ommaya device was placed during initial surgery for metastatic brain tumor to measure CSF penetration of CDDP. In patients 5–9, a closed cavity was made after removal of most of the tumor. In patient 10, intracavitary chemotherapy was performed through the Ommaya device placed during initial surgery as in patient 4. In patient 11, the tumor was subtotally removed except for the tumor tissue extending to the corpus callosum. In patients 12 and 13, the postoperative cavity was also closed as described above during initial surgery. In patient 12, CSF obtained through the Ommaya reservoir returned to positive from negative cytology and progressive marginal enhancement on MRI was observed. Intracavitary chemotherapy with FdUrd through the Ommaya reservoir was started on the day after surgery. FdUrd (1–10 µg) was administered every day at least 25 times. The dose of FdUrd was determined from the clinical study on meningeal carcinomatosis by intraventricular FdUrd administration (3). When patients showed a response or stable disease and they could come to our hospital every day after discharge, intracavitary FdUrd administration was added. There was no background information from which to decide the frequency of FdUrd administration. The first case of recurrent anaplastic astrocytoma (patient 1) showed marked improvement after intracavitary administration of FdUrd 25 times, so thereafter FdUrd was administered 25 times or more. In two patients with primary glioblastoma (patients 6 and 7), radiotherapy was refused because of hair loss and only intracavitary chemotherapy with FdUrd was accepted as adjuvant therapy. In patients 2 and 3, surgical removal and radiotherapy were refused by their families because of the patients’ age and the poor performance status (bed rest.). The Ommaya device was placed in the cyst and tumor cavity under local anesthesia. This treatment was performed during admission and after discharge. In two patients (patients 9 and 11) with primary glioblastoma, intracavitary chemotherapy was started 2 months after completion of radiotherapy to define the efficacy of chemotherapy alone.
|
|
Determination of FdUrd Concentrations in Cyst Fluids After Intracavitary Administration
The time courses of changes in FdUrd concentrations in the closed cavity after intracavitary administration of 5 µg of FdUrd in three patients (patients 1, 5 and 13) were determined. A 2 ml volume of cyst fluid was serially sampled through the same reservoir after FdUrd injection followed by irrigation of the Ommya reservoir with 2.0 ml of saline to wash out residual FdUrd. A 1 ml volume of cyst fluid was discarded at each time point before sampling.
Determination of FdUrd Concentrations in the Tumor After Intracavitary Administration in a Patient with a Metastatic Brain Tumor from Lung Cancer
After exposing the cortical surface, an equivalent volume of saline containing 10 µg of FdUrd to the cyst fluid after completely aspirating 10.8 ml of the cyst fluid was administered into the cyst through a Scott puncturing needle and the fluid was maintained for 30 min. Tumor tissues were quickly sampled after completely aspirating cyst fluid containing FdUrd and exposing the tumor surface. Peripheral blood was also serially sampled and assayed. However, this patient was not enrolled in this study, because the tumor had been totally removed.
Evaluation of the Clinical Effects of Intracavitary Chemotherapy with FdUrd
Clinical evaluation was performed after the twenty-fifth intracavitary administration of FdUrd by comparing the tumor size on CT and MRI before and after intracavitary chemotherapy. Responsiveness to intracavitary administration of FdUrd was evaluated according to the criteria of the Japan Neurosurgical Society considering the duration of chemotherapeutic effectiveness >4 weeks (8). Complete response (CR) was defined as complete disappearance of tumor with the duration of chemotherapeutic effectiveness >4 weeks, partial response (PR) was defined as >50% tumor regression with the duration longer than 4 weeks, minor response (MR) was defined as 25–50% tumor regression or >50% tumor regression with a duration <4 weeks, no change (NC) was defined as no change in tumor size with the duration >4 weeks and progressive disease (PD) was defined as detection of a growing tumor on MRI. The response rate was also evaluated after excluding minor response according to the criteria of the Japan Neurosurgical Society.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Activities of Thymidine Phosphorylase (TPase) and Thymidine Kinase (TK)
Cyst Fluid
TPase and TK were not detected in cyst fluid from benign tumors, i.e. neurinoma, craniopharyngioma or Rathke’s cleft cyst, while low levels of TPase were detected in three of five glioblastomas and eight of nine metastatic brain tumors and high levels of TK were detected in one glioblastoma and two metastatic brain tumors (Table 2).
