Discovery and development of novel anticancer drug capecitabine

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three enzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.     

Capecitabine: a novel agent for the treatment of solid tumors

Although 5-fluorouracil (5-FU) has been used to treat breast and colorectal cancers for several decades, bolus 5-FU has disappointing efficacy. Prolonged infusion schedules and biomodulation with leucovorin have resulted in improved response rates, but these have not translated into significant improvements in survival in patients with metastatic disease. Furthermore, prolonged infusion is inconvenient for patients and can result in medical complications. New oral fluoropyrimidines, including capecitabine, are promising alternatives to i.v. 5-FU. Capecitabine generates 5-FU preferentially within tumors through exploitation of the high intratumoral activity of thymidine phosphorylase. The tumor selectivity of capecitabine has been confirmed in a clinical study of colorectal cancer patients. Clinical trials have shown that capecitabine is an effective, well-tolerated treatment for breast and colorectal cancer, with response rates of 20-26% in anthracycline- and taxane-pretreated metastatic breast cancer. As first-line monotherapy, capecitabine produces response rates of 25-27% in metastatic colorectal cancer and 30% in metastatic breast cancer. In all studies to date, capecitabine has been well tolerated, with adverse events typical of infusional 5-FU and manageable with treatment interruption/dose modification. Myelosuppression and alopecia are rare. Capecitabine is also being investigated in other solid tumors (including ovarian, pancreatic and gastric cancers) as adjuvant monotherapy in breast and colorectal cancer, and in combination with other cytotoxic agents. Results of ongoing trials are eagerly awaited.     

Capecitabine in gastric cancer

Double and triplet regimens comprising a fluoropyrimidine and a platinum compound, with or without an anthracycline or taxane are accepted standards of care for advanced gastric cancer. Capecitabine, an oral fluoropyrimidine designed to selectively deliver 5-fluorouracil (5-FU) to tumor cells, is safe and effective in combination chemotherapy regimens for advanced gastric cancer, and it is noninferior to 5-FU for survival. As capecitabine is more convenient to administer than infused 5-FU, avoiding the need for central venous access and the associated risk of complications, it is also an accepted alternative to 5-FU within perioperative combination chemotherapy regimens for resectable gastric cancer.     

Altered deoxyuridine and thymidine in plasma following capecitabine treatment in colorectal cancer patients

AIMS: To investigate the relationship between changes in plasma deoxynucleoside concentrations and response and toxicity in patients treated with capecitabine. METHODS: Twenty-six patients received 2 g capecitabine twice daily orally for 2 weeks of a 3-week cycle. Blood samples were collected on day 0 (baseline), day 8, day 15 and day 22 of the first cycle for the determination of plasma thymidine (TdR) and deoxyuridine (UdR) concentrations. Patients were reviewed weekly during the first cycle, then 3-weekly for toxicity assessment. Response was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. RESULTS: The plasma UdR and UdR/TdR ratios were significantly elevated (P < 0.001) compared with baseline (49.3 +/- 20.8 nmol l(-1)) for the entire 3-week treatment period. In contrast, the plasma TdR concentrations of these patients were significantly reduced only on day 8 (P < 0.01) compared with baseline (12.1 +/- 3.83 nmol l(-1)), but returned gradually to basal levels by day 15. There were no significant correlations demonstrated between pretreatment or maximal post-treatment plasma nucleoside ratio and either toxicity or response. The TSER genotype frequencies of homozygous TSER*2, TSER*3 and heterozygous TSER*2/*3 were 7.7%, 42.3% and 50%, respectively. These preliminary data also indicate no direct relationship between thymidylate synthase (TS) genotype and plasma nucleoside levels. CONCLUSIONS: Capecitabine mimics continuous infusion of 5-FU to achieve sustained cellular TS inhibitory effects and suggests the antiproliferative mechanism of capectabine is at least partly due to TS inhibition through its active metabolite FdUMP. Although plasma UdR and TdR concentrations and the UdR/TdR ratio can provide some pharmacodynamic indication of TS inhibition, they are unlikely to predict therapeutic response or toxicity accurately following capecitabine treatment in cancer patients.     

