Hypoxia-induced changes in the expression of VEGF,HIF-1 alpha and cell cycle-related molecules in ovarian cancer cells

BACKGROUND: Hypoxia is important in cancer progression, and at the stage of detachment of the cancer cells from the primary lesion. This study was undertaken to analyze the effect of hypoxia on angiogenesis and cell proliferation in ovarian cancer. MATERIALS AND METHODS: We first used immunohistochemistry to examine the expression of VEGF in 42 cases of ovarian carcinoma, with relevance to the p53 expression. Then, the expression of VEGF, HIF-1 alpha, cell cycle-related molecules and cell numbers were examined in 4 ovarian cancer cell lines with various p53 gene status. RESULTS: Immunohistochemistry showed that there was no significant correlation between VEGF and p53 expression. Moreover, hypoxia increased the expression of VEGF via up-regulation of HIF-1 alpha irrespective of p53 gene status. However hypoxia did not change the cell numbers, but influenced the expression of cell cycle-related molecules (increased p27 and decreased cyclin D1 and Rb). CONCLUSION: Hypoxia increased VEGF expression in ovarian cancer cells irrespective of p53 gene status.     

Significance of plasminogen-activation system in the formation of macroscopic types and invasion in esophageal carcinoma

BACKGROUND: The roles of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the formation of macroscopic types and invasion were investigated. MATERIALS AND METHODS: A total of 40 surgically-resected esophageal carcinoma tissues were immunohistochemically stained, and the expression of uPA, PAI-1 and the uPA/PAI-1 ratio, were evaluated. RESULTS: The expression of uPA was significantly stronger in the macroscopically infiltrative type (n = 20: p = 0.0027), whereas PAI-1 was significantly stronger in the localized type (n = 20: p = 0.0005). The uPA/PAI-1 ratio was significantly higher in the infiltrative type (p < 0.0001). A significant correlation was found between the U/P ratio and the depth of tumor invasion (r = 0.511, p = 0.0014). Analysis of tumors of uniform size (4.0-6.0 cm in length), showed that the depth of invasion was significantly greater in the infiltrative type (p = 0.0038). CONCLUSION: The results demonstrated that uPA and PAI-1 play important roles in invasion and formation of macroscopic types of esophageal carcinoma.     

Two novel tumor suppressor gene loci on chromosome 6q and 15q in human osteosarcoma identified through comparative study of allelic imbalances in mouse and man

We have performed a comparative study of allelic imbalances in human and murine osteosarcomas to identify genetic changes critical for osteosarcomagenesis. Two adjacent but discrete loci on mouse chromosome 9 were found to show high levels of allelic imbalance in radiation-induced osteosarcomas arising in (BALB/cxCBA/CA) F1 hybrid mice. The syntenic human chromosomal regions were investigated in 42 sporadic human osteosarcomas. For the distal locus (OSS1) on mouse chromosome 9 the syntenic human locus was identified on chromosome 6q14 and showed allelic imbalance in 77% of the cases. Comparison between the human and mouse syntenic regions narrowed the locus down to a 4 Mbp fragment flanked by the marker genes ME1 and SCL35A1. For the proximal locus (OSS2) on mouse chromosome 9, a candidate human locus was mapped to chromosome 15q21 in a region showing allelic imbalance in 58% of human osteosarcomas. We have used a combination of synteny and microsatellite mapping to identify two potential osteosarcoma suppressor gene loci. This strategy represents a powerful tool for the identification of new genes important for the formation of human tumors.     

A nested case-control study of risk factors for adult T-cell leukemia/lymphoma among human T-cell lymphotropic virus type-I carriers in Japan

