Biomedical subjects

M Schirner

Publications and source records attributed to M Schirner.

17 recordsLinked to original sources

PubMed1997

A highly sensitive model for quantification of in vivo tumor angiogenesis induced by alginate-encapsulated tumor cells.

A remarkable approach to a specific tumor angiogenesis model in vivo is the use of alginate implants encapsulating tumor cells. However, this previously reported approach has often been questioned because of doubts regarding the relevance of hemoglobin at the alginate implant as a parameter of vascularization. In the present investigation, we examined whether or not the use of the blood pool agents FITC-dextran of high molecular weight would significantly improve the determination of vascularization at the alginate implant. In our experiments, we found a rapid distribution of FITC-dextran within the blood circulation of mice after i.v. bolus injection. The amount of FITC-dextran within alginate implants strongly correlated with the number of LL2 carcinoma cells or B16/F10 cells encapsulated. Even a low number of 10(3) cells per alginate implant led to a significantly increased accumulation of FITC-dextran. A more than 10-fold stimulation above that of controls was found with alginate implants containing 10(4) LL2 or B16/F10 tumor cells. Using the investigational compound AGM-1470 in different treatment schedules, we found that quantification of alginate implant anglogenesis with FITC-dextran is a sensitive method for the determination of angiogenesis inhibition. In conclusion, our results demonstrated that the use of FITC-dextran enables highly sensitive, quantitative measurement of blood vessel formation by alginate implants.

Alginates↗

PubMed1997

Novel antibodies directed against the extracellular domain of the human VEGF-receptor type II.

Vascular endothelial cell growth factor (VEGF) plays a pivotal role in the regulation of angiogenesis by binding to its cognate receptor molecule type II (VEGFr-II, KDR). VEGFr-II is an endothelial cell-specific transmembrane tyrosine kinase important for vascular endothelial cell development and differentiation during embryogenesis, angiogenic processes under physiological conditions, and various diseases. An increasing number of reports indicate that VEGF/VEGFr-II also play a fundamental role for tumor angiogenesis. We present the generation and in vitro characterization of the monoclonal antibodies 2-7-9 and 2-10-1. Both antibodies are highly specific for VEGFr-II as demonstrated by Western blotting and immunoprecipitation. MAbs 2-10-1 and 2-7-9 bind to a disulphide bridge-stabilized epitope within domains 6 and 7 of the human VEGFr-II with an affinity of 8 and 80 nM, respectively. Furthermore, the antibodies are suitable for immunohistochemistry and ELISA techniques. Because both antibodies recognize their epitope on living cells, they also have the potential for drug targeting and diagnostic purposes.

Animals↗

PubMed1997

Inhibition of metastasis by cicaprost in rats with established SMT2A mammary carcinoma growth.

Cicaprost, a stable prostacyclin analog has been shown to be antimetastatically active in a series of metastasizing rodent tumors. Whereas starting treatment with Cicaprost on the day of tumor implantation was a characteristic feature of our previous investigations, the present study focused on the antimetastatic potency of Cicaprost in animals with established tumor growth. We have previously reported that, in Wistar-Furth rats bearing subcutaneously implanted SMT2A mammary carcinoma, Cicaprost in daily oral doses of 0.1 to 1.0 mg/kg given from the day of tumor implantation to the end of the experiment led to a strong decrease in the number of lung metastases. The 1.0 mg/kg doses reduced the number of lung metastases by about 95% compared with the control. In the present study, we have examined the effect of delaying the start of treatment in animals with established tumor growth, Cicaprost in daily oral doses of 0.1 mg/kg given from Day 10 until Day 32 reduced the number of lung metastases by about 80% compared with the control. In contrast, surgical removal of palpable primary tumors had no effect on lung metastasis. We conclude that Cicaprost exhibits strong antimetastatic activity in the SMT2A rat mammary carcinoma model and interferes not only with mechanisms of tumor cell-blood cell interaction, tumor cell adhesion, and extravasation, but also with steps following extravasation.

Animals↗

PubMed1996

IL-4 and TNF-alpha induce changes in integrin expression and adhesive properties and decrease the lung-colonizing potential of HT-29 colon carcinoma cells.

The colon carcinoma cell line HT-29 was used to explore the potential of interleukin-4 (IL-4) and tumor necrosis factor alpha (TNF-alpha) to modify integrin expression and adhesive functions of tumor cells in vitro and to examine corresponding metastatic effects in vivo. Preincubation of HT-29 cells with 100 U/ml of IL-4 for 48 h downregulated the surface expression of the integrin subunits alpha 2, alpha 3, beta 1 and beta 4 after 48 h, whereas the alpha 1 subunit was upregulated. In contrast, 100 U/ml to TNF-alpha selectively upmodulated the expression of alpha v. Attachment to fibronectin of cells treated with IL-4 increased twofold (63.5% vs 32.4%). Adhesion to fibronectin (54.0% vs 32.4%) and vitronectin (37.9% vs 16.4%) was elevated in the case of TNF-alpha stimulation. Using an experimental metastasis model, HT-29 cells showed a significant reduction of their lung-colonizing potential in nude mice when preincubated with IL-4 for 48 h before intravenous injection. The decrease also observed for TNF-alpha-treated cells was less pronounced. The data indicate that the cytokines IL-4 and TNF-alpha can act as direct regulators of adhesive mechanisms of tumor cells bearing adequate receptors, thus influencing lung-colony formation.

