Subcutaneous abscess in the shoulder caused by Prevotella bivia infection.

Prevotella bivia (P. bivia) is an anaerobic Gram-negative rod usually inhabiting in the urogenital system, and sometimes in the intra-oral space, whose infection to other parts of body is extremely rare. In this report, we describe a rare case of a recurrent infectious abscess due to P. bivia in the right shoulder of a middle-aged female.

Distinct roles of histamine H1- and H2-receptor signaling pathways in inflammation-associated colonic tumorigenesis.

Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apcmin/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.

Context-specific role of SOX9 in NF-Y mediated gene regulation in colorectal cancer cells.

Roles for SOX9 have been extensively studied in development and particular emphasis has been placed on SOX9 roles in cell lineage determination in a number of discrete tissues. Aberrant expression of SOX9 in many cancers, including colorectal cancer, suggests roles in these diseases as well and recent studies have suggested tissue- and context-specific roles of SOX9. Our genome wide approach by chromatin immunoprecipitation sequencing (ChIP-seq) in human colorectal cancer cells identified a number of physiological targets of SOX9, including ubiquitously expressed cell cycle regulatory genes, such as CCNB1 and CCNB2, CDK1, and TOP2A. These novel high affinity-SOX9 binding peaks precisely overlapped with binding sites for histone-fold NF-Y transcription factor. Furthermore, our data showed that SOX9 is recruited by NF-Y to these promoters of cell cycle regulatory genes and that SOX9 is critical for the full function of NF-Y in activation of the cell cycle genes. Mutagenesis analysis and in vitro binding assays provided additional evidence to show that SOX9 affinity is through NF-Y and that SOX9 DNA binding domain is not necessary for SOX9 affinity to those target genes. Collectively, our results reveal possibly a context-dependent, non-classical regulatory role for SOX9.

Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure.

PURPOSE: Delayed plasma concentration profiles of the active irinotecan metabolite SN-38 were observed in cancer patients with severe renal failure (SRF), even though SN-38 is eliminated mainly via the liver. Here, we examined the plasma concentrations of unbound SN-38 in such patients. METHODS: Plasma unbound concentrations were examined by ultrafiltration. Physiologically-based pharmacokinetic (PBPK) models of irinotecan and SN-38 were established to quantitatively assess the principal mechanism for delayed SN-38 elimination. RESULTS: The area under the plasma unbound concentration-time curve (AUC(u)) of SN-38 in SRF patients was 4.38-fold higher than that in normal kidney patients. The unbound fraction of SN-38 was also 2.6-fold higher in such patients, partly because SN-38 protein binding was displaced by the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). This result was supported by correlation of the unbound fraction of SN-38 with the plasma CMPF concentration, which negatively correlated with renal function. PBPK modeling indicated substantially reduced influx of SN-38 into hepatocytes and approximately one-third irinotecan dose for SRF patients to produce an unbound concentration profile of SN-38 similar to normal kidney patients. CONCLUSION: The AUC(u) of SN-38 in SRF cancer patients is much greater than that of normal kidney patients primarily because of the reduced hepatic uptake of SN-38.

Alkaline phosphatase determines polyphosphate-induced mineralization in a cell-type independent manner.

Polyphosphate [Poly(P)] has positive effects on osteoblast mineralization; however, the underlying mechanism remains unclear. In addition, it is unknown whether Poly(P) promotes mineralization in soft tissues. We investigated this by using various cells. Poly(P) concentrations of 1 and 0.5 mg/mL yielded high levels of mineralization in ROS17/2.8 osteoblast cells. Similarly, Poly(P) induced mineralization in cell types expressing alkaline phosphatase (ALP), namely, ATDC5 and MC3T3-E1, but not in CHO, C3H10T1/2, C2C12, and 3T3-L1 cells. Furthermore, forced expression of ALP caused Poly(P)-induced mineralization in CHO cells. These results suggest that ALP determines Poly(P)-induced mineralization in a cell-type independent manner.

