Biomedical subjects

C Y Hsieh

Publications and source records attributed to C Y Hsieh.

At least 19 recordsLinked to original sources

PubMed2000

Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis.

Curcumin has been widely used as a spice and coloring agent in foods. Recently, curcumin was found to possess chemopreventive effects against skin cancer, forestomach cancer, colon cancer and oral cancer in mice. Clinical trials of curcumin for prevention of human cancers are currently ongoing. In this study, we examine the chemopreventive effect of curcumin on murine hepatocarcinogenesis. C3H/HeN mice were injected i.p. with N-diethylnitrosamine (DEN) at the age of 5 weeks. The curcumin group started eating 0.2% curcumin-containing diet 4 days before DEN injection until death. The mice were then serially killed at the scheduled times to examine the development of hepatocellular carcinoma (HCC) and changes in intermediate biological markers. At the age of 42 weeks, the curcumin group, as compared with the control group (DEN alone), had an 81% reduction in multiplicity (0.5 versus 2.57) and a 62% reduction in incidence (38 versus 100%) of development of HCC. A series of intermediate biological markers were examined by western blot. While hepatic tissues obtained from the DEN-treated mice showed a remarkable increase in the levels of p21(ras), PCNA and CDC2 proteins, eating a curcumin-containing diet reversed the levels to normal values. These results indicate that curcumin effectively inhibits DEN-induced hepatocarcinogenesis in the mouse. The underlying mechanisms of the phenomenon and the feasibility of using curcumin in the chemoprevention of human HCC should be further explored.

Animals↗

PubMed1999

Vascularity index as a novel parameter for the in vivo assessment of angiogenesis in patients with cervical carcinoma.

BACKGROUND: The importance of angiogenesis now is well recognized. Conventionally, tumor angiogenesis is assessed by determination of microvessel density (MVD) in the surgical specimen. This study examines tumor angiogenesis using power Doppler ultrasound and a quantitative image processing system. The authors hope to develop an in vivo and noninvasive method for quantitating tumor angiogenesis. METHODS: Thirty-five patients with FIGO Stage IB-IIA cervical carcinoma exhibiting visible cervical tumors by transvaginal ultrasound were included in this study. All patients underwent radical abdominal hysterectomy and pelvic lymph node dissection. Transvaginal power Doppler ultrasound was performed before surgery to search for blood flow signals from the tumor. The intratumoral vascularity index (VI) and resistance index (RI) were calculated. The VI was defined as the number of colored pixels divided by the number of total pixels in the defined tumor section. Maximal VI and minimal RI of a certain tumor were used for analysis. Clinical and pathologic data also were recorded. The MVD of the excised tumor was assessed immunohistochemically using a monoclonal antibody against CD34. RESULTS: Significantly higher VI values were noted in Stage II tumors compared with Stage 1 tumors (19.01+/-10.90% vs. 9.09+/-6.59%; P = 0.008), tumors invad-ing+/-50% of the cervical stroma compared with tumors invading < 50% of the cervical stroma (13.20+/-8.20% vs. 5.72+/-5.00%; P = 0.003), tumors with lymphovascular emboli compared with tumors without lymphovascular emboli (17.28+/-8.26% vs. 6.98 +/- 5.09%; P = 0.001), and tumors with pelvic lymph node metastases compared with tumors without pelvic lymph node metastases (26.16+/-7.88% vs. 8.00+/-4.95%; P = 0.021). None of the variables mentioned earlier showed a significant difference in terms of the RI values. No correlation was noted between intratumoral RI and VI in respective tumors (P = 0.53). Analysis of VI revealed linear regression with regard to tumor size (P < 0.001, correlation coefficient [r] = 0.586) and depth of stromal invasion (P = 0.002, r = 0.497). In addition, the MVD exhibited a linear relation with VI (P = 0.006, r = 0.454), tumor size (P = 0.005, r = 0.465), and depth of stromal invasion (P = 0.009, r = 0.436) using simple regression analysis. No correlation could be found between MVD and RI. CONCLUSIONS: In cervical carcinoma, intratumoral VI assessment by power Doppler ultrasound and quantitative image processing system showed better correlation with tumor stage, tumor size, and pathologic findings including depth of stromal invasion, lymphovascular emboli, and pelvic lymph node metastases than intratumoral RI. The in vivo indicator of angiogenic activity (VI) is well correlated with the conventional indicator of tumor angiogenic activity (MVD). Thus, VI could be a useful parameter for the in vivo assessment of global tumor angiogenesis.