|
Brain Tumors and Distant and Surrounding Tissue
The level of TPase in the malignant glioma was significantly lower than that in brain metastasis (p < 0.03, unpaired t-test); there were significant differences in TPase levels between surrounding and distant brain tissue (p < 0.03, unpaired t-test). The TPase level in metastatic brain tumors was significantly lower (Table 3) than those in cancer of the stomach (135.6 ± 89.4, 13), colon (147.9 ± 68.6, 12), liver (204.1 ± 85.5, 11) and lung (319.3 ± 128.3, 7) reported by Maehara et al. (5) (values are expressed as means ± SE, number of samples assayed). The TPase level of the surrounding tissue was significantly lower than those in the metastatic brain tumor (p < 0.005) and the distant brain tissue (p < 0.03). The levels of TK in glioma, metastasis and distant brain tissue were similar. However, the level in the surrounding brain tissue seemed to be higher than those in metastatic brain tumors (p < 0.02) and distant brain tissue, although there were no significant differences compared with levels in glioma, metastatic brain tumors or distant brain tissue (Table 3).
|
Clinical Results
Determination of FdUrd Concentrations in Fluids of Tumor Cavity After Intracavitary Administration
The concentrations of FdUrd decreased exponentially after administration into the tumor cavity. However, the concentrations of FdUrd in the fluid of the tumor cavity were maintained high. The mean concentration of FdUrd in the fluid of the tumor cavity showed 60.3 ng/ml at 2 h and 45.6 ng/ml at 3 h after administration of 5 µg of FdUrd into the tumor cavity (Fig. 2).
|
Determination of FdUrd Concentrations in the Tumor and Plasma After Intracavitary Administration in a Patient with Metastatic Brain Tumor from Lung Cancer
The tissue concentrations of FdUrd in the region facing cyst fluid were 31.8 and 73.6 ng/g. The concentrations of FdUrd at the outer marginal region were 7.7, 9.9 and 3.4 ng/g and that in the brain tissue adjacent to the tumor was 0.8 ng/g. However, FdUrd was not detected in the plasma at any sampling point during the course of tissue sampling (Fig. 3).
|
Chemotherapeutic Effects
Progressive disease was observed in four patients and no change in two patients. In patient 2, the cyst shrank, probably due to aspiration of cyst fluid. However, the response was determined to be no change because there was no change in overall enhancement area on MRI. In patient 5, enhancement was initially considered to be a postoperative change on MRI. However, the cyst grew and a final diagnosis of a recurrent tumor was made. This tumor continued to grow despite intracavitary chemotherapy. In patient 7, marginal enhancement of the cavity on MRI was decreased except for the floor of the cavity and this lesion gradually grew after cessation of intracavitary chemotherapy. In patients 6, 8 and 12, the tumors grew despite intracavitary chemotherapy (Table 1) (Fig. 4). On the other hand, CR was observed in six patients and MR was observed in one patient (patient 3). In patient 11, the tumor extending to the corpus callosum disappeared with disappearance of marked edema (Table 1) (Fig. 5). The duration of chemotherapeutic effectiveness in patients showing CR and MR was 3 years and 3 months in patient 1, who has not shown any sign of recurrence on MRI to date, 3 weeks in patient 3, 8 weeks in patient 4, 12 weeks in patient 9, 10 weeks in patient 10, 9 weeks in patient 11 and 32 weeks in patient 13. The duration of chemotherapeutic effectiveness in patient 3 was only 3 weeks and the response was judged a minor response based on the criteria of the Japan Neurosurgical Society. Consequently, the overall response rate based on the criteria of the Japan Neurosurgical Society after excluding minor respose was 46.2%. No side effects such as nausea, vomiting, headache, convulsive attack or bone marrow suppression were observed in any of the patients.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The fluorinated pyrimidines 5-FU and FdUrd are widely used anticancer drugs that exhibit antineoplastic activity against a broad spectrum of solid tumors; these drugs are among the most active agents employed in the treatment of gastrointestinal cancers. The major mechanism of action of both of these agents is the inhibition of thymidylate synthase by their common metabolite, FdUMP, thereby interfering with DNA synthesis (9–11). 5-FU, however, is partially converted to fluoro-ß-alanine, which shows neurotoxicity (12–15). The neurotoxicity is lower if the rate of conversion of FdUrd to 5-FU is reduced.
TPase, which converts FdUrd into 5-FU, and TK, which converts FdUrd into FdUMP, are the two key enzymes involved in the metabolism of FdUrd. Theoretically, a lower level of TPase and a higher level of TK are considered better conditions for chemotherapy with FdUrd. The extremely low levels of TPase and TK in the cyst fluids confirmed in the present study and the high TK activity in tumor cells are conditions that favor intracavitary chemotherapy with FdUrd. In the present study, brain tissue showed low levels of TPase as compared with levels in the stomach, colon, liver and lung reported by Maehara et al. (5) and the levels of TPase in brain tissue surrounding the site of malignant tumor invasion showed significantly lower levels of TPase than those in distant brain tissue. This finding indicated that these were suitable conditions for intracavital chemotherapy to prevent or treat local recurrence or residual tumors that cannot be surgically resected.