Animals↗

PubMed1996

Antimetastatic action of the prostacyclin analogue cicaprost in experimental mammary tumors.

In breast cancer, the survival rate strongly depends on the number of lymph nodes involved. A drug with a specific inhibitory activity on lymph node and organ metastases would therefore be a candidate for adjuvant therapy after surgery. Prostacyclin and its stable analogues have been shown to interfere with certain steps of the metastatic cascade and to inhibit the number of lung colonies after i.v.-inoculation of various tumor cell lines. Our data reveal that cicaprost, a metabolically stable and orally active analogue of prostacyclin, has pronounced antimetastatic effects in a series of spontaneously metastasizing rodent tumors. In the SMT 2a and 13762 MTLn3 mammary carcinomas of the rat, cicaprost given daily from the day of tumor implantation strongly inhibits the number of lung metastases as well as lymph node weights without exerting an effect on the primary tumor. Even starting treatment when palpable primary tumors are present gives a pronounced antimetastatic activity. To demonstrate that cicaprost has an effect on metastases already settled in the respective organ, treatment was started after surgical removal of the primary tumor. In the SMT 2a tumor, a strong inhibition of the number of metastases was shown. Interestingly, a perioperative treatment schedule was also effective in both models used. As primary tumor growth in vivo or proliferation in vitro remained unchanged by cicaprost, its mode of action seems to be related to one or more mechanisms of the metastatic process. In tumor cell lines expressing a functional prostacyclin receptor, stimulated tumor cell migration is inhibited and changes of differentiation status are obvious. In conclusion, cicaprost strongly inhibits lymph node and organ metastases of spontaneously metastasizing rodent mammary tumors with a mode of action different from cytostatic or antihormonal drugs.

Animals↗

PubMed1995

Rodent model of systemic mammary tumor disease by surgical removal of the spontaneously metastasizing SMT2A mammary carcinoma: inhibitory effect of the stable prostacyclin analogue cicaprost on occult metastasis.

Cicaprost, a stable prostacyclin analogue, has been shown to be anti-metastatically active in a series of metastasizing rodent tumors. Start of treatment with cicaprost immediately before tumor implantation was a characteristic feature of our previous investigations. We have reported that in rats bearing mammary-fat-pad-implanted SMT2A mammary carcinoma, cicaprost treatment starting before tumor implantation led to a strong decrease in the number of lung metastases. In order to determine the effect on occult tumor metastasis, the present study examined the effect of starting treatment when tumor metastasis is already present. Cicaprost in daily oral doses of 0.1 mg/kg given from day 10 to day 32 reduced the number of lung metastases by about 75% compared with the control, whereas surgical removal of palpable primary tumors on day 5 or day 10 failed to influence lung metastasis. Using different treatment schedules, a pronounced reduction of the number of lung metastases was achieved by administration of cicaprost until the end of the experiment (from day 5 to day 35), whereas short-term treatments (from day 5 to day 15 or to day 25) were without significant effect. In rats whose SMT2A tumors were surgically removed 10 days after tumor implantation, there was a strong decrease of lung metastases by cicaprost given from day 20 to day 36. In addition to its inhibitory potential in animals with advanced tumor disease, cicaprost showed anti-metastatic action when used in peri-operative treatment of animals whose primary tumors had been removed. In conclusion, the present results demonstrate that cicaprost exhibits strong anti-metastatic activity in the SMT2A rat mammary-carcinoma model with treatment started when occult tumor metastases are already present. Results also indicate that direct effects on tumor cells may contribute to the anti-metastatic action of cicaprost in spontaneously metastasizing tumors.

Adipose Tissue↗

PubMed1995

[Prostaglandins and prostaglandin analogs: experimental studies on their effect of tumor metastasis].

Metastatic tumor spread is regarded as the highest degree of malignancy of tumors and generally determines the prognosis. Before clinically detectable metastases are evident in distant organs, tumor cells interact with cellular and non-cellular components of the host as they complete the multistep process referred to as the metastatic cascade. Many investigational drugs acting at different levels of the metastatic process were tested for beneficial effects on metastasis. Because of the influence of prostaglandins on host components essential for tumor metastasis, this group of a compounds was tested in model of tumor growth and metastasis. Prostaglandins of the E, D and J series inhibit growth of variety of tumor cells and cause a reduction of primary tumor growth in vivo. The antiproliferative action of prostaglandins of the E series seems to be related to an induction of differentiation, whereas prostaglandins of the D and J series mediate growth inhibition by a blockade of the cell cycle and an inhibition of RNA and DNA synthesis. There is no conclusive evidence that prostaglandins of the E, D and J series may specifically interfere with mechanisms of tumor metastasis. In contrast to the prostaglandins of the E, D and J series, prostacyclin has been shown to inhibit several processes involved in tumor metastasis, but without exerting a direct cytotoxic effect on tumor cells. Our own studies have shown that Cicaprost, a stable prostacyclin analogue, prevents metastasis if given continuously from the day of tumor implantation, and is also effective in reducing metastasis if treatment is begun following surgical removal of the primary tumor, when micrometastases are already present.

