Definitive S-1/mitomycin-C chemoradiotherapy for stage II/III anal canal squamous cell carcinoma: a phase I/II dose-finding and single-arm confirmatory study (JCOG0903).

BACKGROUND: Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus mitomycin-C is a standard treatment for stage II/III squamous cell carcinoma of the anal canal (SCCA). We performed this dose-finding and single-arm confirmatory trial of CRT with S-1 plus mitomycin-C to determine the recommended dose (RD) of S-1 and evaluate its efficacy and safety for locally advanced SCCA. METHODS: Patients with clinical stage II/III SCCA (UICC 6th) received CRT comprising mitomycin-C (10 mg/m2 on days 1 and 29) and S-1 (60 mg/m2/day at level 0 and 80 mg/m2/day at level 1 on days 1-14 and 29-42) with concurrent radiotherapy (59.4 Gy). Dose-finding used a 3 + 3 cohort design. The primary endpoint of the confirmatory trial was 3-year event-free survival. The sample size was 65, with one-sided alpha of 5%, power of 80%, and expected and threshold values of 75% and 60%, respectively. RESULTS: Sixty-nine patients (dose-finding, n = 10; confirmatory, n = 59) were enrolled. The RD of S-1 was determined as 80 mg/m2/day. Three-year event-free survival in 63 eligible patients who received the RD was 65.0% (90% confidence interval 54.1-73.9). Three-year overall, progression-free, and colostomy-free survival rates were 87.3%, 85.7%, and 76.2%, respectively; the complete response rate was 81% on central review. Common grade 3/4 acute toxicities were leukopenia (63.1%), neutropenia (40.0%), diarrhea (20.0%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). No treatment-related deaths occurred. CONCLUSIONS: Although the primary endpoint was not met, S-1/mitomycin-C chemoradiotherapy had an acceptable toxicity profile and favorable 3-year survival and could be a treatment option for locally advanced SCCA. CLINICAL TRIAL INFORMATION: jRCTs031180002.

Associations of cigarette smoking, alcohol drinking and body mass index with survival after colorectal cancer diagnosis by anatomic subsite: a prospective patient cohort study in Japan.

BACKGROUND: Cigarette smoking, alcohol drinking and obesity are known to be risk factors for colorectal cancer. These factors may affect survival after diagnosis, but evidence has been inconsistent. We investigated subsite-specific associations between prediagnosis smoking, alcohol drinking and body mass index and survival in colorectal cancer. METHODS: Subjects were 1300 patients (colon 778; rectum 502; concurrent 20) with histologically confirmed colorectal cancer diagnosed during 1997-2013 at a single institution in Japan. Histories of smoking and alcohol drinking, height and prediagnosis weight were assessed using a self-administered questionnaire. Using Cox proportional hazards model, hazard ratios and 95% confidence intervals of mortality were estimated. RESULTS: During a median follow-up period of 6.7 years, 479 deaths were documented. Ever-smoking was associated with an increased risk of all-cause death among patients with colon cancer (hazard ratio: 1.47; 95% confidence interval: 1.07-2.02 compared with never-smoking). According to colon subsite, this increased risk was clear in patients with proximal colon cancer (hazard ratio: 2.09; 95% confidence interval: 1.28-3.40). There was no association between smoking and rectal cancer survival. Alcohol drinking was not associated with survival for either colon or rectal cancer. Among patients with rectal cancer, higher body mass index was associated with a lower risk of all-cause (Ptrend = 0.0006) and disease-specific death (Ptrend = 0.02). For colon cancer, lower body mass index tended to be associated with a higher risk of all-cause death (Ptrend = 0.05). CONCLUSIONS: The results indicate that lifestyles identified as risk factors for colorectal cancer may impact differently on patient survival according to anatomic subsite.

Determination of the origin of oral squamous cell carcinoma by microarray analysis: Squamous epithelium or minor salivary gland?

