SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion.

Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using cis-Apc(+/Delta716) Smad4(+/-) mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-beta family signaling is blocked, we show here that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front. These CD34(+) iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1) and migrate toward the CCR1 ligand CCL9. In adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we further show that lack of CCR1 prevents accumulation of CD34(+) iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of transforming growth factor-beta family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.

Effects of rikkunshito, a kampo medicine, on quality of life after proximal gastrectomy.

BACKGROUND: The loss of the gastroesophageal junction after proximal gastrectomy (PG) induces various gastrointestinal symptoms, such as regurgitation, anorexia, and body weight loss, leading to impairment of the postoperative quality of life. In the present study, we investigated the long-term quality of life and the effects of rikkunshito, a traditional Japanese medicine (kampo), on the gastrointestinal symptoms and plasma ghrelin levels in patients with gastric cancer who had undergone PG. METHODS: Nineteen patients who had undergone PG> 6 mo before entry into the present study were enrolled. The plasma ghrelin levels, body weight, appetite, and Gastrointestinal Symptom Rating Scale (GSRS) scores were examined before and after the 4-wk administration of rikkunshito. A subgroup analysis was performed of patients showing a GSRS score of ≥ 2 before treatment, indicating the presence of gastrointestinal symptoms. RESULTS: The patients' body weight increased significantly after the administration of rikkunshito. Neither their appetite nor plasma acylated and deacylated ghrelin levels were significantly affected. In the subgroup analysis, the mean total GSRS score improved significantly from 2.6 ± 0.6 before the administration of rikkunshito to 1.9 ± 0.7 after administration because of the significant improvement in the subscale scores for abdominal pain, acid reflux, diarrhea, and constipation. CONCLUSIONS: The long-term quality of life was well preserved in the patients who had undergone PG at our hospital. In the patients with a baseline GSRS score of ≥2, rikkunshito significantly improved the symptoms of postgastrectomy syndrome, and its effect was possibly independent of the plasma ghrelin levels.

Adrenal cavernous hemangioma with subclinical Cushing's syndrome: report of a case.

Cavernous hemangioma of the adrenal gland is a rare tumor, which does not usually have endocrinological function. We report to our knowledge, the third documented case of a functioning adrenal hemangioma. Interestingly, this tumor indicated glucocorticoid hypersecretion, whereas the two previous cases showed mineralocorticoid hypersecretion. The tumor was 5 cm in diameter with typical computed tomography and magnetic resonance imaging findings. Subclinical Cushing's syndrome was diagnosed preoperatively, as there was insufficient suppression of cortisol by low-dose dexamethasone, a low adrenocorticotropic hormone (ACTH) concentration, and diminished ACTH and cortisol circadian rhythms without the typical clinical manifestation and symptoms of hypercortisolism. Intraoperative hypotension occurred immediately after tumor removal and following postoperative adrenal insufficiency, which support that the tumor was hyperfunctioning. The postoperative adrenal insufficiency had recovered completely by 12 months after the operation.

Diffusion-weighted magnetic resonance imaging for detecting lymph node metastasis of rectal cancer.

BACKGROUND: Preoperative diagnosis of lymph node metastasis is important in determining the optimal therapy for rectal cancer. It has been shown that diffusion-weighted magnetic resonance imaging (DWI) is a useful tool for detecting malignant tumors. METHODS: One hundred twenty-nine consecutive patients with rectal cancer were examined with DWI + conventional (T1-weighted and T2-weighted) MRI and computed tomography (CT). All 129 patients underwent rectal resection with total mesorectal excision. Findings on DWI + conventional MRI and CT were compared with those from histopathologic examinations. RESULTS: Fifty-nine (46%) patients had metastatic lymph nodes on histopathologic examinations. Two hundred twenty (18%) of 1,250 lymph nodes were pathologically positive for tumor metastasis. The overall patient-based sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of DWI + conventional MRI were 93, 81, 81, 93, and 87%, respectively. Corresponding values of CT were 73, 79, 74, 77, and 76%, respectively. The overall node-based sensitivity, specificity, PPV, NPV, and accuracy of DWI + conventional MRI were 97, 81, 52, 99, and 84%, respectively. Corresponding values of CT were 86, 80, 48, 96, and 81%, respectively. CONCLUSION: DWI + conventional MRI is effective for the detection of lymph node metastasis and useful for selection of the optimal therapy for rectal cancer.

Pancreatic endometrial cyst: report of a case.

