Antitumour activity of coumarin in prostate and mammary cancer models

The antineoplastic and antimetastatic activities of coumarin were evaluated in transplanted prostate tumours of the rat. The growth of Noble Nb-R prostate tumours was strongly inhibited by coumarin (40 mg/kg; administered three times per weck), whereas the hormonally more sensitive Dunning R3327-G rat prostate carcinoma did not respond. Coumarin was also shown to possess antimetastatic activity in a Dunning R3327-MatLu tumour model. The number of lung metastases was reduced significantly by 40%–50% following the adminstration of coumarin (40 mg daily). Preliminary data from experiments with rats bearing DMBA-induced mammary carcinomas showed that these tumours are as sensitive to coumarin as Noble-R-prostate tumours.Work presented at the Satellite Symposium of the International Society of Coumarin Investigators (ISCI) at the 21 st German Cancer Congress, 1994, Hamburg, Germany. Supported by Schaper & Brümmer, Salzgitter. Germany     

Prostatic metastasis of large cell neuroendocrine carcinoma of the lung

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare and aggressive tumour with a poor prognosis. Lung cancer metastases to the prostate are also uncommon, and are usually found incidentally during autopsy. Most reported primary lung cancers with prostatic metastases are small cell carcinomas, and prostatic metastases from LCNEC of the lung have not been reported previously. This case report describes a 70-year-old man with LCNEC of the lung and metastases in the prostate, brain, bone, liver and lymph nodes.     

Mucoepidermoid carcinoma of the salivary glands

Between 1965 and 1993, a total of 52 patients with mucoepidermoid carcinomas underwent surgical treatment. Their TNM stage at the time of initial diagnosis varied (TO: O, T1: 24, T2: 19, T3: 2, T4: 7; NO: 46, N1: 4, N2: 2; MO: 50, M1: 2). In the majority of patients (n=24) the history of symptoms ranged from more than 0.5 to 2 years without any specificity of features. Radical ablative surgery of the primary tumour is the therapy of choice. In patients suspected of having metastases of the regional lymph nodes, resection of the related lymphatic system has to be included in the therapeutic approach. The prognosis is excellent in patients with a localized manifestation. The patients who died for reasons of tumour metastasis had all been classified as having stage III to IV disease at the time of initial diagnosis. Distant metastases are rarely found even decades after surgical therapy. Long-term follow-up is recommended for patients with mucoepidermoid carcinomas.Abbreviation MEC mucoepidermoid carcinoma Partially presented in oral form at the 21th National Congress of the German Cancer Society, Hamburg, 7–11 March 1994     

The EnDA endometrial adenocarcinoma: an oestrogen-sensitive,metastasizing, in vivo tumour model of the rat

A high percentage of endometrial carcinomas contain oestrogen and progesterone receptors. For endocrine therapy of recurrent endometrial carcinoma, only high-dose progestins are in clinical use. As, therefore, the development of new endocrine treatment strategies is of great interest, suitable animal models for this tumour are essential. Up to now, only human tumour xenografts transplanted in immune-deficient nude mice, but no syngeneic in vivo tumour models, have been available. In the present article we describe the hormone sensitivity of the EnDA endometrial adenocarcinoma of the DA/Han rat growing as s.c. implants in DA/Han rats and athymic nude mice in serial passage. In both species, the tumour expresses oestrogen, but no progesterone receptors. Transplanted in DA/Han rats or nude mice, ovariectomy reduced tumour weight by 64% and 46% respectively. In both species substitution of ovariectomized animals with oestradiol restored tumour weights to intact control levels. Oestradiol substitution of intact animals did not further enhance tumour growth. The growth of the primary tumour was inhibited by medroxyprogesterone acetate (MPA) at a dose of 100 mg/kg by 67% and by tamoxifen at a dose of 20 mg/kg by 38%. Lung metastases were regularly seen in both species, although to a lesser extent in nude mice than in DA/Han rats. Tamoxifen treatment did not alter the number of lung metastases, whereas MPA or ovariectomy produced a significant reduction in the number of lung metastases. The EnDA endometrial carcinoma of the DA/Han rat with respect to its oestrogen sensitivity, oestrogen receptor expression, morphology and metastatic growth, grossly resembles a typical endometrial adenocarcinoma and can therefore be regarded as auseful in vivo experimental model for the evaluation of new endocrine treatment strategies.Abbreviations MPA medroxyprogesterone acetate - E₂ oestradiol undecylate     