Osteocytes up-regulate the terminal differentiation of pre-osteoblasts via gap junctions.

We examined cell-to-cell interaction between pre-osteoblasts and osteocytes using MC3T3-E1 and MLO-Y4, respectively. First, GFP expressing MC3T3-E1 (E1-GFP) cells were generated to isolate the cells from co-culture with MLO-Y4. No changes were observed in the expression of osteogenic transcription factors Runx2, Osterix, Dlx5 and Msx2, but expression of alkaline phosphatase (ALP) and bone sialoprotein (BSP) in E1-GFP co-cultured with MLO-Y4 was 300-400-fold greater than that in mono-cultured E1-GFP. In addition, mineralized nodule formation was drastically increased in co-cultured E1-GFP cells compared to mono-cultured cells. Patch clamp assay showed the presence of gap junctions between E1-GFP and MLO-Y4. Furthermore, when the gap junction inhibitor carbenoxolone (CBX) was added to the culture, increased expression of ALP and BSP in E1-GFP co-cultured with MLO-Y4 was suppressed. These results suggest that gap junction detected between pre-osteoblasts and osteocytes plays an important role on the terminal differentiation of pre-osteoblasts.

The P75 neurotrophin receptor regulates proliferation of the human MG63 osteoblast cell line.

The 75 kDa transmembrane protein, p75(NTR), is a marker of mesenchymal stem cells (MSCs). Isolated MSCs are capable of differentiating into osteoblasts, but the molecular function of p75(NTR) in MSCs and osteoblasts is poorly understood. The aim of this study was to examine the function of p75(NTR) in the human MG63 osteoblast cell line compared to the murine MC3T3E-1 pre-osteoblast cell line. MG63 cells and MC3T3-E1 cells expressing exogenous p75(NTR) protein (denoted as p75-MG63 and p75GFP-E1, respectively) were generated to compare osteogenic differentiation and cell proliferation abilities. Overexpression of p75(NTR) induced alkaline phosphatase activity and the mRNA expression of osteoblast-related genes such as osterix and bone sialoprotein in both p75-MG63 and p75GFP-E1. Interestingly, exogenous p75(NTR) stimulated cell proliferation and cell cycle progression in p75GFP-E1, but not in p75-MG63. To elucidate any different effects of p75(NTR) expression on osteogenic differentiation and cell proliferation, we examined the mRNA expression of tropomyosin receptor kinase (trk) genes (trkA, trkB, trkC) and Nogo receptor (NgR), which are binding partners of p75(NTR). Although trkA, trkB, and trkC were detected in both p75-MG63 and p75GFP-E1, only NgR was detected in p75-MG63. We then used the K252a inhibitor of the trks to identify the signaling pathway for osteogenic differentiation and cell proliferation. Inhibition of trks by K252a suppressed p75(NTR)-mediated osteogenic differentiation of p75GFP-E1, whereas deletion of the GDI domain in P75(NTR) from the p75-MG63 produced enhanced cell proliferation compared to p75-MG63. These results suggest that p75(NTR) signaling associated with trk receptors promotes both cell proliferation and osteoblast differentiation, but that p75(NTR)-mediated proliferation may be suppressed by signaling from the p75(NTR)/NgR complex.

Pharmacological evaluation of adipose dysfunction via 11ß-hydroxysteroid dehydrogenase type 1 in the development of diabetes in diet-induced obese mice with cortisone pellet implantation.