Adenocarcinoma↗

PubMed1999

Pregnancy with primary tubal placental site trophoblastic tumor--A case report and literature review.

Placental site trophoblastic tumor (PSTT) is a rare trophoblastic neoplasm with malignant potential. The diagnosis and prognosis of this rare disease remain difficult. A case of tubal PSTT with the primary manifestation of internal bleeding at 30 weeks' gestation is presented. Emergency exploratory laparotomy and right partial salpingectomy were performed initially. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy were done immediately after cesarean section at 34 weeks' gestation. No further adjuvant therapy was given after surgery. No evidence of tumor recurrence or signs of metastasis were noted during 12 months of follow-up. Heterotopic pregnancy, one with intrauterine normal pregnancy and the other with implanting in the right fallopian tube and placental site trophoblastic tumor transformation, was proposed. To our knowledge, this is the first such case in the English literature.

Adult↗

PubMed1999

Influence of histologic type and age on survival rates for invasive cervical carcinoma in Taiwan.

OBJECTIVE: The aim of this study was to assess survival rates and to evaluate histologic type and age as prognostic factors for cervical carcinoma in an ethnically homogenous population in Taiwan. METHODS: A retrospective analysis was conducted of 3678 cases of squamous cell carcinoma and adenocarcinoma that were diagnosed and treated for invasive cervical carcinoma between 1977 and 1994. Observed survival rates were estimated using the Kaplan-Meier method, and prognostic factors were assessed using Cox's proportional hazards regression analysis. RESULTS: Correlating both FIGO stage and age with histologic type revealed a higher proportion of cases with adenocarcinoma in the lower FIGO stages (P = 0.0417). Further, we found that the younger the age group the higher the proportion of cases of cervical adenocarcinoma (P = 0.0006). The 5-year survival rate was lower for patients with adenocarcinoma than for patients with squamous cell carcinoma (66.5 vs 74.0%, P = 0.0009). The 5-year survival rates for FIGO stages I, II, III, and IV squamous cell carcinoma were 81.3, 75.2, 42.7, and 26.1%, respectively, while for adenocarcinoma they were 75.9, 62.9, 29.2, and 0%, respectively. The difference in survival rates between squamous cell carcinoma and adenocarcinoma was found mainly in stage I (P = 0.0039) and stage II (P = 0.0103), where radiotherapy was used as the primary treatment. Age also affected the overall Kaplan-Meier estimate of survival. The younger the age group, the better the survival rate (P < 0.0001). Multivariate analysis confirmed a highly significant association between survival rate and both histologic type (P < 0.0001) and age (P = 0.0037). CONCLUSIONS: Early stage cervical cancer (stages I and II) with a glandular component had a lower 5-year survival rate than squamous cell carcinoma in cases where radiotherapy was the primary treatment. We speculate that this difference in survival rates between cervical adenocarcinoma and squamous cell carcinoma was due to the relative ineffectiveness of radiotherapy as a primary treatment in cases of adenocarcinoma.

Adenocarcinoma↗

PubMed1999

Serum vascular endothelial growth factor in epithelial ovarian neoplasms: correlation with patient survival.