Metastatic patterns of renal carcinoma: An analysis of 687 necropsies

Summary The metastatic behaviour of renal cell carcinoma has been studied in a series of 687 necropsies. The observations were consistent with the concept of metastatic inefficiency, in that in 295 cases, including 25 with renal vein invasion, there were no detectable metastases. In the present series, renal vein involvement was not an important prognostic factor in stage 1 or 2 disease. In 73% of cases without lung metastases there were none in other sites, and in 84% of those with lung metastases there were others elsewhere, consistent with a metastatic cascade in which metastases first developed in the lungs and were later detected in other organs. However, the observations did not permit discrimination between anatomic cascades, in which other organs were seeded from metastasizing pulmonary metastases, and temporal cascades, in which the other were seeded at the same time as the lungs, but with fewer cancer cells. The patterns of arterial metastasis were consistent with the seed-and-soil hypothesis, and a novel index was developed to quantify differential organ soils. The contralateral kidney was not the best soil for metastases from renal carcinoma. Given the presence of lymph node metastasis, the probability of heamatogenous metastasis is 90%. However, in the absence of nodal metastasis, approximately half the cases had haematogenous metastasis.     

Effect of zindoxifene on experimental prostatic tumours of the rat

Summary The anti-oestrogen zindoxifene was originally developed as a drug for the treatment of hormone-dependent mammary carcinomas. Experiments with rats bearing androgen-dependent prostatic tumours revealed antineoplastic activity of zindoxifene on these tumours also. Therefore, the inhibitory effect of this drug was studied in various prostatic tumour models in comparison to the anti-oestrogen tamoxifen and to castration. The growth of the hormone-dependent Dunning R3327 H tumour was strongly inhibited by zindoxifene (4 mg/kg), which was more effective than tamoxifen (43%T/C vs 87%T/C, the ratios of tumour weights in control and drugtreated rats). Zindoxifene was able to delay the relapse of these tumours by 7 weeks in comparison to castration. The experiments with Noble Nb-R prostatic tumours showed that administration of zindoxifene (5 mg) is superior to castration (5%T/C vs 52%T/C). The growth of tumours in castrated rats was completely inhibited by administration of zindoxifene. Therefore a peripheral mode of action has to be assumed.     

Antineoplastic activity of three ruthenium derivatives against chemically induced colorectal carcinoma in rats

Summary The antineoplastic activity of the ruthenium complexestrans-imidazolium[tetrachlorobisimidazoleruthenate(III)], HIm(RuIm₂Cl₄),trans-indazolium-[tetrachlorobis(1H-indazole)ruthenate(III,N ²)], HInd [RuInd₂Cl₄(N ²)], andtrans-indazolium[tetrachlorobis(2H-indazole)ruthenate(III,N ¹)], HInd[RuInd₂Cl₄-(N¹)] was assessed in acetoxymethylmethylnitrosamine-induced autochthonous colorectal carcinomas of Sprague-Dawley rats. The model is not sensitive to clinically established antineoplastic agents, including cisplatin. An exception is the combination therapy with 5-fluorouracil/leucovorin, which shows moderate activity against the tumour model. In contrast to this general trend, the new substances were all active against this tumour. HIm(RuIm₂Cl₄) was very effective at all dosages applied (7.5 mg/kg, 5.3 mg/kg, and 3.8 mg/kg), as indicated by percentage treated/control (T/C values of 23%, 34.5%, and 44%. Toxicity was considerable as shown by a body weight change of –30%, –19%, and –9%. Nevertheless, the medium dose seems to be the optimum in terms of mortality (0% vs 15% in the control group), whereas at the highest dose, mortality increased as a result of substance toxicity, and at the lowest dose mortality increased through tumor growth combined with substance toxicity.HInd[RuInd₂Cl₄(N²)] showed high efficacy at the highest dosage of 13 mg/kg, reaching a T/C value of 27% combined with 0% mortality versus 15% in the control group. In equimolar dosages (10 mg/kg, 7.1 mg/kg and 5.1 mg/kg), the compound is not as active as HIm-(RuIm₂Cl₄), as indicated by T/C values of 50.2%, 45.7%, and 38.6%. HInd[RuInd₂Cl₄(N¹)] was slightly but not significantly better than HInd[RuInd₂Cl₄(N²)] at a dosage of 7.1 mg/kg and is advantageous over combination therapy with 5-fluorouracil and leucovorin (20/20 mg/kg) in terms of efficacy (T/C=37.6% versus 44.7%) and mortality (6% versus 33.3%).     

