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Yuji Toiyama,
Chikao Miki,
Yasuhiro Inoue,
Yoshinaga Okugawa,
Yuki Koike,
Hideki Watanabe,
Takeshi Yokoe,
Junichirou Hiro, Eiki Ojima,
Kouji Tanaka,
Masato Kusunoki
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ABSTRACT: Immunosuppressive acidic protein (IAP) is a potent biological marker for immunological surveillance in patients with malignant tumors. This study aimed to investigate the significance of serum IAP as an index of disease status, clinicopathological findings and prognosis in colorectal cancer.
A total of 101 patients with colorectal cancer and 80 normal volunteers were included in this retrospective trial. Preoperative serum IAP was assayed using a commercially available enzyme-linked immunosorbent assay kit.
The serum IAP level in the patients, which was not associated with clinicopathological features except for tumor size, was significantly higher than that in controls. The serum IAP level was closely correlated with percent body weight loss, serum albumin and cholinesterase, and percentage of circulating lymphocytes reflecting the host's nutritional and immunological conditions. Interestingly, these parameters were not associated with factors reflecting disease progression except for tumor size. The prognosis of patients with higher IAP levels was significantly worse than that of patients with lower IAP levels. Furthermore, an elevated serum IAP level was an independent prognostic marker in all patients.
The preoperative serum IAP level may reflect the general condition of colorectal cancer patients, and thus may predict long-term survival independently of stage progression.
Journal of Surgical Oncology 05/2008; 97(5):404-8. · 2.10 Impact Factor
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ABSTRACT: Chemotherapy remains the main choice of treatment for the management of unresectable or metastatic colorectal cancer. However, drug resistance is a major problem, limiting the effectiveness of the chemotherapies presently used to treat cancer. During treatment, drug resistance can also be acquired by tumors that are initially sensitive to chemotherapy. We present a case of metachronous splenic recurrence after a curative resection of appendical cancer with ovarian metastasis, although the patient had been treated with 5-FU/LV followed by mFOLFOX6 after surgery. Molecular analyses by RT-PCR also showed that the residual tumor after chemotherapy has cancer cells overexpressing 5-FU/l-OHP based chemotherapy-resistant genes. Therefore, it was suggested that a careful assessment of the disease status be undertaken during chemotherapy to ensure that the possibility of surgical resection, especially of the re-growth or partial response tumors, was not missed, since several genes, chemoresistant to the agents used, can be induced in residual tumors during chemotherapy.
Oncology Reports 04/2008; 19(3):755-9. · 1.84 Impact Factor
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ABSTRACT: Our aim was to determine whether the expression levels of specific genes could predict clinical radiosensitivity in human colorectal cancer.
Radioresistant colorectal cancer cell lines were established by repeated X-ray exposure (total, 100 Gy), and the gene expressions of the parent and radioresistant cell lines were compared in a microarray analysis. To verify the microarray data, we carried out a reverse transcriptase-polymerase chain reaction analysis of identified genes in clinical samples from 30 irradiated rectal cancer patients.
A comparison of the intensity data for the parent and three radioresistant cell lines revealed 17 upregulated and 142 downregulated genes in all radioresistant cell lines. Next, we focused on two upregulated genes, PTMA (prothymosin alpha) and EIF5a2 (eukaryotic translation initiation factor 5A), in the radioresistant cell lines. In clinical samples, the expression of PTMA was significantly higher in the minor effect group than in the major effect group (P = 0.004), but there were no significant differences in EIF5a2 expression between the two groups.
We identified radiation-related genes in colorectal cancer and demonstrated that PTMA may play an important role in radiosensitivity. Our findings suggest that PTMA may be a novel marker for predicting the effectiveness of radiotherapy in clinical cases.