OBJECTIVE: To investigate the relationship between serum vascular endothelial growth factor (VEGF) and clinicopathological factors and to determine whether VEGF is an independent prognostic factor of ovarian cancer patients. METHODS: Fifty-six women with International Federation of Gynecology and Obstetrics stages I to IV epithelial ovarian cancer undergoing surgery were enrolled. Clinical and pathologic items were recorded. Pretreatment VEGF serum samples of the 56 women were measured by an enzyme-linked immunosorbent assay. The results were correlated to clinical data. The histopathologic items and serum VEGF influencing clinical outcome were evaluated comparatively. RESULTS: The median VEGF serum level in ovarian cancer patients was 458.7 pg/mL. The 75% quatile was defined as the cutoff level. Elevated vascular endothelial growth factor serum levels before therapy correlated significantly with poorer disease-free survival (DFS) (log rank test, P = 0.001) and overall survival (OS) (log rank test, P < 0.001) on all of the 56 patients. Besides, significantly reduced DFS (log rank test, P = 0.001) and OR (log rank test, P = 0.006) were also observed on 40 patients with residual disease less than 2 cm. High histologic grade (RR = 2.24 for DFS; RR = 2.38 for OS) and elevated serum VEGF levels (RR = 3.34 for DFS; RR = 4.47 for OS) are the prognostic factors on the 56 ovarian carcinoma patients by multivariate analyses. The advanced surgical staging (RR = 3.28 for DFS; RR = 3.84 for OS), high histologic grade (RR = 2.55 for DFS; RR = 2.44 for OS), and elevated serum VEGF levels (RR = 5.62 for DFS; RR = 5.37 for OS) are the prognostic factors for 40 ovarian carcinoma patients with residual disease less than 2 cm by multivariate analyses. CONCLUSIONS: Pretreatment VEGF serum levels might be regarded as an additional factor in predicting the outcome of ovarian cancer patients. It also could provide prognostic information in clinically relevant subsets, such as those of residual disease less than 2 cm. Anti-angiogenic therapy, if is available, might be a new treatment modality for ovarian cancer patients with poor prognosis predicted by VEGF and other clinical parameters.

Adult↗

PubMed1999

Comparison of subcutaneous hydromorphone with intramuscular meperidine for immediate postoperative analgesia.

Intramuscular (i.m.) injection with meperidine is the most common analgesic approach to treat postoperative pain in Taiwan. Hydromorphone (Dilaudid) can provide very potent and rapid analgesic effect through subcutaneous (s.c.) injection. Although hydromorphone is widely used in North America, no study has compared the analgesic efficacy, side effect profiles and patients' satisfaction with the method of injection of hydromorphone s.c. and meperidine i.m. for the immediate post-operative analgesia. In this randomized and double-blind study, 60 female patients scheduled for abdominal total hysterectomy were treated either with 1 mg hydromorphone s.c. (n = 30) or 50 mg meperidine i.m. (n = 30) when they regained consciousness and asked for analgesic treatment in the recovery room. Visual analogue score (VAS) of wound pain was obtained at 0, 10 and 30 min after injection by a blinded observer. The occurrence and severity of nausea, vomiting, dizziness, drowsiness, flatus passage and respiratory depression were recorded. Post-operative analgesia in the ward was maintained by patient-controlled analgesia (PCA) with intravenous morphine. Time to first PCA demand, the number of demands, delivery, delivery/demand ratio and 24 h morphine consumption were documented. We found that VAS was reduced at 10 min and, to a greater extent, at 30 min postinjection in both groups but with no significant difference between the two groups. The occurrence and severity of side effect profiles were similar in both groups except that dizziness was more frequently observed after meperidine injection. Delivery, demand, delivery/demand ratio and 24 hr morphine consumption by PCA were not significantly different between the two groups. Time to first PCA trigger was also similar. Patients receiving hydromorphone s.c. injection exhibited higher satisfactory score than those receiving meperidine i.m. injection. Hydromorphone 1 mg, injected subcutaneously, was as effective as intramuscular meperidine 50 mg while permitting more favorable injection technique and fewer side effects. We suggest that subcutaneous hydromorphone is a good alternative to intramuscular meperidine for postoperative analgesia in the recovery room.

Adult↗

PubMed1998

Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo.