The effect of a combination of zindoxifene and cisplatin on Dunning R3327-G prostatic carcinomas of the rat

Summary Endocrine therapy of hormone-dependent prostatic carcinomas can be very effective at the beginning. However, tumour growth eventually resumes possibly because of the presence of androgen-independent cell clones. Addition of a cytotoxic agent to the hormonally active drug at an early stage could possibly delay progression of disease. Therefore, we studied the effects of hormonal and cytostatic treatment in a rat prostate carcinoma model: freshly transplanted Dunning R3327-G prostatic tumours of the rat were treated with the partial antioestrogen zindoxifene and cisplatin alone and in combination. In addition we tested a 2-phenylindole-linked platinum complex 3-PtCl₂, which contains both effective functions. This particular complex had only a weak non-significant inhibitory effect on tumour growth. Comparing monotherapies with zindoxifene or cisplatin at various dose levels with the corresponding combinations, it became evident that the latter treatment was significantly more effective than the use of single agents. A very low dose of 0.4 mg cisplatin together with 2 mg/kg zindoxifene inhibited tumours by 91%, which was close to the effects of castration or diethylstilbestrol (1 mg). The analyses of accessory sex organs revealed much weaker oestrogenic side-effects than those observed with diethylstilbestrol at an equivalent dose. These results demonstrated that it is possible to increase the efficacy of hormonal therapy of prostatic carcinomas by conconmitant administration of cisplatin and reduce side-effects of oestrogenic drugs.Abbreviations ORG2058 16-ethyl-21-hydroxy-19-norpregn-4-en-3,20-dione - R1881 methyltrienolone - R2858 moxestrol Supported by the Deutsche KrebshilfeDedicated to Prof. Dr. W. Wiegrebe on the occasion of his 60th birthday     

DNA ploidy study of resected hepatocellular carcinoma in cirrhotic liver

Background/Aims: Results of several studies on DNA ploidy as a prognostic indicator in hepatocellular carcinoma are contradictory. The present study analysed the correlations between DNA ploidy of resected hepatocellular carcinoma and tumour characteristics, tumour recurrence, risk factors and survival.Methods: Tumoural DNA ploidy of hepatocellular carcinomas from 37 patients with cirrhosis who underwent curative tumour resection was studied by flow cytometry.Results: A diploid pattern was found in 23 hepatocellular carcinomas (62.2%) and an aneuploid pattern in 14 (37.8%). The tumour recurrence rate did not differ statistically between diploid (69.6%) and aneuploid (50%) hepatocellular carcinomas. The only prognostic variable with significant difference in DNA pattern was the histologic tumour type; the majority of non-trabecular tumours were aneuploid while most trabecular hepatocellular carcinomas had a diploid DNA pattern. Actuarial survival at 1, 2, 3 and 4 years of patients with diploid and aneuploid tumours was 69.6%, 40.6%, 16.2% and 0%, and 69.3%, 59.4%, 49.5% and 32.9%, respectively (log rank p=0.1927).Conclusion: These results indicate that DNA ploidy has no prognostic value in hepatocellular carcinoma.     