More than 90% of oral cancers are histopathologically squamous cell carcinomas (SCCs). According to clinical behavior and histopathological features, we hypothesize that oral SCC can originate from either oral squamous epithelium or minor salivary glands. Here, we examined whether some oral SCCs originate from minor salivary glands, and investigated whether these tumors show particularly aggressive biological behavior. The mRNA expression profiles of samples obtained from six patients with oral floor SCC (five men, one woman; mean age, 62.7 years) were analyzed using a microarray containing 32,878 probes. The six samples were divided into two groups by clustering of expression levels of 845 probes differentially expressed in normal oral squamous epithelium and normal salivary glands. The expression profile in four cases was similar to that of normal oral squamous epithelium, and in two cases was similar to that of normal salivary glands. Furthermore, we identified nine genes that reveal the origin of the oral SCC. Subsequently, we examined the expression levels of these nine marker genes by reverse transcriptase-polymerase chain reaction to determine the origin of 66 oral SCCs. Twelve of the 66 oral SCCs were considered to originate from minor salivary glands, and these tumors showed high metastatic potential (p = 0.044, Chi-square test). Furthermore, SCC derived from minor salivary glands showed a poor event-free survival rate (p = 0.017, Kaplan-Meier analysis). In conclusion, determination of the origin of oral SCC is helpful in planning treatment for patients with oral SCC.

Association between being breastfed in infancy and adult colorectal cancer risk among Japanese men and women.

It has been postulated that being breastfed in infancy affects not only health status in childhood but also disease risk in adulthood. To investigate the association of being breastfed with the risks of adult colorectal cancer and benign tumor, we conducted a case-control study including 1190 colorectal cancer and 1585 benign tumor cases and 5301 controls, admitted to a single hospital in Miyagi Prefecture, Japan, between 1997 and 2013. History of having been breastfed was assessed using a self-administered questionnaire, and odds ratios (ORs) were estimated using unconditional logistic regression. There was no association between being breastfed and colorectal cancer risk (breastfed versus formula-only fed, OR = 1.21; 95% CI 0.87-1.67). There was also no association with the risk of benign tumor (OR = 1.04). On the other hand, analyses stratified by sex and birth year found heterogeneous associations. Women born after 1950 who had been breastfed tended to have increased risks of colorectal cancer (OR = 1.58) and benign tumor (OR = 1.51) relative to those who had been formula-only fed, although not statistically significant. In men born after 1950, being breastfed was associated with a significantly decreased risk of benign tumor (OR = 0.57; 95% CI 0.33-0.98).

tRNADB-CE 2011: tRNA gene database curated manually by experts.

We updated the tRNADB-CE by analyzing 939 complete and 1301 draft genomes of prokaryotes and eukaryotes, 171 complete virus genomes, 121 complete chloroplast genomes and approximately 230 million sequences obtained by metagenome analyses of 210 environmental samples. The 287 102 tRNA genes in total, and thus two times of the tRNA genes compiled previously, are compiled, in which sequence information, clover-leaf structure and results of sequence similarity and oligonucleotide-pattern search can be browsed. In order to pool collective knowledge with help from any experts in the tRNA research field, we included a column to which comments can be added on each tRNA gene. By compiling tRNAs of known prokaryotes with identical sequences, we found high phylogenetic preservation of tRNA sequences, especially at a phylum level. Furthermore, a large number of tRNAs obtained by metagenome analyses of environmental samples had sequences identical to those found in known prokaryotes. The identical sequence group, therefore, can be used as phylogenetic markers to clarify the microbial community structure of an ecosystem. The updated tRNADB-CE provided functions, with which users can obtain the phylotype-specific markers (e.g. genus-specific markers) by themselves and clarify microbial community structures of ecosystems in detail. tRNADB-CE can be accessed freely at http://trna.nagahama-i-bio.ac.jp.

Results of modified uncut Roux-en-Y reconstruction after distal gastrectomy for gastric cancer.

BACKGROUND/AIMS: The frequent occurrence of bile gastritis and esophagitis associated with dehiscence of 'uncut' jejunal portion was of concern for "uncut" Roux-en-Y reconstruction after distal gastrectomy. Our aim was to study if our technique of a modified, uncut Roux-en-Y procedure would decrease this dehiscence. METHODOLOGY: Ten patients with gastric cancer underwent distal gastrectomy with a modified, uncut Roux-en-Y reconstruction. Transmural silk stitches were added around the staples at the "uncut" portion in attempt to prevent dehiscence of the staple line. Dehiscence of the jejunum at the enterically closed site was investigated endoscopically or fluoroscopically. RESULTS: Mean operative time and intraoperative blood loss were 246 minutes and 381 mL, respectively. Morbidity occurred in three patients. No dehiscence was observed in any of the patients examined. CONCLUSIONS: These results suggest the possibility that our technique of a modified, uncut Roux-en-Y reconstruction after distal gastrectomy decreases dehiscence of enterically closed portion.

Infiltration of CD40-positive tumor-associated macrophages indicates a favorable prognosis in colorectal cancer patients.