Capecitabine: Preclinical Pharmacology Studies

Capecitabine (N⁴-pentyloxycarbonyl-5-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate, which was designed to besequentially converted to 5-fluorouracil (5-FU) by three enzymes located inthe liver and in tumors; the final step is the conversion of5-deoxy-5-fluorouridine (5-DFUR) to 5-FU by thymidine phosphorylase (dThdPase) in tumors. In human cancer xenograft models, capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma ornormal tissue (muscle). The tumor 5-FU levels were also much higherthan those achieved by intravenous administration of 5-FU at equitoxic doses.Capecitabine and its intermediates are not cytotoxic by themselves,but become effective after their conversion to 5-FU. This tumor selectivedelivery of 5-FU ensured greater efficacy and a more favorable safety profilethan with other fluoropyrimidines. In 24 human cancer xenograft modelsstudied, capecitabine was more effective at a wider dose range andhad a broader spectrum of antitumor activity than 5-FU, UFT or itsintermediate metabolite 5-DFUR. The susceptibility of the xenografts tocapecitabine correlated with tumor dThdPase levels. Moreover, theconversion of 5-DFUR to 5-FU by dThdPase in tumor was insufficient in axenograft model refractory to capecitabine. In addition, the efficacy ofcapecitabine was enhanced by dThdPase up-regulators, such astaxanes and cyclophosphamide. The efficacy of capecitabine may, therefore, beoptimized by selecting the most appropriate patient population based on dThdPasestatus and/or by combining it with dThdPase up-regulators. Capecitabinehas additional characteristics not found with 5-FU, such as potentantimetastatic and anticachectic actions in mouse tumor models.With this profile, capecitabine may have substantial potential in cancer treatment.     

Bioactivation of capecitabine in human liver: involvement of the cytosolic enzyme on 5'-deoxy-5-fluorocytidine formation.

Capecitabine, an anticancer prodrug, is thought to be biotransformed into active 5-fluorouracil (5-FU) by three enzymes. After oral administration, capecitabine is first metabolized to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase (CES), then 5'-DFCR is converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase. 5'-DFUR is activated to 5-FU by thymidine phosphorylase. Although high activities of drug metabolizing enzymes are expressed in human liver, the involvement of the liver in capecitabine metabolism is not fully understood. In this study, the metabolism of capecitabine in human liver was investigated in vitro. 5'-DFCR, 5'-DFUR, and 5-FU formation from capecitabine were investigated in human liver S9, microsomes, and cytosol in the presence of the inhibitor of dihydropyrimidine dehydrogenase, 5-chloro-2,4-dihydroxypyridine. 5'-DFCR, 5'-DFUR, and 5-FU were formed from capecitabine in cytosol and in the combination of microsomes and cytosol. Only 5'-DFCR formation was detected in microsomes. The apparent K(m) and V(max) values of 5-FU formation catalyzed by cytosol alone and in combination with microsomes were 8.1 mM and 106.5 pmol/min/mg protein, and 4.0 mM and 64.0 pmol/min/mg protein, respectively. The interindividual variability in 5'-DFCR formation in microsomes and cytosol among 14 human liver samples was 8.3- and 12.3-fold, respectively. Capecitabine seems to be metabolized to 5-FU in human liver. 5'-DFCR formation was exhibited in cytosol with large interindividual variability, although CES is located in microsomes in human liver. In the present study, it has been clarified that the cytosolic enzyme would be important in 5'-DFCR formation, as is CES.     