A pancreatic endometrial cyst is an extremely rare disease. Since 1984, only 7 cases have been reported, including the current case. A 35-year-old woman with a history of recurrent severe left upper abdominal pain of 3 months' duration was found to have a cyst in the pancreatic body on the diagnostic imaging findings. With a preoperative diagnosis of mucous cystic adenoma, she underwent a distal pancreatectomy. The histopathological examination of the specimen revealed a pancreatic endometrial cyst. She complained about severe periodic abdominal pain during the convalescence, without any surgical complications. This study reviews previous reports of pancreatic endometrial cysts, and also discusses the clinicopathological features, pathogenesis, and appropriate treatment for this disease.

n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems.

HIF-1 (hypoxia-inducible factor 1) is a master regulator of cellular adaptive responses to hypoxia. The expression and transcriptional activity of the HIF-1alpha subunit is stringently controlled by intracellular oxygen tension through the action of prolyl and asparaginyl hydroxylases. In the present study we demonstrate that PG (n-propyl gallate) activates HIF-1 and expression of its downstream target genes under normoxic conditions in cultured cells and in mice. The stability and transcriptional activity of HIF-1alpha are increased by PG. PG treatment inhibits the interaction between HIF-1alpha and VHL (von Hippel-Lindau protein) and promotes the interaction between HIF-1alpha and p300, indicating that PG inhibits the activity of both prolyl and asparaginyl HIF-1alpha hydroxylases. We conclude that PG activates HIF-1 and enhances the resultant gene expression by directly affecting the intracellular oxygen sensing system in vitro and in vivo and that PG represents a lead compound for the development of a non-toxic activator of HIF-1.

Prognostic significance of the immediate early response gene X-1 (IEX-1) expression in pancreatic cancer.

BACKGROUND: The immediate early response gene X-1 (IEX-1) is a stress-inducible protein that is involved in the regulation of cell proliferation and apoptosis. The aim of this study was to evaluate the prognostic significance of IEX-1 expression in pancreatic cancer. METHODS: IEX-1 protein expression was examined on paraffin-embedded specimens from 78 patients with pancreatic ductal adenocarcinoma using immunohistochemistry. The relationships between the IEX-1 expression and other clinicopathological parameters and patient survival were evaluated. A similar analysis was conducted in a subgroup of 48 patients, who underwent a macroscopically curative resection with detailed information on the pathological findings. RESULTS: Among 78 pancreatic cancer patients, 41 patients (53%) were positive for IEX-1 staining. In a multivariate analysis, curative operation (P < .001), pathological stage I-III (P = .001), and positive IEX-1 expression (P = .002) were significantly favorable factors for survival. In a subgroup of 48 patients undergoing a macroscopically curative surgery, IEX-1 expression was positive in 28 patients (58%). A significant negative correlation was observed between the IEX-1 expression and serosal (P = .032) or arterial (P = .040) invasion of tumors. A multivariate analysis demonstrated limited local invasion (pT1-3, P = .021), negative lymph node involvement (pN0, P < .001), and positive IEX-1 expression (P = .004) to be significantly favorable factors for survival. CONCLUSIONS: The positive IEX-1 expression in tumor tissues may be associated with a better prognosis in pancreatic cancer. An immunohistochemical assessment of IEX-1 expression may therefore be helpful for predicting patient prognosis in this disease.

Uneventful splenectomy and cholecystectomy in a patient treated with anti-interleukin-6 receptor antibody therapy.

INTRODUCTION: Interleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune responses, acute phase reactions, and hematopoiesis. In rodent models, IL-6 has been suggested to be one of the essential mediators for optimal acute phase responses to infection and tissue damage. However, in humans, the roles of IL-6 in acute phase responses after surgery remain poorly understood. CASE REPORT: We present the first case report of successful splenectomy and cholecystectomy in a severe autoimmune-associated hemolytic anemia patient during treatment with a humanized anti-IL-6 receptor antibody. DISCUSSION: This unique case suggests that IL-6 is not an essential cytokine to safely perform surgical intervention and to prevent postoperative complications and that surgical intervention may not be contraindicated but can be selected as a therapeutic modality in patients treated with anti-IL-6 receptor antibody therapy.

[Case report of gastric cancer patient who suffered life-threatening adverse events including severe myelosuppression during neoadjuvant chemotherapy with S-1 and CDDP combination].