Genistein, found in soy products, is a phytochemical with several biological activities. In the current study, our research focused on the estrogenic and proliferation-inducing activity of genistein. We have demonstrated that genistein enhanced the proliferation of estrogen-dependent human breast cancer (MCF-7) cells in vitro at concentrations as low as 10 nM, with a concentration of 100 nM achieving proliferative effects similar to those of 1 nM estradiol. Expression of the estrogen-responsive gene pS2 was also induced in MCF-7 cells in response to treatment with a concentration of genistein as low as 1 microM. At higher concentrations (above 20 microM), genistein inhibits MCF-7 cell growth. In vivo, we have shown that dietary treatment with genistein (750 ppm) for 5 days enhanced mammary gland growth in 28-day-old ovariectomized athymic mice, indicating that genistein acts as an estrogen in normal mammary tissue. To evaluate whether the estrogenic effects observed in vitro with MCF-7 cells could be reproduced in vivo, MCF-7 cells were implanted s.c. in ovariectomized athymic mice, and the growth of the estrogen-dependent tumors was measured weekly. Negative control animals received the American Institute of Nutrition (AIN)-93G diet, the positive control group received a new s.c. estradiol (2 mg) pellet plus the AIN-93G diet, and the third group received genistein at 750 ppm in the AIN-93G diet. Tumors were larger in the genistein (750 ppm)-treated group than they were in the negative control group, demonstrating that dietary genistein was able to enhance the growth of MCF-7 cell tumors in vivo. Increased uterine weights were also observed in the genistein-treated groups. In summary, genistein can act as an estrogen agonist in vivo and in vitro, resulting in the proliferation of cultured human breast cancer cells (MCF-7) and the induction of pS2 gene expression. Here we present new information that dietary genistein stimulates mammary gland growth and enhances the growth of MCF-7 cell tumors in ovariectomized athymic mice.

Animals↗

PubMed1998

Clinical application of intratumoral blood flow study in patients with endometrial carcinoma.

BACKGROUND: The objective of this study was to evaluate the correlation between intratumoral blood flow as assessed by color Doppler ultrasound with stage, tumor grade, depth of invasion, and lymph node metastasis in endometrial carcinoma and determine its clinical usefulness. METHODS: Sixty-six patients with endometrial carcinoma were enrolled. All patients received surgical treatment. Transvaginal color Doppler ultrasound was performed before surgery to detect the arterial blood flow signals within the tumors and the lowest resistance index (RI) was recorded. Formalin fixed, paraffin embedded pathology slides were reviewed by a senior pathologist to evaluate the histologic grading, tumor size, depth of myometrial invasion, and presence of lymph node metastasis. RESULTS: Intratumoral RI correlated well with surgical staging, histologic grading, the depth of myometrial invasion, and the presence of lymph node metastasis. Significantly lower RI was noted in tumors of advanced stage (> than International Federation of Obstetrics and Gynecology [FIGO] Stage I) (0.38 +/- 0.09 vs. 0.54 +/- 0.11; P < 0.001), tumors with higher histologic grade (Grade 3) (0.36 +/- 0.08 vs. 0.53 +/- 0.11; P < 0.001), tumors with deep myometrial invasion (> 50% myometrial thickness) (0.38 +/- 0.07 vs. 0.54 +/- 0.11; P < 0.001), and tumors with lymph node metastasis (0.34 +/- 0.07 vs. 0.52 +/- 0.11; P < 0.001) compared with tumors with Stage I, Grade 1/2 histology, no or superficial myometrial invasion, and absence of lymph node metastasis, respectively. CONCLUSIONS: Intratumoral blood flow analysis assessed by color Doppler ultrasound correlates well with surgical stage, tumor grade, myometrial invasion, and lymph node metastasis in patients with endometrial carcinoma. Assessment of tumor angiogenesis using color Doppler ultrasound provides useful information for the preoperative prediction regarding stage, histologic grade, depth of myometrial invasion, and presence of lymph node metastasis in patients with endometrial carcinoma. The authors believe routine pelvic lymph node dissection should be performed for those patients whose lowest RI values of intratumoral blood flow are < or = 0.4 because those patients are at very high risk for pelvic lymph node involvement.

Adult↗

PubMed1998

Prognostic factors of primary adenocarcinoma of the uterine cervix.