Journal of Gastroenterology 10/2007; 42(9):730-6. · 4.16 Impact Factor
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ABSTRACT: To assess whether preoperative chemo-radiotherapy enhances the expression of vascular endothelial growth factor (VEGF) in patients with colorectal cancer, we investigated in vivo and in vitro the interactions between chemo-radiotherapy and the expression of VEGF, and their possible impact on distant metastasis. Cellular cytotoxicity in the colon cancer cell lines, LoVo, SW480 and Caco2, was determined using a WST-8 colorimetric assay after cells were exposed to 5-fluorouracil combined with radiation. In addition, the VEGF levels in cultured cells were measured by ELISA. Preoperative serum samples and tumor specimens were prospectively collected from 32 rectal cancer patients who received preoperative chemo-radiotherapy. Both local and circulating VEGF expression levels were measured perioperatively by ELISA, and assessed in relation to the clinicopathological findings. Perioperative circulating VEGF levels from irradiated patients were also compared with a non-irradiated control group. There were significant increases in local VEGF levels, both in vivo and in vitro, after chemo-radiotherapy, especially in viable cancer cells. The circulating VEGF levels in the irradiated patients were significantly lower after surgery compared with those in the control group. Although preoperative chemo-radiotherapy enhanced tumor-specific VEGF expression, especially in individual cancer cells both in vitro and in vivo, it did not necessarily enhance systemic VEGF expression, possibly because of tumor volume reduction induced by the chemo-radiotherapy.
Oncology Reports 09/2007; 18(2):369-75. · 1.84 Impact Factor
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ABSTRACT: This study consisted of 2 aims: (i) to determine genes associated with hepatocellular carcinoma (HCC) by microarray analysis; and (ii) to evaluate the clinicopathological significance of human ubiquitin-conjugating enzyme E2C (Ube2c) found to be overexpressed in HCC from microarray analysis. Laser microdissection and cDNA-microarray were performed to identify genes associated with HCC. We then focused on the Ube2c gene. Using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR), Ube2c expression status and clinicopathological significance were studied in 65 clinical HCC samples. A number of genes upregulated in HCC cells compared to noncancerous liver cells were identified, one of which was the Ube2c gene. Ube2c gene expression in the cancer tissue was higher than in the corresponding noncancerous tissue in 62 of the 65 cases (95.4%, p < 0.01). Tumors with high Ube2c expression showed higher frequencies of tumor invasion to capsular formation (fc-inf), invasion to portal vein (vp) and tumor de-differentiation (p < 0.05). Patients with high Ube2c expression also showed significantly worse disease-free survival rates than those with low Ube2c expression (p < 0.01). In addition, Ube2c expression was found to be an independent prognostic factor for disease-free survival rate in multivariate analysis. We identified differentially expressed genes between HCC and normal liver tissues. Of those, the Ube2c gene appeared to be associated with HCC progression, and may be useful as a prognostic indicator for HCC patients.
International Journal of Cancer 07/2007; 121(1):33-8. · 5.44 Impact Factor
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ABSTRACT: This study was performed to investigate the range of optimal concentration and mechanisms of paclitaxel (PXL) radio-enhancement in gastrointestinal cancer cell lines HT29 and MKN45.
Cell growth inhibition by PXL pretreatment at various concentrations (0-10 microM) followed by irradiation was investigated using a modified MTT assay. To investigate the mechanisms of the observed radio-enhancement, flow cytometry was conducted to define the cell cycle distributions. Furthermore, the alterations in expression of a DNA repair molecule [excision repair cross-complementation group1 (ERCC1)] and an angiogenesis factor [vascular endothelial growth factor (VEGF)] induced by PXL were investigated.
Cytotoxic concentrations of PXL (0.1-10 microM) that cause accumulation of cells in the G2/M phase have strong radio-enhancing effects and inhibit total cell growth. The maximal non-cytotoxic concentration of PXL (0.01 microM) also had a radio-enhancing effect. The expression of the genes of ERCC1 and VEGF induced by radiation was suppressed by PXL pretreatment. The protein secretion of VEGF induced by radiation was suppressed at cytotoxic doses of PXL, and the induced protein secretion of ERCC1 was also suppressed even at maximal non-cytotoxic doses of PXL.