Neoadjuvant chemotherapy has been a recent focus in the treatment for advanced gastric cancer. Although the preoperative chemotherapeutic regimen of S-1 and CDDP is regarded as effective, safe and well tolerable according to previous clinical study, we experienced a 74-year-old woman who suffered from life-threatening adverse events including severe myelosuppression during the neoadjuvant chemotherapy. Although the patient did not experience any severe adverse events during the first course of treatment, on day 18 of the second course of chemotherapy, she was hospitalized because of anorexia and severe dehydration, leading to following grade 4 leukopenia/neutropenia, bacteremia, and disseminated intravascular coagulation (DIC). She finally recovered from the life-threatening adverse events with intensive therapy and eventually had a distal gastrectomy. Clinicians need to be alert especially to renal dysfunction that induces severe myelosuppression during chemotherapy with S-1, which contains 5-chloro-2,4-dihydroxypyridine (CDHP), a renal excretory inhibitor of dihydropyrimidine dehydrogenase (DPD).

Phase II study of protracted irinotecan infusion and a low-dose cisplatin for metastatic gastric cancer.

AIM: To test protracted irinotecan infusion plus a low-dose cisplatin in this Phase II trial to decrease its toxicity. METHODS: The eligibility criteria were: (1) histologically proven measurable gastric cancer; (2) performance status of 0 or 1; (3) no prior chemotherapy or completion of prior therapy at least 4 wk before enrollment; (4) adequate function of major organs; (5) no other active malignancy; and (6) written informed consent. The regimen consisted of irinotecan (60 mg/m(2)) on d 1 and 15 by 24-h infusion and cisplatin (10 mg/m(2)) on d 1, 2, 3, 15, 16, and 17. Treatment was repeated every 4 wk. RESULTS: Thirty-one patients were registered between April 2000 and January 2001. The response rate for all 31 patients, 20 patients without prior chemotherapy, and 11 patients with prior chemotherapy was 52% (16/31), 60% (12/20), and 36% (4/11), respectively. The median survival time was 378 d. The median number of courses given to all patients was 2. Grade 4 neutropenia occurred in 11 (35%) patients, while grade 3 to 4 diarrhea or nausea occurred in 1 (3%) and 3 (10%) patients, respectively. Fatigue was minimal as grade 1 fatigue was found only in 3 (10%) patients. Other adverse events were mild and no treatment-related deaths occurred. CONCLUSION: This regimen showed a high level of activity and acceptable toxicity in patients with metastatic gastric cancer.

Immediate early response gene X-1, a stress-inducible antiapoptotic gene, encodes cytotoxic T-lymphocyte (CTL) epitopes capable of inducing human leukocyte antigen-A33-restricted and tumor-reactive CTLs in gastric cancer patients.

Peptide-based vaccine therapy, which is designed to elicit T-cell immunity against tumors, is an attractive approach for the treatment of cancer patients. To provide a scientific basis for peptide therapy, an increasing number of CTL-directed peptides have been identified, and some of them have been tried as antigen-specific immunotherapy in the past decade. Only a few studies, however, have been performed on such peptides restricted with alleles other than HLA-A2 and -A24. In the present study, we show that immediate early response gene X-1 (IEX-1), a stress-inducible protein associated with the regulation of cell proliferation and apoptosis, produces antigenic epitopes recognized by 850B-CTLs, HLA-A33-restricted CTLs newly established from T cells infiltrating into gastric adenocarcinoma. The IEX-1 gene was highly expressed in most cell lines and tissues from various types of cancer at both the mRNA and protein levels. However, it was not expressed at the protein level in any normal epithelium or connective tissues tested. Three IEX-1-derived peptides at positions 47-56, 61-69, and 65-73, which were recognized by the 850B-CTLs, could induce CD8(+) peptide-specific CTL reaction to tumor cells from HLA-A33(+) gastric cancer patients and other epithelial cancer patients, but not from healthy donors, in an HLA class I-restricted manner. Because increased expression of IEX-1 is suggested to be involved in the resistance to apoptosis and in the proliferation of cancer cells, these antigenic peptides could be potent candidates for peptide-based specific immunotherapy against HLA-A33(+) gastric cancer and other epithelial cancers.

Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes.

Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis to specific organs. Here we show that mouse B16F10 melanoma cells constitutively express chemokine receptor CXCR3, and that its ligands CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC induce cellular responses in vitro, such as actin polymerization, migration, invasion, and cell survival. To determine whether CXCR3 could play a role in metastasis to lymph nodes (LNs), we constructed B16F10 cells with reduced CXCR3 expression by antisense RNA and investigated their metastatic activities after s.c. inoculations to syngeneic hosts, C57BL/6 mice. The metastatic frequency of these cells to LNs was markedly reduced to approximately 15% (P < 0.05) compared with the parental or empty vector-transduced cells. On the other hand, pretreatment of mice with complete Freund's adjuvant increased the levels of CXCL9 and CXCL10 in the draining LNs, which caused 2.5-3.0-fold increase (P < 0.05) in the metastatic frequency of B16F10 cells to the nodes with much larger foci. Importantly, such a stimulation of metastasis was largely suppressed when CXCR3 expression in B16F10 cells was reduced by antisense RNA or when mice were treated with specific antibodies against CXCL9 and CXCL10. We also demonstrate that CXCR3 is expressed on several human melanoma cell lines as well as primary human melanoma tissues (5 of 9 samples tested). These results suggest that CXCR3 inhibitors may be promising therapeutic agents for treatment of LN metastasis, including that of melanoma.

Usefulness of 99mTc-sestamibi scintigraphy in suggesting the therapeutic effect of chemotherapy against gastric cancer.

PURPOSE: Imaging with (99m)Tc-sestamibi ((99m)Tc-MIBI) has been used to assess 170-kDa P-glycoprotein (P-gp) expression and predict chemotherapy responses in several types of malignancy, such as breast and lung cancers. The purpose of this study was to evaluate the relationship between (99m)Tc-MIBI accumulation in tumors and sensitivity to chemotherapy in gastric cancer patients. EXPERIMENTAL DESIGN: Thirty-six patients with advanced gastric cancer underwent (99m)Tc-MIBI scintigraphy before chemotherapy. Patients also underwent endoscopic biopsy, and the expression of P-gp or multidrug resistance-associated protein was analyzed by immunohistochemical staining. The relationship between the accumulation of (99m)Tc-MIBI in tumors and responses to chemotherapy with 5-fluorouracil/cis-diamminedichloroplatinum(II) or epirubicin was examined. RESULTS: Higher accumulation of (9m)Tc-MIBI in tumors was observed in 25 and 23 of 36 gastric cancer patients at the early (30 min) and delayed (120 min) images, respectively. Accelerated accumulation of (99m)Tc-MIBI negatively correlates with increased expression of P-gp, but not of multidrug resistance-associated protein, as determined by immunohistochemistry in gastric cancer tissues. The response rate to 5-fluorouracil/cis-diamminedichloroplatinum(II) chemotherapy in patients with high (99m)Tc-MIBI accumulation (15.4%) was much lower than that in patients with low (99m)Tc-MIBI accumulation (54.5%). In contrast, patients with high (99m)Tc-MIBI accumulation show a higher response rate (41.7%) to chemotherapy with epirubicin, which is known to be a substrate of P-gp transporter. CONCLUSIONS: (99m)Tc-MIBI scintigraphy is useful to suggest the responses to chemotherapy of patients with advanced gastric cancer.

Ran, a small GTPase gene, encodes cytotoxic T lymphocyte (CTL) epitopes capable of inducing HLA-A33-restricted and tumor-reactive CTLs in cancer patients.

PURPOSE: The purpose is to identify a gene coding for tumor-associated antigen and peptide capable of inducing CTLs reactive to tumor cells with a HLA-A33-restricted fashion to provide scientific basis for specific immunotherapy to HLA-A33+ cancer patients. EXPERIMENTAL DESIGN: An expression gene-cloning method was used to identify the tumor-associated antigen gene. Northern blot analysis and immunohistochemistry were used to examine the mRNA and protein expression levels in various cells and tissues, respectively. Synthetic peptides were examined for their ability to induce HLA-A33+ tumor-reactive CTLs in peripheral blood mononuclear cells from cancer patients. RESULT: A gene of small GTPase, Ran, which controls the cell cycle through the regulation of nucleocytoplasmic transport, mitotic spindle organization, and nuclear envelope formation, was found to encode epitopes recognized by the HLA-A33-restricted CTLs established from T cells infiltrating into gastric adenocarcinoma. The expression of the Ran gene was increased in most cancer cell lines and cancer tissues at both the mRNA and protein levels. However, it was not enhanced in the surrounding normal cells or tissues. It was also undetectable in normal tissues as far as tested. Ran-derived peptides at positions 48-56 and 87-95 could induce CD8+ peptide-specific CTLs reactive to tumor cells from HLA-A33+ epithelial cancer patients in a HLA class I-restricted manner. CONCLUSIONS: Because of its increased expression in cancer cells and involvement in malignant transformation and/or the enhanced proliferation of cancer cells, the two Ran-directed peptides could be potent candidates in use for specific immunotherapy against HLA-A33+ epithelial cancers.