Prognostic groups in colorectal carcinoma

Summary A system of classifying colorectal carcinomas into five prognostic groups is described. This classification includes not only tumor spread, regional lymph node involvement, and distant metastases, but also resectability and R-classification (residual tumor or curability). All patients with colorectal tumors can be classified by means of this system. The five prognostic groups differ statistically significantly (p<0.01) from one another with respect to age-corrected 5-year survival rates.     

Frequent loss of the short arm of chromosome 9 in resected non-small-cell lung cancers from Japanese patients and its association with squamous cell carcinoma

We analyzed 87 Japanese non-small-cell lung carcinomas (NSCLC), including 30 squamous cell, 51 adenocarcinomas and 6 large-cell carcinomas for loss of heterozygosity (LOH) on the short arm of chromosome 9, and we correlated our findings with clinicopathological features. We used four polymorphic microsatellite markers on 9p (interferon A gene, D9S171, D9S126, and D9S169), which flank the critical region (9p21-22) involved in lung cancer. We observed alterations of DNA sequences at 9p in NSCLC (27 of 82 informative cases or 33%). Concordance among the four markers was high (87%), indicating that the deletions often were relatively large. The 27 genetic alterations observed on 9p include 26 examples of LOH, 1 homozygous deletion, and 1 case with LOH and evidence of microsatellite alteration characterized by shift in band mobility. We noted a high frequency of LOH at 9p especially in, squamous cell carcinoma (17 of 29 informative cases or 59%) and in poorly differentiated NSCLC (12 of 23 informative cases or 52%). There was no correlation between LOH at 9p and the other clinical parameters, including survival, gender, tumor size and the presence of regional or distant metastases. In contrast to other reports we found only rare instances of homozygous deletions (1%) and microsatellite alteration showed as a mobility shift (1%). Our findings demonstrate that LOH at the short arm of chromosome 9 is correlated with squamous cell and poorly differentiated carcinomas in Japanese patients with NSCLC.Abbreviations SCLC small-cell lung cancer - NSCLC non-small-cell lung cancer - LOH loss of heterozygosity - PCR polymerase chain reaction - (CA) _n cytosine adenine - n number of repeats - IFNA interferon A gene     

Chemopreventive effect of selenium and Chinese medicinal herbs on N‐nitrosobis(2‐oxopropyl)amine‐induced hepatocellular carcinoma in Syrian hamsters

Background/Aims: Oxidative DNA damage by reactive oxygen species is involved in the process of liver carcinogenesis. To test the hypothesis that a remedy containing Scutellaria baicalensis Georgi (Sb) and Bupleurum scorzonerifolfium Willd (Bs) (Sb/Bs remedy) modulates hepatic neoplastic growth, BOP (N‐nitrosobis(2‐oxopropyl)amine)‐induced liver cancers in hamsters were established. Methods: Parameters such as survival rate, tumour area, tumour foci, 8‐hydroxydeoxyguanosine (8‐OHdG), caspase‐3, transforming growth factor (TGF‐β1) and tumour necrosis factor‐α (TNF‐α) were measured after Sb/Bs remedy treatment during BOP‐induced carcinogenesis. Results: The results showed that the Sb/Bs remedy and its constituents Sb and Bs suppressed the tumour area in BOP‐induced liver tumours. Because selenium (Sel) is toxic at a high dose (10 mg/kg), with a low survival rate (0%), the combination of Sb/Bs remedy and low‐dose Sel (1 mg/kg) was found to decrease the tumour area and the number of tumour foci while increasing serum TNF‐α and TGF‐β1, but not IL‐6 levels. Besides, the Sb/Bs remedy, when combined with low‐dose Sel, not only decreased the expression of 8‐OHdG and increased caspase‐3 expression within the glutathione S‐transferase placental form‐positive tumour foci but also increased tumour apoptosis in BOP‐induced hamsters. Conclusions: We conclude that low‐dose Sel has a chemoprevention effect on BOP‐induced liver tumours and such an effect was more enhanced when combined with Sb/Bs treatment.     