The range of optimal concentration for PXL pretreatment was 0.01-0.1 microM in these cells. Two major mechanisms of radio-enhancement are suggested: (1) PXL induces G2/M arrest leading to increased DNA damage after radiation, which results in mitotic death, and (2) PXL suppresses the expression of radiation-induced DNA repair molecules and angiogenesis factors, resulting in inhibition of cell growth and cell death.
Cancer Chemotherapy and Pharmacology 06/2007; 59(6):733-42. · 2.83 Impact Factor
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ABSTRACT: This is a first pediatric case about the efficacy of octreotide for improving symptoms of malignant bowel obstruction. A 12-year-old boy was referred to our hospital for treatment of transverse colon cancer with peritoneal dissemination. A transverse colectomy was undertaken with postoperative adjuvant chemotherapy. Seven months later, severe abdominal symptoms occurred caused by incomplete bowel obstruction owing to tumor progression. The patient's quality of life decreased with a resultant disturbed mental condition. His parents sought to stop chemotherapy and for him to receive palliative care at home. We suggested nasogastric tube placement, but this was rejected. After obtaining informed consent, octreotide was administered intravenously. After 1 week, abdominal symptoms improved and the boy's complaints stopped. He had a good appetite and was able to eat small amounts of food. He was able to spend his final 2 months at home without nausea and in his family surroundings.
Journal of Pediatric Surgery 02/2007; 42(1):259-60. · 1.45 Impact Factor
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ABSTRACT: Our aim was to clarify the significance of widely accepted irinotecan (CPT-11)/5-fluorouracil (5-FU) combinations in colon cancer by investigating their sequential effect.
The sequential effect of CPT-11/5-FU in two colon cancer cell lines, LoVo and SW480, was evaluated by WST-8 colorimetric assay. The cell cycle distributions of each drug were analyzed by flow cytometry, and then the chemoresistant mechanisms and expression of a drug transporter (MDR1), the bcl-2 apoptotic pathway, metabolizing enzymes [carboxylesterase (CE), dihydropyrimidine dehydrogenase], and target enzymes (topoisomerase I, thymidine synthase) associated with sequence-dependent cytotoxicity were examined.
The cytotoxicity of 5-FU (10, 100, 1000 microM) followed by CPT-11 (1 microM) was significantly greater than that of CPT-11 (1 microM) followed by 5-FU (10, 100, 1000 microM) (P < 0.05). Reverse transcription-polymerase chain reaction analysis revealed that exposure to 5-FU downregulated both MDR1 and bcl-2 mRNA and simultaneously upregulated CE2 mRNA expression, suggesting enhancement of subsequent CPT-11 cytotoxicity.
The cytotoxic effects of the CPT-11/5-FU combinations were shown to be schedule-dependent in human colon cancer cells. The findings suggest that 5-FU followed by CPT-11 administration might be the optimal sequence for CPT-11/5-FU treatment of advanced colon cancer.
Journal of Gastroenterology 01/2007; 41(12):1149-57. · 4.16 Impact Factor
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ABSTRACT: We have previously demonstrated that the combined use of doxifluridine and irinotecan shows a different molecular mechanism than that of the protracted venous infusion of 5-FU and irinotecan. In this analysis, there is a suggestion that doxifluridine may enhance irinotecan and enable us to decrease the dose of irinotecan without losing the strong effect by using doxifluridine instead of 5-FU. We present a colon cancer patient with the UGT1A1 polymorphism (UGT1A1 *28) as a known high risk for irinotecan, who was treated with a combination of doxifluridine and irinotecan for peritoneal dissemination resulting in stable disease for 2 years without adverse reactions, although the patient initially developed severe adverse effects to the combination of the protracted venous infusion of 5-FU and irinotecan. Even with the same ratios of fluoropyrimidine and irinotecan combinations, replacing 5-FU with doxifluridine or capecitabine could provide new strategies to obtain not only convenience but also better efficacy and safety at the molecular level.
