No abstract

Acyclic retinoid (ACR), a novel synthetic retinoid, has been demonstrated by us to inhibit the in vitro growth of human hepatoma cells, and this effect was associated with modification of cell cycle control molecules, suggesting that this agent may be useful in the chemoprevention and therapy of various types of malignancies. However, whether or not ACR exerts anticancer activities on human colon carcinoma cells has not yet been elucidated. The purpose of this study was to examine the inhibitory effects of ACR in human colon carcinoma cells and to characterize the molecular mechanism of action of this agent. ACR inhibited the growth of the HCT116 and SW480 human colon carcinoma cell lines with IC 50 values of about 30 and 60 μM, respectively. ACR also induced G1-phase cell cycle arrest and apoptosis in these cell lines. When the HCT116 cells were treated with 5-25 μM ACR, there was a marked decrease in the cellular levels of cyclin D1 mRNA and an approximate 2.5-to 3-fold increase in those of p21 CIP1 mRNA, and this induction occurred via a p53-independent mechanism. Furthermore, ACR induced a dose-dependent mRNA elevation of differentiation markers at concentrations of ACR that affect the levels of expression of p21 CIP1 . These novel results suggest that ACR inhibits cell proliferation by inducing G1 arrest and apoptosis and that cyclin D1 and p21 CIP1 play critical roles in the molecular mechanisms of growth inhibition and differentiation induced by ACR. Collectively, these findings provide further evidence that ACR may be a potential agent for the chemoprevention and therapy of human colon cancer.

Abstract. This study aimed to investigate whether glucose transporter-1 (GLUT-1) expression in a pretreatment esophageal cancer biopsy was predictive of clinical outcomes in patients with esophageal cancer undergoing concurrent chemoradiotherapy (CRT). A total of 25 patients with esophageal cancer treated with concurrent CRT were reviewed. Radiotherapy was administered up to total doses of 40-66.6 Gy (median 66.6 Gy) with a single fraction of 1.8-2 Gy. Regarding chemotherapy, cisplatin (80 mg/m 2 on day 1) and 5-fluorouracil (800 mg/m 2 on days 2-6) were used concurrently with radiotherapy, every 3-4 weeks for a total of 1-2 courses. Tissue samples from esophageal carcinoma were obtained from the 25 patients by biopsy prior to concurrent CRT, and a semiquantitative analysis of GLUT-1 expression was performed using immunohistochemical staining. High GLUT-1 expression was observed in 7 of 25 (28%) patients, and GLUT-1 expression was significantly correlated with clinical T stage (p=0.0454), clinical N stage (p=0.0324) and initial response to CRT (p=0.0185). Patients with a high GLUT-1 expression had significantly poorer local control (LC) (5-year LC 28.6%) than those with a low expression (5-year LC 73.4%, p<005). Multivariate analysis revealed that GLUT-1 and the number of chemotherapy courses were independent prognostic factors for LC. Patients with a high GLUT-1 expression had significantly lower recurrence-free survival (RFS) compared to those with a low GLUT-1 expression (p=0.0405). Multivariate analysis revealed that GLUT-1, the number of chemotherapy courses and clinical M stage were independent prognostic factors for RFS. GLUT-1 expression was significantly correlated with clinical T stage, clinical N stage and initial response to concurrent CRT, and was predictive of LC and RFS for patients with esophageal cancer treated with concurrent CRT.

Abstract. The aim of the present study was to examine whether crude glycosphingolipid (cGSL) has short-term chemopreventive effects on the preneoplastic biomarker lesions involved in carcinogen-induced rat colon carcinogenesis. We also examined whether cGSL affects cell proliferation and apoptosis in these lesions. The crude preparation was obtained by the simple ethanol extraction method. Five-week-old male F344 rats were divided into 6 groups. Rats in groups 1-4 were given subcutaneous injections of azoxymethane (AOM) (20 mg/kg body weight) once a week for 2 weeks. Starting 1 week before the first injection of AOM, the rats in groups 2, 3 and 4 were fed a diet containing 250, 1,000 and 3,000 ppm cGSL, respectively, for 5 weeks. The experiment was terminated 5 weeks after the start date, and the number of aberrant crypt foci (ACF) and mucin-depleted foci (MDF) was counted. Dietary cGSL significantly inhibited the induction of ACF (group 3, P<0.01; group 4, P<0.05) and MDF (groups 2 and 3, P<0.001; group 4, P<0.05) as compared to group 1 treated with AOM alone. In groups 3 and 4, proliferating cell nuclear antigen-positive indices of epithelial cells were significantly lower than in group 1 (group 3, P<0.05; group 4, P<0.005). Caspase-3-positive indices were significantly higher in groups 3 and 4 than in group 1 (group 3, P<0.01; group 4, P<0.001). These results suggest that dietary cGSL had a potent chemopreventive effect in the present short-term colon carcinogenesis bioassays, and that this effect may be associated with the inhibition of ACF and MDF and the induction of apoptosis.

To assess the clinical significance of 201Tl-SPECT after postoperative radiotherapy in patients with glioblastoma multiforme (GM). Eighteen patients with macroscopically residual GM who underwent 201Tl-SPECT just after postoperative radiotherapy were analyzed. Fifteen patients (83%) received radiotherapy with a total dose of 60 Gy in conventional fractionation, and the remaining three patients were treated with 72 Gy with hyperfractionation schedules. Sixteen patients (89%) were treated with chemotherapy that consisted of procarbazine, nimustine (ACNU) and vincristine. Concerning 201Tl-SPECT, we calculated the radioactivity ratio of the tumors to contralateral normal brain (T/N ratio) on early and delayed images after 111 MBq 201Tl chloride injections. The median follow-up of all 18 patients was 14.7 months (range, 2.7-38.0 months). At the time of this analysis, 15 patients (83%) had died, and the 1-year overall survival and the median survival time were 67% and 16.2 months, respectively. Fifteen patients (83%) had disease recurrence, and the 1-year progression-free survival (PFS) rate and the median time to progression in all 18 patients were 29% and 7.6 months, respectively. Patients with a high early T/N ratio had a significantly poorer PFS than those with a low T/N ratio (P = 0.0131). On univariate analysis, early T/N ratio alone had a significant impact on PFS, and on mutivariate analysis, early T/N ratio alone was a significant prognostic factor for PFS. 201Tl-SPECT after postoperative radiotherapy was predictive of PFS in patients with macroscopically residual GM.