Evolution of 5-fluorouracil-based chemoradiation in the management of rectal cancer

5-Fluorouracil (5-FU) is the most widely used agent for the management of colorectal cancer. Capecitabine is metabolized by three enzymatic actions, the last of which is mediated by thymidine phosphorylase, to produce 5-FU. Given the oral bioavailability of capecitabine as well as in-vitro and in-vivo findings showing higher expression of thymidine phosphorylase in tumor cells and xenografts compared with normal tissue, capecitabine is an evolving candidate in the management of colorectal cancer with antimetabolite-based therapy. An ideal radiosensitizing agent must balance oncological outcomes with adverse effects and feasibility of administration. This discussion addresses the evolving role of 5-FU in the management of rectal cancer in the neoadjuvant setting in combination with ionizing radiation.     

孕16～28周胎儿脐血β-地中海贫血基因及其血红蛋白电泳、红细胞参数变异分析

目的：探讨红细胞参数和毛细管血红蛋白电泳及β-地中海贫血基因检测在产前诊断β-地中海贫血中的互补作用。方法：210例孕16～28周胎儿脐血标本根据β-地中海贫血基因型测定结果分为4组,对4组血常规结果中的平均红细胞体积（MCV）、平均红细胞血红蛋白含量（MCH）、平均红细胞血红蛋白浓度（MCHC）及血红蛋白A（HbA％）、等多参数进行统计分析。结果：对照组MCV、MCH、MCHC与其他各组结果对比差异无统计学意义（P〉0．05）;但HbA（％）在其他组间的结果均低于对照组,差异有统计学意义（P〈0．05）。结论：孕16～28周胎儿脐血MCV、MCH及MCHC检测对β-地中海贫血的产前诊断价值不大,而脐血毛细管血红蛋白电泳及β-地中海贫血基因联合检测则有很好的互补作用。     

Assessment of Drug–drug Interaction and Optimization in Capecitabine and Irinotecan Combination Regimen using a Physiologically Based Pharmacokinetic Model

Capecitabine and irinotecan (CPT-11) combination regimen (XELIRI) is used for colorectal cancer treatment. Capecitabine is metabolized to 5-fluorouracil (5-FU) by three enzymes, including carboxylesterase (CES). CES can also convert CPT-11 to 7-ethyl-10-hydroxycamptotecin (SN-38). CES is involved in the metabolic activation of both capecitabine and CPT-11, and it is possible that drug–drug interactions occur in XELIRI. Here, a physiologically based pharmacokinetic (PBPK) model was developed to evaluate drug–drug interactions. Capecitabine (180 mg/kg) and CPT-11 (180 mg/m²) were administered to rats, and blood (250 μL) was collected from the jugular vein nine times after administration. Metabolic enzyme activities and K_i values were calculated through in vitro experiments. The plasma concentration of 5-FU in XELIRI was significantly decreased compared to capecitabine monotherapy, and metabolism of capecitabine by CES was inhibited by CPT-11. A PBPK model was developed based on the in vivo and in vitro results. Furthermore, a PBPK model-based simulation was performed with the capecitabin dose ranging from 0 to 1000mol/kg in XELIRI, and it was found that an approximately 1.7-fold dosage of capecitabine was required in XELIRI for comparable 5-FU exposure with capecitabine monotherapy. PBPK model-based simulation will contribute to the optimization of colorectal cancer chemotherapy using XELIRI.     

Capecitabine: effective oral fluoropyrimidine chemotherapy

Fluoropyrimidine chemotherapy, principally with 5-fluorouracil (5-FU), has been a standard of care for a range of solid tumours for many years. Capecitabine, a precursor of 5-FU, is an oral fluoropyrimidine cytotoxic agent developed with the aim of providing a more effective, less toxic alternative to 5-FU, with the added advantage of oral administration. In clinical trials, capecitabine has proven to be an effective substitute for 5-FU in colorectal and breast cancer, and has become an accepted standard treatment in these tumours, both as a single agent and as a component of combination chemotherapy. It is also effective in a number of other solid tumours and as a radiosensitising agent. Capecitabine has significantly less serious toxicity than 5-FU when used alone or in combination with other cytotoxic agents. It has been shown to be resource saving in comparison with accepted standard comparator regimens in breast and colorectal cancer. Ongoing and future clinical trials will continue to examine, and are likely to expand, the role of capecitabine in the treatment of breast and colorectal cancer, as well as a number of other malignancies, both in the advanced palliative and adjuvant curative settings. This will involve the use of capecitabine as a single agent and increasingly in combination with other new anticancer agents.     