Location of liver metastases reflects the site of the primary colorectal carcinoma

Objective. The present study was designed to investigate whether the different venous return of different locations of colorectal carcinomas affects the lobar distribution of metastases to the liver, due to the “streaming” within the portal vein. Material and methods. The site of the primary colorectal carcinoma was divided into the right- and left hemicolon according to the different venous drainage via the superior and the inferior mesenteric/splenic vein. Both groups were analyzed for the distribution of the metastases in the liver. The anatomic site of the liver metastases was detected by intraoperative exploration and differentiated between the two lobes using the Cantlie line. Results. Out of a total of 178 patients, 109 men and 69 women with 264 metastases were eligible for the study. The ratio of metastases in the right and left hemiliver was 3.6:1 for 35 right-sided primary tumors (p=0.002) compared with 2.1:1 for 143 left-sided primary tumors (p=NS). No significant differences were evident for the sub-analysis of involved liver segments. Conclusions. The results of our study support the existence of the “streaming” effect in the portal vein. Right-sided colon carcinomas predominantly involve the right hemiliver, while left-sided colon carcinomas involve the liver homogeneously, considering the size ratio of the right to left liver lobe, which is about 2:1. Knowledge of streaming may help us to understand the spread of abdominal malignancies and may provide a reference concerning the possible primary site depending on metastatic distribution in the liver.     

Proposed indications for limited resection of early ampulla of Vater carcinoma: clinico-histopathological criteria to confirm cure

Background

Limited resection is reserved for patients with high operative risk or benign adenomas. We aimed to define indications for limited resection of early ampulla of Vater carcinoma with curative intent through detailed preoperative examinations and histopathological evaluations.

Methods

We performed a retrospective cohort study of all consecutive Japanese patients who underwent resection for ampulla of Vater neoplasms at our hospital from 1986 to 2010.

Results

A total of 75 patients were identified. Moderately/poorly differentiated histology, lympho-vascular/perineural invasion, and duodenal/pancreatic invasion were significant risk factors for lymph node metastases. Macroscopically, non-exposed protruded- or ulcerative-type disease did not correlate directly with lymph node metastases; however, these tumor types were associated with other invasive features. In a subset of early carcinomas fulfilling the conditions of exposed protruded adenoma or papillary/well-differentiated adenocarcinoma determined by endoscopic biopsy, negative duodenal invasion determined by endoscopic ultrasonography, no tumor infiltration into the pancreatic duct determined by intraductal ultrasound, and diameter of the pancreatic duct ≤3?mm determined by endoscopic retrograde cholangiopancreatography (N?=?11), the incidence of lymph node metastasis and tumor infiltration into the pancreatic duct was 0%.

Conclusion

Strictly selected patients with early ampulla of Vater carcinomas may benefit from limited resection if the resected specimen is evaluated to confirm all histopathological criteria.     

Significance of human papillomavirus 16/18 infection in association with p53 mutation in lung carcinomas

Introduction: The role of high‐risk human papillomavius (HPV) 16/18 in the development of lung cancer has recently been explored, and p53 mutation is a finding in lung cancer; however, its association with HPV infection is not well studied. Objectives: To investigate HPV 16/18 infection and p53 mutation in lung carcinomas and their association with tumor behavior. Methods and Results: We expanded our prior study to include 107 squamous cell carcinoma (SCC), 63 adenocarcinoma (AC) and 91 non‐cancer control cases of lung from a population of Western China. The results confirmed that HPV infection is more prevalent in SCC (59.8%) comparing with that of AC (17.5%) and the control cases (23.1%) (P < 0.001), and genotyping demonstrated predominant HPV 16/18 infection in the carcinomas and HPV 6 in the control cases. By immunohistochemistry, p53 mutation was detected in 67.3% of SCC and 60.3% of AC, in comparison with 9.9% in the control (P < 0.001). Within the group of SCC, the p53 mutation rate is significantly higher in those with HPV infection (78.1%) than that of the non‐infected carcinomas (51.2%, P = 0.004). However, this difference is not proven to be significant in the groups of AC and the controls. Clinicopathological analysis demonstrated that the coexistence of p53 mutation and HPV infection was associated with lymph node metastasis (P = 0.001) and high‐clinical TNM stage of SCC (P = 0.001). As there was no sequencing data, the evidence for HPV 16/18 E₆ induced p53 mutation is still indirect. Conclusion: This study indicates that p53 mutation and HPV 16/18 infection might coordinate in the development of lung squamous cell carcinomas, and their coexistence is associated with poor prognosis. Please cite this paper as: Yu Y, Yang A, Hu S, Zhang J and Yan H. Significance of human papillomavirus 16/18 infection in association with p53 mutation in lung carcinomas. Clin Respir J 2013; 7: 27–33.     