BACKGROUND/AIMS: Recently the role of tumor-associated macrophages (TAMs) on immunity has been variously discussed. We studied a series of cell surface antigens in TAMs in colorectal cancer tissues and their corresponding normal tissues using flow cytometry to find out prognostic indicators of these patients. METHODOLOGY: We assessed the numbers of CD14+ macrophages positive for each of the cell surface antigens (CD80, CD86, HLA-DR, CD1a, CD40 and CD83) in cancer tissues and corresponding normal tissues among 31 patients with colorectal cancer, and performed the univariate and multivariate analysis to find out prognostic indicators for overall survival among the patients. RESULTS: The numbers of CD80+, CD86+ and HLA-DR+ TAMs in the cancer tissues were higher than those in corresponding normal tissues. Inversely CD40+ and CD83+ macrophages in cancer tissues were less than those in normal tissues. With the multivariate analysis, the number of CD40+ TAMs, as well as lymph node metastasis and distant metastasis, was shown to be an independent prognostic factor of colorectal cancer patients. CONCLUSIONS: The dense infiltration of CD40+ TAM in colorectal cancer tissues indicates a favorable prognosis, which suggests that CD40 plays an important role in the tumor immunity of colorectal cancer.

Criteria for the glucagon provocative test in the diagnosis of gastrinoma.

INTRODUCTION: The glucagon provocative test is useful for the diagnosis of gastrinoma. The aim of this study was to determine the criteria for the glucagon provocative test. METHODS: This study reviewed 8 patients that underwent the glucagon provocative test preoperatively and in whom the diagnosis was confirmed as gastrinoma histologically. The glucagon provocative test was performed by administering glucagon (20 µg/kg) intravenously, followed by 20 µg/kg h for the next 30 min, and plasma gastrin levels were measured 3 and 1 min before and 3, 5, 7, 10, 15, 20, and 30 min after the administration of glucagon. This study evaluated the peak value of plasma gastrin and the time required to reach the peak. RESULTS: Two of the 8 patients had multiple endocrine neoplasm type 1. The basal plasma gastrin levels ranged from 524 to 10,300 pg/ml. The time required to reach the peak was 3-10 min for all patients. The increase in the peak from the basal value was 235-8,920 pg/ml, and the percentage of increase was 38-337 %. CONCLUSIONS: These results suggest that a diagnosis of gastrinoma should thus be made when plasma gastrin levels peak within 10 min after glucagon administration, with an increase of greater than 200 pg/ml and greater than 35 % of the basal value.

Current status of pylorus-preserving gastrectomy for the treatment of gastric cancer: a questionnaire survey and review of literatures.

PURPOSE: This study was designed to investigate the current status of pylorus-preserving gastrectomy (PPG) for the treatment of gastric cancer by sending a questionnaire to institutions in Japan. METHODS: The questionnaire was prepared and sent to 930 institutions approved by the Japanese Society of Gastroenterological Surgery. Questions were the indications for PPG, preservation of the vagus nerves and the infra-pyloric artery, whether suprapyloric lymph nodes are dissected, distance between the pylorus and the gastrogastrostomy, and the advantages and disadvantages of PPG. RESULTS: Responses were obtained from 345 institutions (37.1%). In 148 institutions, PPG was included in the choices of operations for gastric cancer and indicated for patients with tumors no deeper than the submucosal layer for differentiated-type carcinoma, or for tumors limited to the mucosa even in poorly differentiated types in 105 institutions. The vagus was preserved in 73.5%, the infrapyloric artery was preserved in 49.4%, and the dissection of suprapyloric lymph nodes were partly performed in 56.2%. The distance between gastrogastrostomy and the pyloric ring was 3-3.9 cm in 43.4% and 2-2.9 cm in 39%. Layer-to-layer anastomosis was the most representative technique for gastrogastrostomy. The advantages of PPG with decreased incidence of dumping syndrome and remnant gastritis were quoted in 130 and 82 institutions, respectively. Delayed gastric emptying was considered as the most frequent disadvantage of PPG, as quoted by 111 institutions. CONCLUSIONS: These results indicate that standard technique in PPG includes the preservation of the vagus and infrapyloric artery, in part dissection of suprapyloric lymph nodes, and layer-to-layer anastomosis for reconstruction. The optimal length of the antral cuff is still controversial.

tRNADB-CE: tRNA gene database curated manually by experts.