Thioredoxin-mediated redox control of human T cell lymphotropic virus type I (HTLV-I) gene expression.

Thioredoxin (TRX) is a small ubiquitous protein with multiple biological functions, including the thiol-mediated redox-regulation of gene expression. We have previously demonstrated that human TRX is overexpressed as a major protein oxidoreductase in human T cell lymphotropic virus type I (HTLV-I)-infected cells. In the present study, we investigated the relationship between TRX and viral gene expression in HTLV-I infection. To study the mechanism that causes overexpression of TRX in HTLV-I-infected cells, we first examined the effect of the HTLV-I transactivator, Tax, on TRX expression. Induction of HTLV-I Tax protein increased the expression of TRX protein in a Tax-transfected Jurkat cell line, JPX-9. Moreover, chloramphenicol acetyltransferase (CAT) analysis with a reporter gene containing the TRX promoter revealed that Tax activates the transcription of TRX gene. To study the role of overexpressed TRX in HTLV-I infection, we next examined the effect of TRX on HTLV-I long terminal repeat (LTR)-mediated transcription using CAT analysis. In an HTLV-I-infected human T cell line MT-2, the HTLV-I LTR transactivation was suppressed by the overexpression of wild-type TRX, but activated by the introduction of inactive mutant TRX. Moreover, in HTLV-I negative Jurkat T cells, the HTLV-I LTR transactivation induced by Tax was also repressed by overexpression of wild-type TRX. Because cellular redox changes were shown to affect the HTLV-I gene expression, it is likely that TRX modulates the HTLV-I gene expression by regulating cellular redox state. Taken together, these findings suggest that overexpressed TRX, which is induced by HTLV-I Tax, may play an important role in HTLV-I infection through the negative regulation of viral gene expression.

Baicalin induces apoptosis via mitochondrial pathway as prooxidant.

Baicalin is a flavonoid and a major component of a herbal medicine, Sho-saiko-to, which is commonly used for treatment of chronic hepatitis in Japan and China. Flavonoids including baicalin have been reported to not only function as anti-oxidants but also cause cytotoxic effect. We investigated the mechanism of baicalin-induced cytotoxicity in leukemia-derived T cell line, Jurkat cells. When cells were cultured with 50-200 microg/ml baicalin for 6h, caspase-3 was activated and then cells fell into apoptosis. Induction of apoptosis by baicalin was accompanied with the marginal generation of intracellular reactive oxygen species (ROS), the increase of the cytosolic fractions of cytochrome c, and the disruption of mitochondrial transmembrane potential (DeltaPsi(m)) prior to the activation of caspase-3. The pre-culture with 5 mM of buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, facilitated baicalin-induced disruption of DeltaPsi(m) and induction of apoptosis. The pre-culture with N-benzyloxycarbonyl-valyl-alanyl-aspartyl fluoromethylketone (Z-VAD-fmk), a pan-caspase inhibitor, partially suppressed the induction of apoptosis. On the other hand, baicalin showed little toxic effect on peripheral blood mononuclear cells (PBMCs) from healthy volunteers. These results indicate that baicalin acts as a prooxidant and induces caspase-3 activation and apoptosis via mitochondrial pathway.

The intravenous anesthetic propofol inhibits hypoxia-inducible factor 1 activity in an oxygen tension-dependent manner.

Hypoxia elicits a wide range of responses that occur at different organizational levels in the body. Hypoxia is not only a signal for energy conservation and metabolic change, but triggers expression of a select set of genes. The transcription factor hypoxia-inducible factor 1 (HIF-1) is now appreciated to be a master factor of the gene induction. Although knowledge on molecular mechanisms of HIF-1 activation in response to hypoxia is accumulating, the molecular mechanism of maintenance of HIF-1 activity under normoxic conditions remains to be elucidated. We demonstrate that the intravenous anesthetic propofol reversibly inhibits HIF-1 activity and the gene expression mediated by HIF-1 by blocking the synthesis of the HIF-1alpha subunit under 20% or 5% O2 conditions, but not under 1% O2 conditions.