Accelerated hyperfractionated radiotherapy with concurrent chemotherapy in locally advanced nasopharyngeal carcinoma: a phase II study

Purpose: The incidence of nasopharyngeal carcinoma in Germany is relatively low in comparison with certain regions in south-east Asia. However, standardised therapeutical regimes are required in the treatment of these tumours. Methods: Between August 1990 and December 1997, 25 patients with stage III and IV nasopharyngeal carcinoma received an accelerated and hyperfractionated radiotherapy with concurrent chemotherapy (5-FU and mitomycin C). The primary tumour and positive lymph nodes received a total dose of 72 Gy over a period of 6 weeks. In the first 3 weeks, irradiation fields were treated five times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving two daily fractions of 1.4 Gy. Salvage surgery was offered for residual lymph node disease after radiotherapy. Results: The overall response rate defined as complete and partial response of the primary was 100%. Sixteen of the 25 patients were still alive and were free of any evidence of tumour recurrence or distant metastases at a mean follow-up period of 34 months (range 7–95 months). Six patients received salvage surgery. Only one of these six patients had histologically proven evidence of vital tumour. No severe late complications such as blindness or temporal lobe necrosis were observed. Conclusions: The presented data are promising and show that the combination of hyperfractionated accelerated radiotherapy and chemotherapy is feasible and effective. Received: 10 January 2000 / Accepted: 22 January 2001     

Expression of nm23-H1 predicts lymph node involvement in colorectal carcinoma

PURPOSE: Reduced expression of the metastasis suppressor gene nm23-H1 has previously been correlated with high tumor metastatic potential and fatal clinical outcome in some tumors (e.g.,breast). For colorectal carcinomas, the findings are equivocal. METHODS: We have used a monoclonal antibody against nm23-H1 to investigate the expression in colorectal carcinomas at the time of primary curative surgery (RO resection) to assess if there was any relation between nm23-H1 expression and stage or histologic grade at the time of primary tumor removal. RESULTS: Of 100 colorectal carcinomas studied (Stages I, II, and III according UICC, all resected curatively), nm23-H1 immunoreactivity was weak in 41 (41 percent), moderate in 24 (24 percent), and strong in 35 (35 percent) cases. The grade of positivity against nm23-H1 was significantly lower in advanced stages of the disease (Stages II or III) (P < 0.001, chi-squared=52.8). In tumors with low or weak immunoreactivity against nm23-H1, frequency of lymph node metastases was significantly higher compared with those with moderate or strong staining (P < 0.001; chi-squared=50.58). Therefore, with a sensitivity of 93 percent and a specificity of 58 percent, low nm23-H1 immunoreactivity of the primary tumor, assessed at the time of surgery, is an indicator of the presence of lymph node metastases. CONCLUSIONS: Immunohisto-chemical evaluation of nm23-H1 in the primary tumor or in a biopsy is a useful predictor of stage of disease and presence of lymph node metastases in colorectal carcinomas and may have clinical significance,e.g.,in predicting optimal therapeutic regimes.     