Signals from intracellular glucocorticoids (GCs) via 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in adipose tissues have been reported to serve as amplifiers leading to deterioration of glucose metabolism associated with obesity. To elucidate adipose dysfunction via 11ß-HSD1 activation in the development of obesity-related diabetes, we established novel diabetic mice by implanting a cortisone pellet (CP) in diet-induced obesity (DIO) mice. Cortisone pellet-implanted DIO mice (DIO/CP mice) showed hyperglycemia, insulin resistance, hyperlipidemia, and ectopic fat accumulation, whereas cortisone pellet implantation in lean mice did not induce hyperglycemia. In DIO/CP mice, indexes of lipolysis such as plasma glycerol and nonesterified fatty acids (NEFAs) increased before hyperglycemia appeared. Furthermore, the adipose mRNA level of 11ß-HSD1 was up-regulated in DIO/CP mice compared with sham-operated DIO mice. RU486 (mifepristone, 11ß-[p-(dimethylamino)phenyl]-17ß-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), a glucocorticoid receptor antagonist, decreased adipose mRNA levels of 11ß-HSD1 as well as adipose triglyceride lipase. RU486 also improved plasma NEFA, glycerol, and glucose levels in DIO/CP mice. These results demonstrate that lipolysis in adipose tissues caused by GC activation via 11ß-HSD1 serves as a trigger for diabetes with ectopic fat accumulation. Our findings also indicate the possibility of a vicious circle of GC signals via 11ß-HSD1 up-regulation in adipose tissues, contributing to deterioration of glucose metabolism to result in diabetes. Our DIO/CP mouse could be a suitable model of type 2 diabetes to evaluate adipose dysfunction via 11ß-HSD1.

Paneth cell-mediated multiorgan dysfunction after acute kidney injury.

Acute kidney injury (AKI) is frequently complicated by extrarenal multiorgan injury, including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of proinflammatory mediators drives multiorgan injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage-depleted mice decreased markedly. In addition, intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI.

SOX9 directly regulates IGFBP-4 in the intestinal epithelium.

SOX9 regulates cell lineage specification by directly regulating target genes in a discrete number of tissues, and previous reports have shown cell proliferative and suppressive roles for SOX9. Although SOX9 is expressed in colorectal cancer, only a few direct targets have been identified in intestinal epithelial cells. We previously demonstrated increased proliferation in Sox9-deficient crypts through loss-of-function studies, indicating that SOX9 suppresses cell proliferation. In this study, crypt epithelial cells isolated from Sox9-deficient mice were used to identify potential target genes of SOX9. Insulin-like growth factor (IGF)-binding protein 4 (IGFBP-4), an inhibitor of the IGF/IGF receptor pathway, was significantly downregulated in Sox9-deficient intestinal epithelial cells and adenoma cells of Sox9-deficient ApcMin/+ mice. Immunolocalization experiments revealed that IGFBP-4 colocalized with SOX9 in mouse and human intestinal epithelial cells and in specimens from patients with primary colorectal cancer. Reporter assays and chromatin immunoprecipitation demonstrated direct binding of SOX9 to the IGFBP-4 promoter. Overexpression of SOX9 attenuated cell proliferation, which was restored following treatment with a neutralizing antibody against IGFBP-4. These results suggest that SOX9 regulates cell proliferation, at least in part via IGFBP-4. Furthermore, the antiproliferative effect of SOX9 was confirmed in vivo using Sox9-deficient mice, which showed increased tumor burden when bred with ApcMin/+ mice. Our results demonstrate, for the first time, that SOX9 is a transcriptional regulator of IGFBP-4 and that SOX9-induced activation of IGFBP-4 may be one of the mechanisms by which SOX9 suppresses cell proliferation and progression of colon cancer.

Critical role of interleukin-17A in murine intestinal ischemia-reperfusion injury.