Mitochondrial membrane potential is reduced in peripheral natural killer cells following partial hepatectomy.

The mechanism underlying immunosuppression after partial hepatectomy remains unclear. Hepatectomy induces lymphopenia, which is related to immunomodulation. The aim of this study was to determine whether peripheral blood lymphocytes (PBL) are susceptible to mitochondria-mediated apoptosis after hepatic resection. We compared the changes in mitochondrial membrane potential in lymphocytes from hepatectomized patients with metastatic liver tumor with the corresponding changes in lymphocytes from cholechystectomized patients, because changes in mitochondrial membrane potential have been reported to frequently occur during the early stages of apoptosis. Mitochondrial membrane potential, subpopulation, and apoptosis of lymphocytes were estimated with flow cytometry. Hepatectomy significantly (P<0.001) reduced postoperative mitochondrial membrane potential, while cholecystectomy slightly decreased it. Apoptosis of lymphocytes was increased on post-hepatectomy day, and this increase was correlated with the extent of mitochondrial membrane potential reduction. The major subset of lymphocytes with low mitochondrial membrane potential consisted of CD56(+) natural killer (NK) cells, and NK cell activity and cell counts significantly decreased after hepatectomy. Mitochondrial membrane potential of PBL was reduced after hepatectomy, and some lymphocytes underwent apoptosis through the mitochondrial pathway, which was one of the causes for lymphopenia. NK cells were more responsible for the decrease of mitochondrial membrane potential after hepatectomy than other lymphocytes, and the reduction in mitochondrial membrane potential in NK cells appeared to reflect modulation of the innate immune system.

Role of retinoblastoma protein and E2F-1 transcription factor in the acquisition of 5-fluorouracil resistance by colon cancer cells.

5-fluorouracil (5-FU) is an important antineoplastic agent that has proven to be effective in the treatment of colorectal cancer. However, one of the main obstacles to the clinical use of 5-FU is the acquisition of resistance to the drug by cancer cells. In vitro studies have demonstrated that the resistance to 5-FU is correlated with increased activity of thymidylate synthase (TS), whose gene has a E2F binding site in its promoter region. To understand the mechanisms through which cancer cells acquire resistance to 5-FU, human colon cancer-derived cell line DLD-1 and its subcloned cell line DLD-1/5-FU, which has acquired resistance to 5-FU, were compared by assessing their phosphorylation of retinoblastoma protein (pRb) and E2F-1 transcriptional activity. The level of pRb phosphorylation in the DLD-1/5-FU cells was higher than in the parental DLD-1cells. In parallel with the increased phosphorylation of pRb, E2F-1 transcriptional activity, which has been shown to be a result of E2F-1 dissociation from hyperphosphorylated pRb, was increased in the DLD-1/5-FU cells. Examination of the effect of E2F-1 decoy oligodeoxynucleotides (ODNs) on the proliferation of DLD-1/5-FU cells in the presence of 5-FU to confirm the importance of E2F-1 in the mechanisms of the acquisition of 5-FU resistance showed that DLD-1/5-FU cells transfected with E2F-1 decoy ODNs recovered their sensitivity to 5-FU. These results suggested that pRb and E2F-1 play important roles in the acquisition of 5-FU resistance by cancer cells and that cancer therapy targeting transcription factor E2F might be effective.

Usefulness of FDG-positron emission tomography in diagnosing peritoneal recurrence of colorectal cancer.

BACKGROUND: Accurate detection of peritoneal recurrence in colorectal cancer remains a diagnostic challenge. We retrospectively examined sensitivity and accuracy of fluorine-18-2-fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the diagnosis of peritoneal recurrence. METHODS: FDG-PET and computed tomography (CT) were performed on 23 patients with colorectal cancer suspected of having a recurrence based on clinical symptoms, a tumor marker (CEA), and so forth. The final diagnosis was compared with the results of FDG-PET and CT. RESULTS: Peritoneal recurrence was suspected in 6 patients with FDG-PET, and 5 of them were finally diagnosed as recurrences. The sensitivity of FDG-PET was 88% and its diagnostic accuracy was 78%, whereas those of CT were 38% and 44%, respectively. A lesion as small as 15 mm in diameter was diagnosed by FDG-PET. CONCLUSIONS: FDG-PET is an effective method for diagnosing peritoneal recurrence of colorectal cancer. FDG-PET is expected to become more important for detecting peritoneal recurrence at an early stage.