OBJECTIVE: To determine which clinicopathological factors influence the prognosis of cervical adenocarcinoma. METHODS: Three hundred and two cases of primary adenocarcinoma of the uterine cervix, treated between 1977 and 1994, were studied retrospectively. Clinical data and pathological findings with respect to primary therapy were reviewed and evaluated. RESULTS: The 5-year survival rates for stages I, II, and III/IV were 75.9, 62.9, and 25.1%, respectively. International Federation of Gynecology and Obstetrics stage (P < 0. 0001), cell type (P = 0.0176), tumor grade (P = 0.023), lymph node status (P = 0.018), and bulky tumor (P = 0.007) were found to be independent factors using the stepwise Cox proportional hazards model. Old age (P = 0.0581), presence of hypertension (P = 0.46), diabetes mellitus (P = 0.18), obesity (P = 0.15), and oral contraceptive use (P = 0.42) were not found to adversely influence survival rates for cervical adenocarcinoma after adjusting for other covariates. Adenosquamous adenocarcinoma had a better prognosis than endocervical columnar cell adenocarcinoma in stages I and II (P = 0. 0235). Also, in cervical adenocarcinoma's early stages, multivariate modeling revealed that chances of survival were significantly better for patients treated by radical surgery than for patients treated by radiation therapy (P < 0.001). CONCLUSIONS: Survival rates for cervical adenocarcinoma were significantly influenced by stage, histologic subtype, tumor grade, the presence of a positive lymph node, and tumor size. Although a randomized prospective study is needed, our data imply that radical surgery may be considered a better primary modality of treatment than radiation therapy for the early stages of cervical adenocarcinoma. Further, the presence of hypertension, diabetes mellitus, or obesity may not adversely influence survival rates.

Adenocarcinoma↗

PubMed1998

Preoperative ultrasound study in predicting lymph node metastasis for endometrial cancer patients.

OBJECTIVE: The objective of this study was to evaluate the efficacy of preoperative ultrasound (US) findings such as tumor size, status of myometrial invasion, and intratumoral "resistance index" (RI) in predicting lymph node metastasis in endometrial carcinoma patients. METHODS: Forty-two patients with endometrial cancer were enrolled. All patients underwent total abdominal hysterectomy, pelvic lymph node dissection or sampling, and para-aortic lymph node sampling. Two-dimensional and color Doppler US were performed before surgery to measure tumor size, depth of myometrial invasion, and intratumoral arterial RI. Formalin-fixed, paraffin-embedded pathologic slides from surgical specimens were reviewed by a senior pathologist to evaluate histologic type and grade, depth of myometrial invasion, cervical involvement, lymph-vascular emboli, and status of lymph node metastasis. RESULTS: There were 12 patients with pelvic and/or para-aortic lymph node metastases and 30 patients without nodal metastases. Patients with tumors larger than 2.5 cm by US (11/12 vs 14/30, P = 0.008), more than half myometrial invasion by US (9/12 vs 5/30, P < 0.001), and intratumoral RI values less than 0.4 by US (12/12 vs 4/30, P < 0.001) had a significantly higher incidence of nodal metastases as compared with patients with tumors smaller than 2.5 cm, no or superficial myometrial invasion, and RI values higher than 0.4, respectively. Multiple regression analysis showed that only intratumoral RI values less than 0.4 were significantly correlated with nodal metastasis (P < 0.001, r2 = 0. 650). We used the intratumoral RI value as the parameter to evaluate nodal metastasis in endometrial cancer patients. Twelve of sixteen patients with intratumoral RI values <0.4 had a high incidence of nodal metastases. None of the 26 patients with intratumoral RI values >0.4 had nodal metastases. CONCLUSIONS: Preoperative ultrasound features can offer important information for predicting lymph node metastasis in endometrial cancer patients. Patients with tumors with intratumoral RI values less than 0.4 should be highly suspected of having lymph node metastases and further management such as pelvic lymph node dissection or postoperative pelvic radiotherapy would be needed for these patients.

Adult↗

PubMed1998

Megestrol acetate antagonizes cisplatin cytotoxicity.