Objectives: The purpose of this study was to investigate the serological risk factors for development of adult T-cell leukemia/lymphoma (ATL) among human T-cell lymphotropic virus type-I (HTLV-I) carriers. Methods: A nested case–control study was performed. The source population comprised 23,922 subjects who had either visited the outpatient clinic or who had received annual health check-ups at the K Hospital, Nagasaki, Japan, at least once during 1985–1996 (HTLV-I seroprevalence = 16.1%). Markers of HTLV-I infection were examined in stored sera from 29 incident cases of ATL diagnosed during 1985–1997, and 158 controls matched for sex, birth year, date of sample collection, and HTLV-I seropositivity (median follow-up = 6.4 years). Results: In exact conditional logistic regression analysis, high levels of soluble interleukin-2 receptor ( 500 U/ml) and high HTLV-I antibody titers ( 1024) were independently associated with an increased risk of developing ATL (Odds ratio 20.5, 95% confidence interval (CI) 4.5–194 and 2.9, 95% CI 0.98–9.5, respectively). The results remained essentially unchanged when the subjects were restricted to those whose histories were followed for two years or longer. Conclusions: These findings indicate that high soluble interleukin-2 receptor levels and high HTLV-I antibody titers are strong predictors of ATL among carriers of HTLV-I.     

Apoptosis and apoptosis-associated gene products related to the response to neoadjuvant chemotherapy for gastric cancer

To evaluate the effect of neoadjuvant chemotherapy on gastric cancer, we examined the correlation between induction of apoptosis and expression of p53, Bcl-2, and Bax. Eighty-five patients with advanced gastric cancer were retrospectively divided into the following two groups: 54 patients received 5-fluorouracil (5-FU) at 300 mg/body/day for 14 days and cisplatin (CDDP) at 15 mg/body/day for 2 days as group A; 31 patients without any preoperative chemotherapy as group B. According to histological changes in tumors due to neoadjuvant chemotherapy, the therapeutic effects on tumors were evaluated. The apoptotic index (AI) of group A was significantly higher than that of group B (1.12+/-0.40 vs. 0.67+/-0.24; p<0.01). In group A, the AI of p53-positive cases was significantly lower than that of negative cases (0.92+/-0.32 vs. 1.39+/-0.32; p<0.01). The AI of histological responders was significantly higher than that of non-responders (1.34+/-0.35 vs. 1.02+/-0.38; p<0.01). There was no significant correlation between AI and expression of Bcl-2 or Bax. In group A, histological responders, Bcl-2 positive, and high AI patients had better prognosis, respectively. In conclusion, neoadjuvant chemotherapy for gastric cancer enhanced induction of apoptosis, and AI might be useful to evaluate the effect of neoadjuvant chemotherapy.     

Postoperative adjuvant chemotherapy is effective in gastric cancer with serosal invasion: significance in patients chosen for multivariate analysis

There are few reports on overall usefulness of adjuvant chemotherapy in gastric cancer patients. We tried to clarify, using multivariate analysis, usefulness of postoperative adjuvant oral chemotherapy in advanced gastric cancer patients after curative resection. Four hundred and eighty-two gastric cancer patients enrolled in a randomized controlled trial were classified into 2 groups based on postoperative chemotherapeutic regimen: oral doxifluridine (5'-DFUR, an intermediate metabolite of capecitabine) (n=245) or oral 5-fluorouracil (5-FU) (n=237). The significant prognostic factors in patients with serosal invasion were chemotherapeutics (5'-DFUR vs. 5-FU) (risk ratio 1.649; 95% CI, 1.112-2.437), lymph node metastasis (no vs. yes) (2.823; 1.422-5.604), and tumor differentiation (differentiated vs. undifferentiated) (1.727; 1.068-2.791). Significant factors influencing peritoneal recurrence time were chemotherapeutics (1.756; 1.063-2.902), serosal invasion (no vs. yes) (2.237; 1.264-3.961), lymph node metastasis (2.541; 1.267-5.095), tumor differentiation (2.656; 1.374-5.136), and tumor location (others vs. total) (3.595; 2.006-6.443). There were no differences in the overall survival between chemotherapy. However, 5'-DFUR produced a better survival time of patients with serosal invasion than 5-FU, that might be attributed to the prevention of peritoneal recurrence in this subset.     