Intestinal ischemia-reperfusion (I/R) injury causes severe illness frequently complicated by remote multiorgan dysfunction and sepsis. Recent studies implicated interleukin-17A (IL-17A) in regulating inflammation, autoimmunity, and I/R injury. Here, we determined whether IL-17A is critical for generation of intestinal I/R injury and subsequent liver and kidney injury. Mice subjected to 30 min of superior mesenteric artery ischemia not only developed severe small intestinal injury (necrosis, apoptosis, and neutrophil infiltration) but also developed significant renal and hepatic injury. We detected large increases in IL-17A in the small intestine, liver, and plasma. IL-17A is critical for generating these injuries, since genetic deletion of IL-17A- or IL-17A-neutralizing antibody treatment markedly protected against intestinal I/R injury and subsequent liver and kidney dysfunction. Intestinal I/R caused greater increases in portal plasma and small intestine IL-17A, suggesting an intestinal source for IL-17A generation. We also observed that intestinal I/R caused rapid small intestinal Paneth cell degranulation and induced murine α-defensin cryptdin-1 expression. Furthermore, genetic or pharmacological depletion of Paneth cells significantly attenuated the intestinal I/R injury as well as hepatic and renal dysfunction. Finally, Paneth cell depletion significantly decreased small intestinal, hepatic, and plasma IL-17A levels after intestinal I/R. Taken together, we propose that Paneth cell-derived IL-17A may play a critical role in intestinal I/R injury as well as extraintestinal organ dysfunction.

Analysis of a force system for upper molar distalization using a trans-palatal arch and mini-implant: a finite element analysis study.

The purpose of this study was to analyse distal movements of molars in a force system using a trans-palatal arch (TPA), fixed to the maxillary first molar, and mini-implants placed at the palatal midline, considering the diagnostic standard for placement site in association with variation in upper molar locations, using finite element (FE) analysis. Three-dimensional FE models, divided by the differing direction of traction force, mesiodistal locations of the left and right molars, and the lateral location of the mini-implant were constructed. (1) When a traction force was fixed from the height of alveolar crest to the mini-implant placed at the middle of palate, the molars underwent bodily movement. (2) When the location of the mini-implant was moved to the left of the midline, the amount of distal movement of the left molar increased. When the mesiodistal locations of the left and right molars differed, the amount of distal movement of the molar located mesially was larger than that of the contralateral molar, even when the mini-implant was located on the midline.

N-Isopropyl-p-iodoamphetamine hydrochloride Is predominantly metabolized by CYP2C19.

[(123)I]N-Isopropyl-p-iodoamphetamine hydrochloride ([(123)I]IMP) is clinically used to evaluate blood flow in the brain on single photon emission-computed tomography. This is a rare radiopharmaceutical that undergoes metabolism. The first step is reported to be [(123)I]p-iodoamphetamine formation. The drug-metabolizing enzyme(s) involved remain(s) unclear. This study examined the roles of human cytochrome P450 (P450) in the metabolism of nonradiolabeled IMP with the use of human liver microsomes (HLM) and recombinant human CYP1A1, -1A2, -1B1, -2A6, -2B6, -2C8, -2C9, -2C19, -2D6, -2E1, -3A4, and -3A5. Disappearance of IMP was examined because p-iodoamphetamine was not available. IMP (0.5 µM) time-dependently disappeared when HLM and NADPH-generating system were added to the reaction mixture. (S)-Mephenytoin (1 mM) inhibited the IMP disappearance by approximately 90%. The disappearance of IMP was predominantly catalyzed by recombinant CYP2C19, with K(m) and V(max) of 8.6 µM and 9.7 nmol · min(-1) · nmol P450(-1), respectively. IMP disappearance in CYP2C19-deficient HLM (CYP2C19*2/*2) was approximately 30% of that in the presence of HLM harboring wild-type CYP2C19, indicating that IMP is polymorphically metabolized by CYP2C19. High-performance liquid chromatography of the incubation mixture of IMP and CYP2C19 revealed an unidentified peak. As the area of the IMP peak decreased, the area of this unidentified peak increased in a time-dependent fashion. The peak was also detectable on incubation of IMP with HLM. Mass spectrometry revealed that the molecular weight of a compound in this unidentified peak was the same as that of p-iodoamphetamine. Thus, we demonstrated that IMP was predominantly metabolized by CYP2C19 to form p-iodoamphetamine.