We constructed a new large-scale database of tRNA genes by analyzing 534 complete genomes of prokaryotes and 394 draft genomes in WGS (Whole Genome Shotgun) division in DDBJ/EMBL/GenBank and approximately 6.2 million DNA fragment sequences obtained from metagenomic analyses. This exhaustive search for tRNA genes was performed by running three computer programs to enhance completeness and accuracy of the prediction. Discordances of assignment among three programs were found for approximately 4% of the total of tRNA gene candidates obtained from these prokaryote genomes analyzed. The discordant cases were manually checked by experts in the tRNA experimental field. In total, 144,061 tRNA genes were registered in the database 'tRNADB-CE', and the number of the genes was more than four times of that of the genes previously reported by the database from analyses of complete genomes with tRNAscan-SE program. The tRNADB-CE allows for browsing sequence information, cloverleaf structures and results of similarity searches among all tRNA genes. For each of the complete genomes, the number of tRNA genes for individual anticodons and the codon usage frequency in all protein genes and the positioning of individual tRNA genes in each genome can be browsed. tRNADB-CE can be accessed freely at http://trna.nagahama-i-bio.ac.jp.

Infiltration of CD14-positive macrophages at the invasive front indicates a favorable prognosis in colorectal cancer patients with lymph node metastasis.

BACKGROUND/AIMS: To clarify the distribution of CD14+ macrophages in colorectal cancer using flow cytometry and immunohistochemistry, and to elucidate the roles of CD14+ macrophages in colorectal cancer. METHODOLOGY: We studied the paired cancerous and corresponding normal tissues from 52 patients with colorectal cancer for the distribution of CD14+, CD1a+, CD83+ and CD68+ cells, and correlated the findings with the clinicopathological characteristics and with the expression of CD86 and CD80 in the CD14+ macrophages, which are co-stimulatory factors for T cell activation. RESULTS: 1) CD14+ macrophages were distributed predominantly at the invasive front of colorectal cancer tissues, rather than in the normal tissues, 2) a high percentage of the CD14+ macrophages expressed CD86 and CD80, and 3) in the colorectal cancer cases with lymph node metastasis, the 5-year overall survival rate of the high CD14 group, in which the number of CD14+ macrophages was higher than the median, was better than that of the low CD14 group. CONCLUSION: The infiltration of CD140 macrophages at the invasive front indicates a favorable prognosis in colorectal cancer patients with lymph node metastasis. In addition, the activation of CD14+ macrophages and T cells may facilitate the development of new immunotherapeutic strategies for colorectal cancer patients.

Effect of viscosity of enteral nutrient on gut motility and hormone secretion in dogs.

BACKGROUND/AIMS: Our aim was to study the effect of the viscosity of enteral nutrient solutions on upper gut motility and gut hormone secretion. METHODOLOGY: We used 5 beagle dogs equipped with strain gauge force transducers to measure upper gastrointestinal motility. Upper gut motility and gut hormone secretion were compared across 6 experimental conditions; control (oral solid meal), liquid-120, liquid-5 (liquid enteral nutrients administered for 120 and 5 min, respectively), low, middle, and high viscosity conditions. RESULTS: The magnitude of receptive relaxation was decreased in the liquid-120 compared to control, but this decrease was reversed with the increase of viscosity. The duration of the postprandial contractions in the proximal jejunum was decreased in the liquid-5 compared to the control, but this decrease was reversed in the middle and high viscosity conditions (p < 0.05). Rapid increase in plasma concentrations of gastric inhibitory polypeptide observed in the liquid-5 compared to the control was reversed in the low, middle, and high viscosity conditions. CONCLUSIONS: Although patterns of upper gut motility and gut hormone secretion after liquid enteral nutrients were considerably altered compared to those after solid meal ingestion, increasing the viscosity of liquid enteral nutrients reversed those altered patterns.

[A case of anal cancer with rapidly rising CEA in longstanding perianal Crohn disease after infliximab administration].

Infliximab is effective in the treatment of steroid-resistant Crohn disease. However, there is clinical concern about a possible correlation between an increased risk of anorectal cancer and infliximab treatment. We report a case of anorectal cancer in long-standing perianal Crohn disease. A 34-year-old patient with a long-standing perianal lesion of Crohn disease underwent 3 sessions of infliximab therapy. After therapy, the concentration of plasma CEA was 36.5ng/ml and rose to 91.4ng/ml. We suspected anorectal cancer, so abdominoperineal resection was performed. The histological findings indicated mucinous adenocarcinoma. Monitoring of patients with long-standing perianal Crohn disease is considered essential for early diagnosis of anal cancer after obtaining biopsy samples from perianal lesions. Additionally, when infliximab is started for perianal Crohn disease, thorough examination for perianal lesion should be performed.