Megestrol acetate (MGA) is being widely used for the improvement of appetite and performance status in patients receiving chemotherapy, especially cisplatin-containing therapy. However, little is known about whether MGA has an effect on cisplatin cytotoxicity. We have investigated this using two transitional carcinoma cell lines, i.e. the cisplatin-sensitive parental line NTUB1 and the resistant daughter line NTUB1/P. Combined effects of MGA and cisplatin were assayed with a microculture chemosensitivity method. We explored the level changes of several cisplatin detoxification mechanisms, including metallothionein (MT), glutathione S-transferase-pi (GST-pi) and glutathione (GSH) levels in cells treated with or without MGA. After treatment with 10 microns MGA for 24 h, the cisplatin IC50s of NTUB1 and NTUB1/P increased 1.4- (p = 0.03) and 1.6- (p = 0.02) fold, respectively. By median effect analysis, the combinations of MGA and cisplatin in the two cells appeared to produce an antagonistic interaction. By Northern analysis, MT transcript levels in both cells were significantly upregulated after treatment with MGA, as compared to those without treatment. Exposure to MGA in either sensitive or resistant cells did not alter GST-pi levels as shown by immunoblotting analysis. Cellular GSH content was increased only in NTUB1/P (p = 0.0036) but remained unchanged in NTUB1 cells (p = 0.29) after MGA exposure. In conclusion, MGA may antagonize cisplatin cytotoxicity by upregulating cellular MT and GSH levels. Use of MGA in cisplatin-containing chemotherapy may impair tumor response by antagonizing cisplatin antitumor activity.

Antineoplastic Agents↗

PubMed1997

Stability of curcumin in buffer solutions and characterization of its degradation products.

The degradation kinetics of curcumin under various pH conditions and the stability of curcumin in physiological matrices were investigated. When curcumin was incubated in 0.1 M phosphate buffer and serum-free medium, pH 7.2 at 37 degrees C, about 90% decomposed within 30 min. A series of pH conditions ranging from 3 to 10 were tested and the result showed that decomposition was pH-dependent and occurred faster at neutral-basic conditions. It is more stable in cell culture medium containing 10% fetal calf serum and in human blood; less than 20% of curcumin decomposed within 1 h, and after incubation for 8 h, about 50% of curcumin is still remained. Trans-6-(4'-hydroxy-3'-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted as major degradation product and vanillin, ferulic acid, feruloyl methane were identified as minor degradation products. The amount of vanillin increased with incubation time.

Antioxidants↗

PubMed1996

The expression of the human chorionic gonadotropin beta subunit gene depends on negative control.

Transcription of the human chorionic gonadotropin (hCG) genes begins in the very early embryo stage and decreases or even disappears in nonplacental tissues. We have studied the regulation of hCG-beta genes by cell fusion and by the reverse transcription-polymerase chain reaction (RT-PCR). The choriocarcinoma cell lines, JAR and JEG-3, express high levels of the hCG-beta subunit while HeLa cells express extremely low levels of it. Most HeLa x JAR and HeLa x JEG-3 fusion clones expressed only a trace of the hCG-beta subunit mRNA, while JAR x JEG-3 fusion clones still expressed high levels of the hCG-beta subunit. Most transcripts of the hCG-beta subunit genes in JAR and JEG-3 came from the hCG-beta 5 subunit. Even the trace amount of hCG-beta transcripts from fusion clones came mainly from the beta-5 gene. The results suggest that the expression of the hCG-beta subunit genes depends on negative control. Probably when embryonic cells differentiate to form nonplacental tissues, specific inhibitors may appear and inhibit the expression of the hCG-beta subunit genes.

Cell Fusion↗

PubMed1996

Factors influencing tumor cell kinetics in cervical cancer.

Fresh tumor tissues instead of paraffin-embedded sections were used to study the clinical significance of the tumor cell kinetics in cervical carcinomas by flow cytometry. We analyzed specimens from 153 women with cervical cancer, and DNA aneuploidy was found in 61 cases (39.9%). The mean age of patients with aneuploid tumors was significantly higher than the age of patients with diploid tumors (P < 0.001). The mean proliferation index for aneuploid tumors was significantly higher than those for diploid tumors. There was a significant correlation between the proliferation index and age. However, tumor cell kinetics is not related to the status of human papillomavirus, herpes simplex virsuses I and II, lymph nodes, histology or tumor size. The mean age and S-phase fraction for stage-II tumors were significantly higher than those for stage-I tumors (P < 0.01). The tumors of menopausal patients exhibited a relatively higher rate of lymph node metastasis, and significantly higher aneuploidy rate and proliferation index than tumors of premenopausal patients. In summary, age and, what is more important, menopausal status may significantly influence DNA ploidy and cell kinetics of tumors, and subsequently influence clinical stage and lymph node metastasis. However, tumor cell kinetics is of limited value in the prediction of lymph node metastasis and prognosis.