Experience of intravenous digital subtraction angiography (IV-DSA) in evaluation of neoadjuvant chemotherapy for advanced breast cancer

 Intravenous digital subtraction angiography (IV-DSA) was performed before and after neoadjuvant chemotherapy (NACT) in five patients with locally advanced breast cancer, and the efficacy of NACT was evaluated on the basis of the results of IV-DSA and histopathological examination. Following NACT, the maximum density of tumor enhancement (MAX) in the IV-DSA image decreased by 61.6% in case 1, 50% in case 2, 58.1% in case 3, 90.8% in case 4, and 97.2% in case 5. In all five patients, the efficacy of chemotherapy was rated as a partial response in terms of tumor size, while histological efficacy was rated as slightly effective in cases 1–4 and moderately effective in case 5. The pathological efficacy of NACT was highest in case 5, which showed the greatest decrease in MAX. These results indicate that variations in MAX reflect clinical efficacy, and, to some extent, also permit prediction of pathological efficacy. Received: March 4, 2002 / Accepted: June 10, 2002 Correspondence to:O. Watanabe     

Nakirodin A,a bromotyrosine alkaloid from a Verongid sponge

A new bromotyrosine alkaloid, nakirodin A (1), has been isolated from an Okinawan marine Verongid sponge. The structure was elucidated on the basis of spectroscopic data.     

Usefulness of analytical CEA doubling time and half-life time for overlooked synchronous metastases in colorectal carcinoma

BACKGROUND: Measurement of carcinoembryonic antigen (CEA) has been widely applied to detect recurrence, especially of colorectal carcinoma. The validity however, is still controversial. We investigated serial changes in CEA values to calculate whether the CEA doubling time and half-life time could predict metastatic progression or prognosis in colorectal carcinoma. METHODS: Pre- and post-operative serial serum CEA contents were determined in 22 cases of colorectal cancer with or without metastasis. CEA values were determined by enzyme immunoassay (EIA). Patients were assigned depending upon survival time (within vs. more than 18 months after primary resection) for assessment of CEA doubling time. From the gradient of the semi-logarithmic CEA graph, the preoperative doubling time was calculated and the postoperative half-life time was estimated according to the diagnosis of metastases within 2 years after primary resection [metastasis (+) or (-)]. RESULTS: In spite of the effect of curative re-operation of metastatic lesions or of postoperative adjuvant chemotherapy, the CEA doubling time of the groups showed a relation with prognosis (p = 0.045, Student's t-test) when the patients were divided into >18 and < or =18 months survival time. The CEA half-life time of the groups without overlooked metastases was statistically longer than those with (mean +/- SD 8.01 +/- 2.07 and 4.33 +/- 1.11, respectively, p < 0.01, one-factor ANOVA test). Clearance (k) showed a significant difference between the groups (p < 0.001, Student's t-test). CONCLUSION: The CEA doubling time appeared to be a less independent prognostic factor, whereas prolongation of the CEA half-life time might potentially suggest the existence of overlooked synchronous metastases from colorectal carcinoma.     

Adjuvant chemotherapy after curative resection for gastric cancer-5'-DFUR + cisplatin vs 5'-DFUR

A prospective randomized study involving gastric cancer patients was conducted to evaluate combined adjuvant chemotherapy. Forty-two patients under 80 years of age who underwent a curative resection of pathologic stage II or III gastric cancer were randomly assigned to receive adjuvant chemotherapy containing the following two regimens from 1993 to 1996. A) Oral 5'-deoxy-5-fluorouridin (5'-DFUR) plus cisplatin: 5'-DFUR, daily administration, combined with CDDP 15 mg/m2/day, 30-min drip infusion, fortnightly for 8 weeks, repeated every 16 weeks. B) Oral 5'-DFUR alone: 5'-DFUR, daily administration. The dosages of 5'-DFUR were assigned according to the patients' body surface area (BSA): BSA < 1.7 m2, 600 mg and BSA > or = 1.7 m2, 800 mg, daily administration, bid. Twenty patients were assigned to regimen A, and 22 to regimen B. All clinicopathological factors were equally distributed in each regimen. No adverse reactions greater than grade 3 occurred in either regimen. There was no significant difference between the two regimens in overall survival or overall disease-free survival. For patients with positive nodes, the 5-year disease-free survival rates were 56.4% in A and 38.3% in B (p = 0.29). In stage III patients, the 5-year disease-free survival rates were 55.6% in A and 20.7% in B (p = 0.26). No significant survival benefit was observed with the combined chemotherapeutic regimen, 5'-DFUR plus cisplatin, compared with 5'-DFUR alone.