Down-regulation of cIAP2 enhances 5-FU sensitivity through the apoptotic pathway in human colon cancer cells.

Currently 5-fluorouracil (5-FU) plays a central role in the chemotherapeutic regimens for colorectal cancers and thus it is important to understand the mechanisms that determine 5-FU sensitivity. The expression profiles of human colon cancer cell line DLD-1, its 5-FU-resistant subclone DLD-1/FU and a further 21 types of colon cancer cell lines were compared to identify the novel genes defining the sensitivity to 5-FU and to estimate which population of genes is responsible for 5-FU sensitivity. In the hierarchical clustering, DLD-1 and DLD-1/FU were most closely clustered despite over 100 times difference in their 50% inhibitory concentration of 5-FU. In DLD-1/FU, the population of genes differentially expressed compared to DLD-1 was limited to 3.3%, although it ranged from 4.8% to 24.0% in the other 21 cell lines, thus indicating that the difference of 5-FU sensitivity was defined by a limited number of genes. Next, the role of the cellular inhibitor of apoptosis 2 (cIAP2) gene, which was up-regulated in DLD-1/FU, was investigated for 5-FU resistance using RNA interference. The down-regulation of cIAP2 efficiently enhanced 5-FU sensitivity, the activation of caspase 3/7 and apoptosis under exposure to 5-FU. The immunohistochemistry of cIAP2 in cancer and corresponding normal tissues from colorectal cancer patients in stage III revealed that cIAP2 was more frequently expressed in cancer tissues than in normal tissues, and cIAP2-positive patients had a trend toward early recurrence after fluorouracil-based chemotherapy. Although the association between drug sensitivity and the IAP family in colorectal cancer has not yet been discussed, cIAP2 may therefore play an important role as a target therapy in colorectal cancer.

Results of reconstruction with jejunal pouch after gastrectomy: correlation with gastrointestinal motor activity.

BACKGROUND/AIMS: To investigate if restoration of esophago-intestinal or esophago-gastric continuity with a jejunal pouch after total or proximal gastrectomy has clinical benefits. METHODS: We reviewed all relevant reports published after 1990 that dealt with the clinical results of reconstruction with a jejunal pouch after total and proximal gastrectomies and correlated those findings with results for gastrointestinal motility. Reports were chosen from a search of the literature using PubMed. RESULTS: After total gastrectomy, the benefit of a jejunal J pouch interposition was not apparent compared to simple jejunal interposition; indeed, one trial concluded that simple interposition was better than pouch interposition in terms of food intake. In contrast, results with a jejunal J pouch during Roux-en-Y (RY) type reconstruction were better than with conventional RY reconstruction in terms of food intake, nutritional status, body weight (BW) and symptoms. Advantages were also shown for a jejunal pouch with an inverted U shape interposed between the esophagus and residual stomach after proximal gastrectomy. Reconstruction using a jejunal pouch after proximal gastrectomy was better than esophagogastrostomy or simple jejunal interposition in terms of food intake, BW and symptoms. There were not enough data to conclude any benefits of a jejunal J pouch between the gastric remnant and the duodenum after distal gastrectomy. CONCLUSIONS: Clinical results of restoration of intestinal continuity with a jejunal pouch after total and proximal gastrectomies may be attributed, at least in part, to the relationship between the motor activity of the gastric remnant, duodenum and jejunal pouch.

[Analysis of patients with locally advanced gastric cancer undergoing gastrectomy after pre-operative chemotherapy including S-1].

To improve the prognosis of advanced gastric cancer, various adjuvant therapies were tried. We retrospectively examined 7 cases of gastrectomy after pre-operative chemotherapy using S-1+CDDP, and reported its effectiveness and the result. An adverse event of more than Grade 3 showed neutropenia in two cases. Anti-tumor effect on the imaging was found in 6 cases of PR and one case of SD. We performed gastrectomy within 4 weeks after completion of chemotherapy in each case. The histological antitumor effect was more than Grade 2 in four cases, but there was no complete response. We compared the overall survival of a patient of more than Grade 2 by histological antitumor effect under grade 1b. In the former, MST was 982 days and the two-year survival rate was 50.0%; in the latter, MST was 443 days and the two-year survival rate was 33.3%. We can perform pre-operative chemotherapy using S-1+CDDP and expect prognostic improvement for a histologically effective case of chemotherapy. If the utility of preoperative chemotherapy mainly with S-1 is proved in a phase III trial, this would appear to be a therapy of choice for advanced gastric cancer in future.