A phase I study of infusional 5-fluorouracil, leucovorin, oxaliplatin and irinotecan in Japanese patients with advanced colorectal cancer who harbor UGT1A1*1/*1,*1/*6 or *1/*28.

OBJECTIVE: To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. METHODS: This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. RESULTS: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3-4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. CONCLUSIONS: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.

Prophylactic antimicrobials may not be needed to prevent surgical site infection after skin biopsy: a retrospective study.

BACKGROUND: Two types of skin biopsies are routinely performed in dermatology: excisional and punch biopsies. A punch biopsy is a relatively low-risk procedure for surgical site infections (SSIs) because of the shallow wound depth and short operative time. In Japan, prophylactic antimicrobial agents are often used after skin biopsies due to lack of consensus, and there is no mention of antimicrobial use after skin biopsies in Japanese guidelines. In this study, we investigated whether prophylactic antibiotic use after punch biopsies reduces the risk of SSI development. METHODS: Cases of punch biopsy performed in our dermatology department during a one-year period from April 2018 to March 2019 were included retrospectively. The cases were divided into a group with and another without prophylactic antimicrobial use after biopsy. RESULTS: A total of 75 cases of punch skin biopsy were reviewed. There were no cases of wound infection after punch biopsy in any of the groups. The number of years of experience of the physicians in the group that used antimicrobials was significantly higher than that in the group that did not use antimicrobials (P < 0.0001). CONCLUSIONS: Our result suggests that the incidence of SSI in punch biopsies without prophylaxis seems to be low. However, further research is needed due to the small number of cases in this study.

Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in Mice.

BACKGROUND & AIMS: We previously showed that histamine suppressed inflammation-associated colonic tumorigenesis through histamine type 2 receptor (H2R) signaling in mice. This study aimed to precisely elucidate the downstream effects of H2R activation in innate immune cells. METHODS: Analyses using online databases of single-cell RNA sequencing of intestinal epithelial cells in mice and RNA sequencing of mouse immune cells were performed to determine the relative abundances of 4 histamine receptors among different cell types. Mouse neutrophils, which expressed greater amounts of H2R, were collected from the peritoneum of wild-type and H2R-deficient mice, of which low-density and high-density neutrophils were extracted by centrifugation and were subjected to RNA sequencing. The effects of H2R activation on neutrophil differentiation and its functions in colitis and inflammation-associated colon tumors were investigated in a mouse model of dextran sulfate sodium-induced colitis. RESULTS: Data analysis of RNA sequencing and quantitative reverse-transcription polymerase chain reaction showed that Hrh2 is highly expressed in neutrophils, but barely detectable in intestinal epithelial cells. In mice, the absence of H2R activation promoted infiltration of neutrophils into both sites of inflammation and colonic tumors. H2R-deficient high-density neutrophils yielded proinflammatory features via nuclear factor-κB and mitogen-activated protein kinase signaling pathways, and suppressed T-cell proliferation. On the other hand, low-density neutrophils, which totally lack H2R activation, showed an immature phenotype compared with wild-type low-density neutrophils, with enhanced MYC pathway signaling and reduced expression of the maturation marker Toll-like receptor 4. CONCLUSIONS: Blocking H2R signaling enhanced proinflammatory responses of mature neutrophils and suppressed neutrophil maturation, leading to accelerated progression of inflammation-associated colonic tumorigenesis.

Sorafenib and sunitinib, two anticancer drugs, inhibit CYP3A4-mediated and activate CY3A5-mediated midazolam 1'-hydroxylation.