The most favorable characteristic of intrathecal chemotherapy with FdUrd for central nervous system tumors is that this agent exhibits acceptable neurotoxicity. In this study, TPase activity was decreased and TK activity was increased in brain tissue surrounding metastatic brain tumors. One possible explanation for the increased level of TK in the surrounding brain tissue is that these elevated TK levels result from cells damaged by surrounding edema fluid, as suggested by Piersanti et al. (16); although they discussed high serum levels of TK in cerebral thrombosis, hematomas and subarachnoid hemorrhage, this explanation seems feasible in the light of our findings. Alternatively, TK is a good indicator of cell proliferation because it is formed in the cells prior to cell division (17) and tumor cells invading the surrounding brain tissue as well as reactive astrocytes may be the most actively proliferating cells.
In intracavitary chemotherapy with anticancer drugs, the rate of drug diffusion through the tumor into the tumor margin is important, because the antitumor effect is minimal if it is low. In this study, the concentrations of FdUrd at the margins of the tumor were 7.7, 9.9 and 3.4 ng/g tumor tissue after intracavitary administration of 10 µg of FdUrd (10 µg/11 ml ) during surgical resection of a metastatic brain tumor, although this was studied in only one patient. This level of FdUrd concentration at the tumor margin exceeded the concentration of 1 ng/g tissue and the concentrations required for 50% growth inhibition of various kinds of experimental brain tumors in vitro on a microgram basis (IC50) (1). We can speculate on the rate of diffusion through tumor cells from the diffusion rate in the brain. Therefore, it is necessary to measure the diffusion constant of FdUrd in the brain in comparison with drugs that can be administered intrathecally, such as methotrexate and cytosine arabinoside.
The changes in FdUrd concentration in the tumor cavity over time following intracavitary administration may be more important than peak levels in determining tumor response and in predicting neurotoxicity. Therefore, we compared FdUrd concentrations in the tumor cavity over time following intracavitary administration with CSF FdUrd concentrations over time following intraventricular administration of an equivalent dose of FdUrd in seven (5 µg) and nine (3 µg) patients with meningeal carcinomatosis. The results showed long-lasting higher levels of FdUrd following intracavitary administration. The concentrations of FdUrd in the fluid of the tumor cavity were significantly higher than those in CSF of the lateral ventricle at 30, 60, 90 and 120 min after administration of FdUrd (p < 0.05, p < 0.001, p < 0.005 and p < 0.001, respectively). The mean concentration of FdUrd in the fluid of the tumor cavity at 2 h after administration of 5 µg FdUrd into the tumor cavity was 60.3 and 3.4 ng/ml in the CSF when administered intraventricularly (unpublished data). These findings may lead to long-lasting FdUrd distribution within the tumor itself, resulting in a good antitumor effect.
Intracavitary chemotherapy with FdUrd showed a 46.2% response rate according to the criteria of the Japan Neurosurgical Society. In this study, the duration of chemotherapeutic effectiveness is important, because intracavitary administration frequently alters the vascular permeability of tumor tissue exposed to the drugs, resulting in a decrease in the enhanced effect on tumor tissue by contrast medium on CT scans and MRI. The durations of effectiveness were 3.25 years and 8, 12, 10, 9 and 32 weeks in six patients. Based on these durations of chemotherapeutic effectiveness, the modified vascular permeability of tumor tissue induced by direct exposure to anticancer drug was negligible.
In the present study, TPase in surrounding brain tissue was lower than that in distant brain tissue and the level of TPase was very low in the cyst fluid of malignant tumors. FdUrd administered into the tumor cavity was maintained at higher concentrations and for longer periods than following intraventricular administration. Moreover, FdUrd was distributed in the marginal region of the tumor at concentrations >1 ng/g tissue on 30 min exposure of the cyst to FdUrd. These findings suggest that the intracavitary space after tumor resection or cystic metastatic brain tumors situated in the eloquent zone provide a favorable environment for FdUrd administration. However, a good response to intracavitary chemotherapy with FdUrd was observed only for small malignant tumors such as recurrent tumors in the margin of surgically resected tumors or surgically inoperable remnant tumors. Further studies are required to obtain better results, e.g. using higher doses or continuous intracavitary administration using a pump system.