Oncology Reports 12/2006; 16(5):971-4. · 1.84 Impact Factor
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ABSTRACT: To evaluate the optimal schedule of 5-fluorouracil (5-FU) radiosensitization in rectal cancer, we investigated the interaction between radiation and several doses of 5-FU on colon cancer cell lines based on pharmacokinetics of oral fluoropyrimidine. Cellular cytotoxicity in colon cancer cell lines, LoVo, WiDr and Caco-2 was determined, using a WST-8 colorimetric assay, after 24 h exposure to several concentrations of 5-FU and a radiation dose of 5 Gy. Cells were exposed to 5-FU 24 and 0 h before radiation. 5-FU doses were classified into three groups: uracil-tegafur (0.01-0.1 microM), S-1 (0.1-1.0 microM) and pharmacokinetic modulating chemotherapy (0.1-10 microM). In addition, the effect of 5-FU on the steady-state levels of a human excision repair cross-complementing 1 gene and cell cycle distribution were examined. Regardless of time of 5-FU exposure, all cell growth was significantly inhibited in a dose-dependent manner. In Caco-2 cells, the cytotoxicity of radiation followed by 5-FU was significantly greater than that of 5-FU followed by radiation, unlike in the other cell lines. The growth inhibitory effect of radiation followed by 5-FU increased in a dose-dependent manner to reach a plateau at S-1 doses in all cell lines. In cell cycle distribution, 5-FU exposure for 24 h increased the S phase fraction in a dose-dependent manner. RT-PCR showed that 5-FU post-treatment graduallly inhibited mRNA expression of ERCC1, which may affect recombination repair efficiency, accounting for the higher tumor sensitivity. Oral fluoropyrimidines, like S-1, that can maintain a constant level of 5-FU may be an acceptable alternative radiosensitizer to protracted 5-FU infusion, when the aim of neoadjuvant chemoradiotherapy for rectal cancer is locoregional control.
Oncology Reports 12/2006; 16(5):1085-91. · 1.84 Impact Factor
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ABSTRACT: There is no marker capable of differentiating patients with Dukes A and B colorectal cancer with aggressive diseases from those with indolent diseases. We evaluated the results of five years of actuarial survival data to determine whether serial monitoring of serum hepatocyte growth factor could provide prognostic information on these patients.
Blood samples of 147 colorectal cancer patients were obtained and the serum concentration of hepatocyte growth factor was measured.
Elevated serum hepatocyte growth factor levels were associated with stage progression. Although the overall positive rate of hepatocyte growth factor in the patients was the same as that of the carcinoembryonic antigen, the positive rate of hepatocyte growth factor in the Dukes A patients was two times higher than that of the carcinoembryonic antigen, and nearly 40 percent of the carcinoembryonic antigen-negative patients had a positive serum hepatocyte growth factor in the Dukes A and B classification. In this subgroup, patients with positive serum hepatocyte growth factor or carcinoembryonic antigen levels had a poorer prognosis, whereas positive serum hepatocyte growth factor level after surgery could predict disease recurrence.
A combination of serum hepatocyte growth factor and carcinoembryonic antigen tests might be useful for selecting patients with aggressive diseases in Dukes A and B classification.
Diseases of the Colon & Rectum 12/2006; 49(11):1710-8. · 3.13 Impact Factor
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ABSTRACT: Chromosomal instability evidenced by a loss of heterozygosity (LOH) is implicated as a predictor of poor survival in patients with colorectal cancer, whereas microsatellite instability (MSI) is associated with improved survival rates. We investigated the relationship between tumor expression of angiogenic growth factors and genomic alterations in colorectal cancer.