Comparison of in vitro metabolic conversion of capecitabine to 5-FU in rats, mice, monkeys and humans--toxicological implications

Capecitabine is an oral anticancer prodrug which is converted to 5-fluorouracil (5-FU) via 3 enzymatic steps, these being 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU by carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TP), respectively. Because rats, mice and monkeys are used for preclinical safety studies, we investigated the in vitro conversion from capecitabine to 5-FU by hepatic and intestinal mucosal microsomes and cytosols, to compare their metabolic activity to that of humans. Capecitabine was hydrolyzed to 5'-DFCR in hepatic and intestinal mucosal microsomes in these animal species. In humans and monkeys, CL(int) (V(max)/K(m)) for the hydrolysis of capecitabine in intestine (expressed as μl/min/g tissue) was much lower than that in hepatic microsomes but, in rats and mice, CL(int) was higher in intestine than in liver. In humans and monkeys, similar K(m) values and inhibition patterns by tetrahydrouridine (THU) a CDA inhibitor, were observed in CDA activity of hepatic and intestinal cytosols. However, rats showed very low CDA activity and mice showed non-Michaelis-Menten kinetics and a different inhibition pattern by THU. K(m) values for TP activity were almost similar in rats, mice, monkeys and humans. In conclusion, it was confirmed that monkeys are a suitable animal model for the safety assessment of capecitabine in terms of metabolic enzymes and it was suggested that higher toxic incidences in mouse small intestine were related to high hydrolytic activity of capecitabine in the small intestine.     

苯磺酸氨氯地平叶酸片治疗H型高血压疗效观察

目的 观察苯磺酸氨氯地平叶酸片对伴有同型半胱氨酸(Hcy)升高的轻、中度原发性高血压病人降血压同时降低血浆Hcy作用的有效性.方法 选择符合标准的120例Ⅰ级、Ⅱ级原发性H型高血压病人,按苯磺酸氨氯地平叶酸片不同剂量采用随机数字表法分为3组:A组:5 mg/0.4 mg苯磺酸氨氯地平叶酸片 40例;B组:5 mg/0.8 mg苯磺酸氨氯地平叶酸片40例;C组:5 mg苯磺酸氨氯地平片40例.均每天1次,口服,连续服用8周.在入组前测量所有病人的血压、血浆Hcy、血清叶酸,并在治疗第2、4、6、8周进行随访,记录血压、血浆Hcy、心率,并记录不良事件.结果 最终一共115例病人进入随机试验,A、B、C组降压同时降Hcy的有效率分别为23.08%、26.32%、5.26%.A、B组有效性均优于C组.结论 苯磺酸氨氯地平叶酸片对于伴血浆Hcy升高的原发性轻、中度高血压病人有效.     

Hematological parameters in tench Tinca tinca after short term exposure to lead

Alterations in the hematological parameters of Tinca tinca were studied after exposure to lead at different concentrations and durations of exposure. Dose of 75/24 (ppm/h) did not cause significant change in any blood parameter. The 300/48 dose caused a significant increase in hematocrit (Hct), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) and a significant decrease in red blood cell (RBC) count and mean corpuscular hemoglobin concentration (MCHC). The 30/24 dose caused a significant increase in Hct and RBC count only. The 30/96 dose caused a significant increase in Hct and a significant decrease in MCHC only. The 30/504 dose caused a significant decrease in RBC count and a significant increase in MCV and MCH. The 75/96 dose caused a significant increase in Hct and a significant decrease in MCH and MCHC. The 75/504 dose caused a significant decrease in Hct, hemoglobin (Hb) and RBC count, and a significant increase in MCV and MCH. These alterations were attributed to direct or feedback responses of structural damage to RBC membranes resulting in hemolysis and impairment in hemoglobin synthesis, stress related release of RBCs from the spleen and hypoxia, induced by exposure to lead.     