Adult↗

PubMed1996

Combined cytotoxic effects of tamoxifen and chemotherapeutic agents on bladder cancer cells: a potential use in intravesical chemotherapy.

OBJECTIVE: To evaluate whether tamoxifen enhances the cytotoxicity of chemotherapeutic agents on bladder cancer cells, and the possible mechanism(s) of action. MATERIALS AND METHODS: The in vitro inhibition of cell growth was examined in a model simulating intravesical chemotherapy using two bladder cancer cell lines (TSGH-8301, HTB9) and three commonly used intravesical cytotoxic agents (doxorubicin, mitomycin C, and thiotepa) in the presence or absence of tamoxifen or verapamil as modulators. The expression of the multi-drug resistance-related gene mdr-1 was evaluated by reverse-transcription polymerase chain reaction and Southern blotting (RT-PCR-SB) to determine its transcript level, by flow cytometric analysis of the P-glycoprotein (P-gp) product level with C-219 monoclonal antibody and by the rhodamine-123 retention and efflux assay for P-gp activity. Transforming growth factor beta-1 (TGF beta-1) levels in tamoxifen-conditioned culture medium were determined with enzyme-linked immunosorbant assay (ELISA). RESULTS: Tamoxifen at concentrations > or = 30 microM significantly enhanced the cytotoxicity of the three chemotherapeutic agents to both cell lines, as shown by a marked reduction in the drug concentration which inhibited growth by 50% (IC50). The enhancement of cytotoxicity was significantly dependent on the concentration of tamoxifen. However, tamoxifen alone caused significant toxic effects to TSGH-8301 at > or = 40 microM and to HTB9 at > or = 30 microM. Median-effect analysis showed additive or less-than-additive combination effects between tamoxifen and chemotherapeutic agents and only a minimal synergism in a narrow range of maximal cytotoxicity (fraction affected > 0.9). Thus, the reduction of IC50s by tamoxifen was mostly because it was cytotoxic to the bladder cancer cells used. No enhancement of cytotoxicity was observed in verapamil-modulated cells. Transcripts of mdr-1 could not be detected by RT-PCR-SB, nor was P-gp detected by flow cytometric analysis in the two cell lines. Furthermore, no active P-gp function was detected by the rhodamine-123 retention and efflux study, indicating that the primary chemoresistance mechanisms of the two cell lines were not mediated by mdr-1, nor could tamoxifen or verapamil act through modulation of the mdr-1 pathway in the two cell lines. Tamoxifen at 3 and 10 microM down-regulated the secretion of TGF beta-1 from TSGH-8301 in a concentration-dependent manner, in contrast to the findings that tamoxifen was cytotoxic to the bladder cancer cells used and that tamoxifen up-regulated TGF beta-1 in a breast cancer model, suggesting that there may be a different mechanism of response to TGF beta-1 in these bladder cancer cells. CONCLUSION: Tamoxifen enhanced the cytotoxicity of chemotherapeutic agents largely through its toxic effects on the bladder cancer cells. The mode of action of tamoxifen was not through the regulation of TGF beta-1 or the function of mdr-1. Although cytotoxic levels of tamoxifen (> 50 microM) can be achieved easily in the intravesical model, further study is necessary before tamoxifen can be used clinically in intravesical chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Sonographic characteristics of adenofibroma of the endometrium following tamoxifen therapy for breast cancer: two case reports.

Adenofibroma of the endometrium is thought to be a rare benign variant of the mixed mesodermal tumor, and its preoperative diagnosis is difficult. We describe the sonographic characteristics of two cases of adenofibroma of the endometrium. In both cases the patient was receiving prolonged tamoxifen therapy following surgery for breast cancer. Sonographically, this rare disease is observed as an intracavitary mass containing multiple small cysts with low-resistance intratumor blood flow. The unique sonographic findings make the preoperative diagnosis possible.