Evaluation of the antitumour activity of coumarin in prostate cancer models

Responses to coumarin have been reported for patients suffering from malignant melanoma, metastatic renal carcinoma and, recently, advanced prostate cancer. These data together with some experimental evidence for antiprostatic effect prompted us to study the activity of coumarin in various prostate tumour models and evaluate the endocrine properties of this drug. In rats no antiandrogenic activity was found. The growth of Noble Nb-R prostate tumours of the rat was strongly inhibited by coumarin (40 mg/kg; administered three times per week), whereas the hormonally more sensitive Dunning R3327-G rat prostate carcinoma did not respond to coumarin (40 mg) even when the drug was administered daily. Coumarin was also shown to posses antimetastatic activity in a Dunning R3327-MatLu tumour model. In this model small pieces of the hormone-independent tumour were implanted into the ear of the animal and later resected to mimic the clinical situation where primary tumours have been removed. The number of lung metastases was reduced significantly by 40%–50% following the administration of coumarin (40 mg daily).     

Relation of oestradiol-mediated growth stimulation with the expression of c-erbB-2 protein in xenotransplanted oestradiol-receptor-positive and -negative breast carcinomas

Attempts were made to correlate growth effects induced by oestradiol and tamoxifen with the hormonal regulation of c-erbB-2 protein in experiments in vivo. We report here the responsiveness of four xenotransplanted oestrogen-receptor(ER)-positive and four ER-negative human mammary carcinomas to oestradiol and tamoxifen. Oestradiol in a dose of 0.5 mg/kg significantly increased the growth of the ER-positive mammary carcinomas 3366, MCF-7, 4134 and 4049, but not the ER-negative tumours 4000, 4296 and MT-3. However, within the group of the ER-negative breast carcinomas the tumour 4151 ES deviates from this growth behaviour, as we could prove an estrogen induced growth. The stimulation of tumour growth by oestradiol was always accompanied by a down-regulation of c-erbB-2 protein both in the ER-positive mammary carcinomas and in the ER-negative mammary carcinoma 4151 ES. Tamoxifen significantly inhibited the growth of the ER/PR-positive mammary carcinomas 3366 and MCF-7 but not the ER-positive/PR-negative mammary carcinomas 4049 and 4134. In the group of ER-negative mammary carcinomas only the growth of the oestrogen-responsive tumour 4151 ES was significantly inhibited by tamoxifen. The inhibition of tumour growth by tamoxifen was correlated with a reversion of the oestradiol-induced down-regulation of c-erbB-2, also in the ER-negative/oestradiol-responsive mammary carcinoma 4151 ES. From our results we hypothesize that the oestrogen-dependent growth of ER-negative breast carcinoma 4151 ES could also be correlated with the oestradiol-regulated expression of c-erbB-2 protein.Abbreviations ER Oestradiol receptor - PR Progesterone receptor     

Individual and combined effects of a thromboxane receptor antagonist and different antithrombotic agents in a rat microcirculatory thrombosis model.

The antithrombotic effect of a thromboxane A2 receptor antagonist (HN-11501:5-[2-(4-chlorophenylsulfonylamino)-ethyl]-2-thienylox y-acetic acid) alone and in combination with other antithrombotic agents has been studied in an experimental thrombosis model in which laser lesions are used to induce a defined thrombosis in rat mesenteric venules. The thromboxane receptor antagonist showed a significant and dose-dependent antithrombotic effect if given orally. The strongest additive thrombosis-inhibiting effect was observed after oral administration of HN-11501 at a dose of 2.5 mg/kg together with an intravenous infusion of 1 microgram/kg/h of a prostacyclin analogue (cicaprost). An additive antithrombotic effect was also observed after oral application of 2.5 mg/kg of HN-11501 and intravenous injection of 0.2 mg/kg of a low molecular weight heparin (Fraxiparine). The combination of 2.5 mg/kg of HN-11501 orally with an intravenous injection of 0.1 mg/kg molsidomine also had a significant additive effect. No significant additive effect was observed when 2.5 mg/kg of HN-11501 and 10 mg/kg of acetylsalicylic acid were orally administered simultaneously.