Capecitabine: an overview of the side effects and their management

Xeloda (capecitabine), a thymidine phosphorylase activated fluoropyrimidine carbamate, is currently the only universally approved orally administered 5-fluorouracil (5-FU) prodrug. It belongs to a newer generation of orally administered fluoropyrimidines. It has been developed because of the clinical need for efficient, tolerable and convenient agents, which do not require continuous infusion. Capecitabine is not a cytotoxic drug in itself, but via a three-step enzymatic cascade, it is converted to 5-FU mainly within human cancer cells. While the drug compares favorably with 5-FU in patients with advanced or metastatic colorectal cancer and pretreated breast cancer, it also has an improved toxicity profile, mainly of gastrointestinal and dermatologic effects with a significantly lower incidence of grade 3/4 myelotoxicity compared with infusional 5-FU-based chemotherapy. Capecitabine's selective activation within the tumor allows for less systemic toxicity events. A gradient of fluoropyrimidine toxicity is observed: high in the US and low in East Asia. In addition, there is a discrepancy in tolerance of dose among patients treated in the US vs. Europe. Although patients can take the drug orally in the convenience of their own home, the key to successful management of capecitabine is the clinician's awareness of its severe, but low in incidence, adverse effects, and the patients' education, emphasizing compliance with the treatment plan, prevention and timely recognition of its toxicities.     

溶血性贫血患者与正常人血红蛋白浓度的比较

目的通过比较溶血性贫血（HA）患者与正常人的血红蛋白浓度,探讨平均红细胞血红蛋白浓度（MCHC）对溶血性贫血诊断的临床意义。方法统计HA、小细胞HA（先天遗传小细胞或合并IDA）、缺铁性贫血（IDA）、巨幼细胞性贫血（MA）各50例患者外周血象平均红细胞血红蛋白量（MCH）、MCHC、平均红细胞体积（MCV）数据,以健康人群50名为对照组,比较各实验组与对照组的MCH、MCHC、MCV均值。结果外周血象MCHC比较显示HA患者MCHC明显比MA、IDA及对照组要高,差异有统计学意义（P〈0．01）;小细胞HA患者和MA患者外周血象MCHC与对照组差异无统计学意义（P〉0．05）,而小细胞HA患者MCV明显比对照组低（P〈0．01）,MA患者MCV则明显高于对照组（P〈0．01）;外周血象MCHC最低的IDA患者与对照组及其他实验组差异有统计学意义（P〈0．01）。结论MCHC可作为早期溶血性贫血的诊断指标。     

Capecitabine monotherapy and in combination with immunotherapy in the treatment of metastatic renal cell carcinoma

This prospective trial aimed to evaluate the therapeutic effects and systemic toxicities of capecitabine monotherapy and capecitabine treatment combined with biological response modifiers in patients with metastatic renal cell carcinoma. Fifty-four patients suffering from metastatic renal cell carcinoma progressing under first-, second- or third-line treatment entered the trial. Capecitabine was given orally at a dose of 2500 mg/m2 daily divided into two doses for 14 days, followed by a 7-day rest in the monotherapy as well as in the combination treatment. This schedule was repeated in 3-week cycles. The combination therapy consisted of capecitabine and an immunotherapy treatment, which consisted either of interferon (IFN)-gamma1b (100 mg/day) administered consecutively 5 times weekly during weeks 1 and 2, and recombinant interleukin (IL)-2 (4.5 MU/day) administered on 4 consecutive days during weeks 3 and 4, every 6 weeks, or IFN-alpha (6 MioIE/day) administered 3 times a week. Fifty-two patients are now evaluable for response and 54 patients for toxicity. We observed a partial response to treatment in five patients (9.6%), minor response in five patients (9.6%), stable disease in 32 patients (61.6%) and only 10 patients (19.2%) showed continued disease progression despite treatment. Outpatient capecitabine was well tolerated. We did not observe any WHO grade IV toxicities. We conclude that capecitabine monotherapy and capecitabine treatment in combination with biological response modifiers appear to be effective regimens with favorable toxicity profiles in patients with advanced renal cell carcinoma. Capecitabine monotherapy seems to be superior than the combination treatment because of its easier application form.     