Sorafenib and sunitinib are novel small-molecule molecularly targeted anticancer drugs that inhibit multiple tyrosine kinases. These medicines have shown survival benefits in advanced renal cell carcinomas as well as in advanced hepatocellular carcinomas and gastrointestinal stromal tumors, respectively. The effects of sorafenib and sunitinib on midazolam 1'-hydroxylation catalyzed by human CYP3A4 or CYP3A5 were investigated. Sorafenib and sunitinib inhibited metabolic reactions catalyzed by recombinant CYP3A4. Midazolam hydroxylation was also inhibited in human liver microsomes harboring the CYP3A5*3/*3 genotype (poor CYP3A5 expressor). In contrast, midazolam 1'-hydroxylation catalyzed by recombinant CYP3A5 was enhanced by the coexistence of sorafenib or sunitinib in a concentration-dependent manner, with saturation occurring at approximately 10 µM. Midazolam hydroxylation was also enhanced in human liver microsomal samples harboring the CYP3A5*1/*1 genotype (extensive CYP3A5 expressor). Sorafenib N-oxidation and sunitinib N-deethylation, the primary routes of metabolism, were predominantly catalyzed by CYP3A4 but not by CYP3A5. The preincubation period of sorafenib and sunitinib before the midazolam addition in the reaction mixture did not affect the enhancement of CYP3A5-catalyzed midazolam hydroxylation, indicating that the enhancement was caused by parent sorafenib and sunitinib. Docking studies with a CYP3A5 homology model based on the structure of CYP3A4 revealed that midazolam closely docked to the heme of CYP3A5 compared with sorafenib or sunitinib, suggesting that these anticancer drugs act as enhancers, not as substrates. Our results thus showed that sorafenib and sunitinib activated midazolam 1'-hydroxylation by CYP3A5 but inhibited that by CYP3A4. Unexpected drug interactions involving sorafenib and sunitinib might occur via heterotropic cooperativity of CYP3A5.

Delayed elimination of SN-38 in cancer patients with severe renal failure.

This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) ≤ 20 ml/min] who were undergoing dialysis and received 100 mg/m(2) irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr ≥ 60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28 were enrolled. The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was approximately one tenth of that in patients with normal renal function (P = 0.025). Approximately 50% of SN-38 was dialyzed with a 2.1-m(2) dialysis membrane, whereas 27% was dialyzed with a 1.5-m(2) membrane. Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure compared with patients with normal renal function. We demonstrated that SN-38 was partly dialyzed.

Phase I/II study of FOLFIRI in Japanese patients with advanced colorectal cancer.

OBJECTIVE: This phase I/II study determined the recommended dose of FOLFIRI (irinotecan, infusional 5-fluorouracil and leucovorin) for Japanese patients with advanced colorectal cancer, and evaluated safety at the recommended dose in patients without the UDP-glucuronosyltransferase 1A1*28 allele which caused reduced enzyme expression. METHODS: The phase I part assessed the maximum tolerated dose of FOLFIRI to determine the recommended doses of irinotecan and infusional 5-fluorouracil. The doses were escalated from 150 to 180 mg/m(2) (irinotecan) and 2000 to 2400 mg/m(2) (5-fluorouracil). UDP-glucuronosyltransferase 1A1*6 and *28, and pharmacokinetics of irinotecan were observationally examined. In the phase II part, patients without the UDP-glucuronosyltransferase 1A1*28 allele received FOLFIRI at the recommended dose to evaluate safety. RESULTS: Among 15 patients in the phase I part, dose-limiting toxicity (diarrhea) occurred in one patient who received 150 mg/m(2) irinotecan and 2400 mg/m(2) infusional 5-fluorouracil. The respective recommended doses were 180 and 2400 mg/m(2) for irinotecan and infusional 5-fluorouracil, without reaching the maximum tolerated dose. Twenty-five patients received FOLFIRI at the recommended doses. Grade 3 or 4 neutropenia occurred in 44%, and Grade 3 diarrhea in 4%. CONCLUSIONS: This phase I/II study demonstrates that the recommended doses of irinotecan and infusional 5-fluorouracil in FOLFIRI for Japanese patients with advanced colorectal cancer who do not possess the UDP-glucuronosyltransferase 1A1*28 allele are 180 and 2400 mg/m(2), respectively. Toxicities occurring at the recommended doses are manageable in these patients.