Orthotopic implantation mouse model and cDNA microarray analysis indicates several genes potentially involved in lymph node metastasis of colorectal cancer.

In colorectal cancer (CRC) patients, metastasis to the regional lymph node (LN) is an important first step in the dissemination of cancers. To identify the genes possibly involved in LN metastasis of CRC, we analyzed LN metastases in an orthotopic implantation mouse model with 22 CRC cell lines using Matrigel, an extracellular matrix protein derived from mice sarcoma, and combined the data with gene expression profiles of cDNA microarray of those cell lines. With this implantation analysis, the incidence of LN metastasis was 60% in 228 orthotopically implanted mice and varied from 100% to 0% among the cell lines. KM12c and Clone A showed LN metastasis in all orthotopically implanted mice, but DLD-1, HCT-8, and SW948 did not show LN metastases at all. In contrast, the incidence of liver and lung metastasis in 22 CRC cell lines was 13% and 1%, respectively. Combining those data with cDNA microarray in vitro, we isolated 636 genes that were differentially expressed depending on the incidence of LN metastasis. Among those genes, the expression level of ring finger protein 125 (RNF125), previously known as an E3 ubiquitin ligase in T cell activation, was significantly different between primary tumors in Stage III CRC patients with LN metastasis and Stage II patients without LN metastasis. In conclusion, the orthotopic implantation mice model with Matrigel was useful, and we isolated candidate genes such as RNF125 that possibly play an important role in LN metastasis of CRC cells.

Tissue oxygenation in a murine SCC VII tumor after X-ray irradiation as determined by EPR spectroscopy.

PURPOSE: The goal of this study was to clarify the dynamics of oxygenation (partial pressure of oxygen, pO(2)) in SCC VII murine tumors in mice after X-ray irradiation. MATERIALS AND METHODS: Changes in pO(2) in tumors were measured by 1.2-GHz electron paramagnetic resonance (EPR) spectroscopy after they were exposed to various doses of irradiation. The pO(2) in tumors was followed for up to six days after irradiation at doses of 0, 5, 10, 15, and 20 Gy. Paramagnetic crystals were used as an oximetry probe and implanted into normal or tumor tissues in mice for prolonged periods. RESULTS: The pattern of tumor oxygen after a single dose of radiation with the 5-Gy dose was different from those with other doses (10, 15, and 20 Gy). After 5 Gy, pO(2) increased rapidly (P<0.01, Student's t test) and then returned to the level observed before irradiation by 12h (P<0.01). In contrast, after 10, 15, or 20 Gy, pO(2) increased rapidly by 6h after irradiation, continued to increase until at least 24h (P<0.01), and then gradually decreased. CONCLUSIONS: In tumors that received 5 Gy, post-irradiation increases in pO(2) at 4h after irradiation were detected by EPR oximetry (P<0.01) noninvasively.

Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells.

We have previously demonstrated that the stromal cell­derived factor (SDF­1)/CXCR4 system is involved in the metastasis of head and neck cancer. Additionally, it has been revealed that the blockade of CXCR4 by subcutaneous daily injection with AMD3100, a CXCR4 antagonist, may be effective in preventing metastasis in CXCR4­related head and neck cancer. Recent investigations have suggested that AMD070, a novel orally bioavailable inhibitor of CXCR4, may be minimally invasive compared with AMD3100. In the present study, we examined the effect of AMD070 on metastasis induced by the SDF­1/CXCR4 axis in B88­SDF­1 oral cancer cells, which express high levels of SDF­1 and CXCR4. Although treatment with AMD070 did not affect the anchorage­dependent growth of B88­SDF­1 cells, it significantly suppressed the anchorage­independent growth. Moreover, the SDF­1/CXCR4­dependent migration and invasion of B88­SDF­1 cells was significantly inhibited following treatment with AMD070. Subsequently, we performed an experimental therapy using AMD070 to prevent the distant metastasis of B88­SDF­1 cells in vivo. Daily oral administration of AMD070 significantly inhibited the lung metastasis of B88­SDF­1 cells in nude mice. These results indicated that AMD070 could be useful as a novel orally bioavailable inhibitor of oral cancer metastasis.

Drug delivery of oral anti-cancer fluoropyrimidine agents.

INTRODUCTION: Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.