Relationship between AUC of 5'-DFUR and toxicity of capecitabine, fluoropyrimidine carbamate analogs, and 5'-DFUR in monkeys, mice, and rats

Capecitabine is an oral fluoropyrimidine carbamate which is converted to 5-fluorouracil (5-FU) via 3 enzymatic step to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU. We performed 4-week toxicity studies of capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorouridine), galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), 4 different fluoropyrimidine carbamate analogs (R=butyl, isopentyl, propyl, or phenethyl), and 5'-DFUR in cynomolgus monkeys with toxicokinetic measurements of intact molecules, 5'-DFCR, and 5'-DFUR. Four-week toxicity data for capecitabine in rats and mice were also obtained for comparison. Capecitabine, galocitabine, butyl, and isopentyl analogs showed similar toxicities in hematopoietic and intestinal organs at 1.0 mmol/kg and the AUCs of 5'-DFUR were approximately 40 to 60 microg*hr/ml. These compounds showed slight toxicity at 0.5 mmol/kg and no toxicity at 0.1 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 5 microg*hr/ml, respectively. Propyl and phenethyl analogs showed slight toxicity at 1.0 mmol/kg and no toxicity at 0.5 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 10 microg*hr/ml, respectively. On the other hand, severe and slight-to-moderate toxicity was observed at 0.5 and 0.25 mmol/kg in 5'-DFUR-treated monkeys and AUCs of 5'DFUR were 35.6 and 5.2 microg*hr/ml, respectively. In mice and rats, the toxicity of capecitabine was less than in monkeys relative to dose, but 5'-DFUR AUCs were almost the same. In conclusion, 5'-DFUR AUC correlated with toxicity following oral administration of capecitabine and its analogs in monkeys, mice, and rats, although this relationship is not seen in humans. Capecitabine was less toxic in monkeys than oral 5'-DFUR according to dose (mmol/kg) and 5'-DFUR AUC.     

The role of capecitabine in locally advanced rectal cancer treatment: an update

Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. Capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m(2) twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. Oxaliplatin and irinotecan are therefore good candidates. However, two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and, by contrast, increased toxicity. Capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial. New strategies with induction chemotherapy with or without chemoradiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further development of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropyrimidine-based regimen remains investigational.     

Pharmacological and clinical properties of Xeloda (Capecitabine), a new oral active derivative of fluoropyrimidine

Xeloda (Capecitabine) is a fluorocytidine derivative that is selectively tumor-activated to its cytotoxic moiety, fluorouracil. Capecitabine is readily absorbed from the gastrointestinal tract. In the liver, a 60-kDa carboxylesterase(CE) hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase(CD), an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-deoxy-5-fluorouridine (5'-DFUR). The enzyme thymidine phosphorylase (TP) then hydrolyzes 5'-DFUR to the active drug 5-FU. It is proved that some human carcinomas express TP in higher concentrations than surrounding normal tissues. In Japan, one of the phase 2 clinical trials tested the efficacy of twice daily oral Capecitabine at 1,657 mg/m(2)/d given for 3 weeks followed by a 1-week rest period and repeated in 4-week cycles in advanced/metastatic breast cancer patients resistant to or recurring during or after docetaxel therapy. The response rate was 20.0% (1 CR, 10 PRs). The median time to progression was 84 days and the median survival time was 452 days. The most common treatment-related adverse events throughout the phase 1 to 2 trials of capecitabine were hand-foot syndrome (50.7%), erythropenia (37.9%), lymphopenia (31.0%), hyperbilirubinemia (33.0%) and so on. Capecitabine is expected to provide a new alternative for the treatment of advanced/metastatic breast cancer.