Two genotypes, LOH and MSI, determined by microsatellite markers in the 4 cancer-related chromosomes 2p, 3p, 17p, and 18q, were analyzed in 73 patients with colorectal cancer. The tumor-specific expression of vascular endothelial growth factor and hepatocyte growth factor (HGF) were quantified, and the interleukin-6 network also was evaluated.
MSI-positive neoplasms showed a lesser expression of both tumor growth factors and interleukin-6. In contrast, LOH-positive neoplasms showed a greater expression of HGF and a lesser expression of interleukin-1-receptor antagonist. MSI neoplasms were correlated with favorable prognosis in agreement with previous findings.
The suppressed production of angiogenic growth factors in MSI cancers partly might explain the better prognosis in MSI-positive patients. The interleukin-6 network, which upregulates production of vascular endothelial growth factor and HGF, might be involved in this mechanism.
Surgery 04/2006; 139(3):305-11. · 3.10 Impact Factor
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ABSTRACT: This retrospective study was conducted to assess the safety, efficacy, and long-term results of multi-modality therapy including radio-frequency thermal ablation (RFA) and radiotherapy as an additional cytoreductive method for eliciting the marked effects of chemotherapy in treating unresectable lung metastases from colorectal cancer. Total of 21 patients with lung metastasis from colorectal cancer were included. They were treated with modified pharmacokinetic modulating chemotherapy (PMC). Eleven were also treated with RFA and/or radiotherapy (multi-modality group), and 10 were treated with chemotherapy alone (chemotherapy group). Characteristics and survival of patients in the multi-modality group were compared with those of the chemotherapy group. The median survival of all patients was 38.6 months after the initial PMC. The cumulative 3-year survival rate of patients in the multi-modality group was 87.5% compared with 33.3% in the chemotherapy group (p=0.0041). The course of multi-modality therapy was uneventful except for pneumothorax in those who received RFA. Although pneumothorax developed in 4 of 11 patients (36.4%) treated with RFA, all were able to receive chemotherapy within 2 weeks after RFA. In conclusion, multi-modality therapy combined with modified PMC, radiation and RFA is a feasible choice of treatment associated with reasonable morbidity and mortality in patients with inoperable lung metastases from colorectal cancer.
Oncology Reports 01/2006; 14(6):1571-6. · 1.84 Impact Factor
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ABSTRACT: Aging and tumor-related malnutrition are associated with increased inflammatory cytokine levels. However, it is unclear whether this influences the outcomes of surgery. We explored the relationships between cytokines and surgical complications among patients undergoing surgery for colorectal cancer.
Laboratory experiment.
Surgery department of school of medicine.
One hundred patients with colorectal cancer.
The perioperative circulating levels of interleukin (IL)-1beta, IL-6, and IL-1 receptor antagonist (Ra) were determined, and the numbers of circulating lymphocytes and neutrophils were counted.
Trends toward increasing postoperative infection were observed among patients who were older and had lower body mass index. Preoperative IL-1Ra and intraoperative blood loss, however, remained the only two independent predictors of postoperative infection. Clinically, patients with low preoperative IL-1Ra most frequently were the elderly with low body mass index. Postoperatively, elderly patients with low body mass index showed an exaggerated IL-6 response, followed by an exaggerated postoperative inflammatory response and increased postoperative loss of body weight. In contrast, normal immunoreactivity was preserved in well-nourished elderly patients.
In colorectal cancer patients undergoing surgery, low preoperative IL-1Ra is associated with postoperative infection. In our patient population, lower IL-1Ra level is commonly observed in the elderly with low body mass index. These findings suggest that postoperative infection, frequently seen in the nutritionally deficient elderly, may be the result of defective immunoinflammatory adaptation system.