Adenofibroma↗

PubMed1996

Endometrial stromal sarcoma of twenty cases.

BACKGROUND: Endometrial stromal sarcoma is a rare neoplasm. We reviewed twenty cases to study the characteristics of this disease. METHODS: Twenty cases of endometrial stromal sarcoma were treated at our hospital. The clinical stage, treatment and outcome were retrospectively analyzed. RESULTS: Endometrial stromal sarcoma comprised 4.3% of corpus cancers and 46.4% of uterine sarcomas at our hospital. Seven cases were stage I, one was stage II, ten were stage III, and two were stage IV at the time of diagnosis. Histopathologically, seventeen cases were classified as low-grade sarcoma and three were high-grade sarcoma. Seven patients had recurrence and five of them had already died of disease. Among these recurrent patients, one was stage II and six were stage III. All three patients with high-grade sarcoma and four with low-grade sarcoma had recurrence. CONCLUSIONS: We think mitotic count is an important prognostic factor in low-grade endometrial stromal sarcoma and high-grade endometrial stromal sarcoma has a poor prognosis even with post-operative adjuvant treatment.

Adjuvants, Pharmaceutic↗

PubMed1996

Expression of MDR-1 gene in transitional cell carcinoma and its correlation with chemotherapy response.

PURPOSE: Expression of the mdr-1 gene has been correlated with the chemoresistance mechanisms of some cancer models. In the present study, we tried to evaluate mdr-1 gene expression in transitional cell carcinoma (TCC) in both cultured cells and clinical tumors. The expression status of mdr-1 was further correlated with the response to chemotherapy in both systemic and intravesical models. MATERIALS AND METHODS: We evaluated mdr-1 expression levels by reverse transcription polymerase chain reaction and Southern blotting (RT-PCR-SB) and the activity of P-glycoprotein (P-gp) by flow cytometric rhodamine-123 retention and efflux study in 10 TCC cell lines, 2 doxorubicin-resistant sublines (RLs), T24/A and NTUB1/A, and 2 cisplatin-RLs, T24/P and NTUB1/P. Eighty-eight clinical tumors with their benign counterparts were also assayed by RT-PCR-SB to determine mdr-1 expression status. Of the 88 TCC cases, 28 were treated with systemic and 60 with intravesical chemotherapy. Response to chemotherapy in either form was correlated with mdr-1 expression status. RESULTS: By RT-PCR-SB, mdr-1 expression signals were observed in only 2 of the 10 TCC cell lines; only 1 of these had a strong signal and active P-gp function. The other, bearing a weak signal, was negative for active P-gp function. All of the 4 RLs studied showed elevated mdr-1 transcript levels as compared with their mdr-1 negative parental cell lines. Doxorubicin-RLs showed much stronger expression signals than cisplatin-RLs. Active P-gp functions were observed in the 2 doxorubicin-RLs but not in the 2 cisplatin-RLs. The efflux of rhodamine-123 in cells with active P-gp function can be significantly inhibited by 10 microM. verapamil. Of the 88 clinical tumors, 62 (70.5%) were positive and 26 (29.5%) were negative for mdr-1 expression by RT-PCR-SB. All benign counterparts of the 88 tumors were positive for mdr-1 expression. However, no differences in chemotherapy responses were found between the positive and negative mdr-1 expression groups in either systemic chemotherapy (p = 0.32, one-tailed Fisher's exact test) or intravesical chemotherapy (p = 0.52, Cox-Mantel log rank test). CONCLUSIONS: Expression of mdr-1 was not commonly seen in TCC cell lines but can be significantly induced by chronic exposure to doxorubicin. Benign transitional cell epithelia seemed to universally express the mdr-1 gene. However, clinical TCCs lost mdr-1 transcript expressions in about 30% of cases. Most important, it appeared that mdr-1 expression status did not correlate with the response to chemotherapy in either systemic or intravesical models.

ATP Binding Cassette Transporter, Subfamily B, Mem↗