|
FOOTNOTES |
|---|
+ For reprints and all correspondence: Hidemitsu Nakagawa, Department of Neurosurgery, Osaka Medical Center for Cancer and Cardiovascular Diseases (OMCC), 3 Nakamichi l-chome, Higashinari-ku, Osaka 537-8511, Japan. E-mail: hidemitu@osaka.macnet.or.jp
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1 Yamada M, Nakagawa H, Fukushima M, Shimizu K, Hayakawa T, Ikenaka K. In vitro study on intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for meningeal dissemination of malignant brain tumors. J Neuro-oncol 1998;37:115–21.[Medline]
2 Nakagawa H, Yamada M, Fukushima M, Ikenaka K. Intrathecal 5-fluoro-2'-deoxyuridine (FdUrd) for the treatment of solid tumor neoplastic meningitis: an in vivo study. Cancer Chemother Pharmacol 1998;43:247–56.[Web of Science]
3 Nakagawa H, Yamada M, Maeda M, Iwatsuki K, Hirayama A, Ikenaka K. Clinical trial of intrathecal administration of 5-fluoro-2'-deoxyuridine for treatment of meningeal dissemination of malignant tumors. J Neuro-oncol 1999;45:175–83.[Medline]
4 Birnie GD, Kroeger H, Heidelberger C. Studies of fluorinated pyrimidines. XVIII. The degradation of 5-fluoro-2'-deoxyuridine and related compounds by nucleoside phosphorylase. Biochemistry 1963;2:566–72.
5 Maehara Y, Nakamura H, Nakane Y, Kawai K, Okamoto M, Nagayama S, et al. Activities of various enzymes of pyrimidine nucleotide and DNA synthesis in normal and neoplastic human tissues. Gann 1982;73:289–98.[Web of Science][Medline]
6 Hashimoto T, Arima T, Okuda H, Fujii S. Purification and properties of deoxythymidine kinases from the Yoshida sarcoma. Cancer Res 1972;32:67–72.
7 Yamada EW. Pyrimidine nucleoside phophorylases of rat liver. Separation by ion exchange chromatography and studies of the effect of cytidine or uridine administration. J Biol Chem 1968;243:1649–55.
8 Committee of Brain Tumor Registry of Japan, Japan Neurosurgical Society. The criteria of clinical effects on brain tumor. In: Committee of Brain Tumor Registry of Japan, Japanese Pathological Society, editors. General Rules for Clinical and Pathological Studies on Brain Tumors. Tokyo: Kanehara 1995;54–6 (in Japanese).
9 Cox S, Harmenberg J. Assay of intracellular thymidylate synthetase activity and inhibition by 5-fluoro-2'-deoxyuridine in lymphocytes. J Biochem Biophys Methods 1992;25:17–23.[Web of Science][Medline]
10 Ritter EJ, Scott WJ, Wilson JG, Lampkin BC, Neely JE. Effect of 5-fluoro-2'-deoxyuridine on deoxyribonucleotide pools in vivo. J Natl Cancer Inst 1980;65:603–5.
11 Cheng Y, Nakayama K. Effects of 5-fluoro-2'-deoxyuridine on DNA metabolism in HeLa cells. Mol Pharmacol 1982;23:171–4.[Abstract]
12 Koenig H, Patel A. Biochemical basis for fluorouracil neurotoxicity. The role of Krebs cycle inhibition by fluoroacetate. Arch Neurol 1970;23:155–60.
13 Okada R, Shibutani M, Matsuo T, Kuroiwa T, Tajima T. Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning the monofluorinated organic metabolites, monofluoroacetic acid and alpha-fluoro-beta-alanine. Acta Neuropathol (Berl) 1990;81:66–73.[Medline]
14 Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988;6:1653–64.
15 Zhang R, Soong S-J, Liu T, Barnes S, Diasis RB. Pharmacokinetics and tissue distribution of 2-fluoro-beta-alanine in rats. Potential relevance to toxicity pattern of 5-fluorouracil. Drug Metab Dispos 1992;20:113–9.[Abstract]
16 Piersanti F, Feltrin F, Chiapetta F, Santilli S. Deoxythymidine kinase: a marker of brain damage? Preliminary observations and considerations. Presented at Biochemica Clinica del Sistema Nervoso, Fisiopatologia, Diagnostica, Morfologia, Vicenza, Italy, May 26–27, 1989.
17 Bello LJ. Regulation of thymidine kinase synthesis in human cells. Exp Cell Res 1974;89:263–4.[Web of Science][Medline]
Received November 21, 2000; accepted February 22, 2001.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||