Critical Care Medicine 02/2005; 33(1):177-80. · 6.33 Impact Factor
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ABSTRACT: Up-regulation of the IL-1-IL-6 network stimulates systemic expression of C-reactive protein (CRP). This cytokine network system plays a pivotal role in inducing angiogenic growth factors in intestinal mucosa. Serum CRP level and tissue concentrations of cytokines in colorectal cancer patients were determined and an in vitro model was employed to determine the time course of induction of IL-6 in Caco-2 cells. Increased serum CRP was associated with recurrent disease and shorter survival time. Intense surgical stress and the presence of an acute phase reactant were independently associated with overexpression of IL-6 in the tumor. Enhanced IL-6 protein expression in Caco-2 cells induced by the initial treatment with IL-1beta or lipopolysaccharide could be abrogated by additional presupplementation of IL-1ra. The presence of an acute phase reactant reflects uncontrolled up-regulation of the local IL-1-IL-6 network system in the tumor, which may enhance the survival and proliferation of remnant cancer cells after tumor resection.
Digestive Diseases and Sciences 07/2004; 49(6):970-6. · 2.12 Impact Factor
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ABSTRACT: Insufficiency fractures of the pelvic bones are rare complications of radiotherapy, but they can cause significant morbidity. We report a patient who developed pelvic insufficiency fractures because of preoperative hypofractionated radiotherapy with chemotherapy for rectal carcinoma. She was treated with a four-field box technique, receiving 20 Gy in four fractions, and she underwent concurrent pharmacokinetic modulating chemotherapy (PMC; intravenous infusion of 5-fluorouracil [FU], 750 mg/body per 24 h and oral administration of uracil and futrafur [UFT] 400 mg/day) over a 1-week period. She developed severe buttock and femoral pain 10 months after this preoperative therapy. Physical examination at this time was unremarkable, with an absence of neurological signs, and radiographic examination was also normal, resulting in the patient initially being undiagnosed. However, 2 months after the onset of her initial pain, she was diagnosed as having pelvic insufficiency fractures on conventional radiographs. Although preoperative chemoradiotherapy has been widely accepted for improving local control and survival in patients with primary rectal carcinoma, surgeons need to be aware of this rare complication that can arise even 10 months after preoperative chemoradiotherapy.
International Journal of Clinical Oncology 11/2003; 8(5):336-9. · 1.41 Impact Factor
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ABSTRACT: A 51-year-old man underwent right hemicolectomy due to ascending colon cancer with multiple liver metastases. Administration of modified pharmacokinetic modulating chemotherapy (PMC) using Leucovorin (intravenous infusion of 5-FU, 600 mg/m2/24 hours; oral administration of UFT, Taiho Pharmaceutical Co., Tokyo, Japan, 400 mg/day; and Isovorin, Wyeth Lederle Co., Tokyo Japan, 250 mg/body) was started postoperatively. Two months of modified PMC produced a drastic tumor reduction without any adverse reactions such as diarrhea or myelosuppression observed. At present the patient continues to tolerate the chemotherapy and is being followed as an outpatient clinic. This case suggests the usefulness of modified PMC using Leucovorin for progressive recurrent colon cancer.
Gan to kagaku ryoho. Cancer & chemotherapy 12/2002; 29(11):2009-12.
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ABSTRACT: We administered pharmacokinetic modulating chemotherapy (PMC, oral tegafur/uracil [UFT] plus fluorouracil infusion) together with irinotecan hydrochloride (CPT-11) in a patient with rectal cancer, who had multiple lung metastases at 2 years and 7 months after surgery. However, because the patient showed resistance, we attempted combination therapy with CPT-11 and doxifluridine (5'-DFUR) on an outpatient basis, which resulted in NC after 9 months. During this period, the therapy was performed safely without any observable adverse reactions such as diarrhea or myelosuppression. This case suggests the efficacy of combination therapy with CPT-11 and 5'-DFUR, which was expected since this is an established treatment for progressive recurrent colon cancer.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2002; 29(10):1845-8.