Animals↗

PubMed1994

Prostacyclin and its analogues: antimetastatic effects and mechanisms of action.

More than a decade ago, prostacyclin, a dienoic bicyclic eicosanoid derived from the metabolism of arachidnoic acid, was found to possess potent inhibitory effects on tumor cell metastasis. Thereafter, several laboratories demonstrated the metastasis-suppressive activity of prostacyclin in a wide spectrum of tumor types. Due to the short half-life of prostacyclin, researchers have focused on looking for stable prostacyclin analogues which have extended half lives and increased bioavailabilities. Cicaprost, among other prostacyclin analogues tested, has been demonstrated, like prostacyclin, to effectively inhibit metastasis in several different animal models (i.e., both experimental and spontaneous metastasis models). Prostacyclin as well as cicaprost prevent not only hematogenous, but also lymphatic metastasis. Furthermore, these compounds also inhibit the growth of established micrometastases after removal of the primary tumors. Mechanistic studies revealed that the antimetastatic effects of prostacyclin and its analogues are more related to their interference with tumor cell-host interactions (such as tumor cell induced platelet aggregation, tumor cell adhesion to endothelial cells and subendothelial matrix, tumor cell induced endothelial cell retraction, etc.) than their direct inhibition of the growth of primary tumors. The potent and widespread metastasis-retarding effects of prostacyclin and its stable analogues in animal tumor models warrant their clinical trial in treating human cancer patients and preventing metastasis.

Animals↗

PubMed1994

The stable prostacyclin analogue Cicaprost inhibits metastasis to lungs and lymph nodes in the 13762NF MTLn3 rat mammary carcinoma.

Prostacyclin and its stable analogues have been shown to interfere specifically with certain steps of the metastatic cascade. The antimetastatic activity of the stable prostacyclin analogue Cicaprost (Schering AG) on haematogenous metastasis in a series of tumours in rats and mice has been well established. In order to test the effect of Cicaprost on lymphogenous metastasis we chose the metastatic cell clone MTLn3 derived from the 13762NF rat mammary carcinoma. The effect of Cicaprost on prevention of lung metastasis, lymph node metastasis and primary tumour growth was investigated. Cicaprost given in daily doses of 0.01, 0.03 and 0.1 mg/kg orally, reduced the number of lung metastases in a dose-dependent manner. Whereas the median number of lung metastases in the controls was greater than 1000, Cicaprost at a dose of 0.1 mg/kg reduced the number of lung metastases to between 11 and 100. The weight of the ipsilateral axillary lymph nodes was diminished by Cicaprost to 30-50% of controls. Moreover, metastasis to the contralateral axillary lymph node was completely inhibited by Cicaprost at all three doses tested. Cicaprost did not influence the growth rate of the MTLn3 cell clone implanted into the mammary fat pad or the weight of the primary tumour at the end of treatment. In conclusion, in addition to its dose-dependent effect on haematogenous metastasis, Cicaprost strongly inhibits lymph node metastasis.

Animals↗

PubMed1993

Effect of cisplatin on primary tumour growth and liver metastases in the M 5076 reticulum sarcoma: implication for new screening modalities.

We investigated the effect of cisplatin given at different treatment intervals on growth of the s.c.-implanted M 5076 reticulum sarcoma and the number of liver metastases at the end of the experiment (day 24). The later the treatment was started, the smaller was the tumour-inhibiting effect of cisplatin on primary tumour growth. Initiation of cisplatin treatment before day 14 after tumour implantation inhibited liver metastases completely. Treatment starting from day 14 or later did not influence the number of liver metastases. With regard to the clinical situation, the data imply that in the search for new leads in anticancer compounds, experimental conditions should concentrate on the inhibition of metastatic tumour growth.

Animals↗

PubMed1993

U 46619 induces different blood pressure effects in male and female spontaneously hypertensive rats (SHR).

The effect of U 46619 (5 micrograms/kg i.v.) alone or in combination with acetylsalicylic acid (ASA) (100 mg/kg po.) on mean arterial blood pressure (MABP) was investigated in male and female spontaneously hypertensive rats (SHR). In male SHR, a significant increase of MABP was observed 1 min after administration of U 46619. Pretreatment of male SHR with ASA delayed the increase of MABP after intravenous injection of U 46619 compared to U 46619 alone. Whereas in control animals the elevated MABP returned to baseline values 5 min after intravenous application of U 46619, the MABP of ASA-pretreated male SHR remained significantly increased by about 30 mmHg. In contrast, the MABP of female SHR did not respond to U 46619 alone or to the combination of U 46619 and ASA. Sex differences were further shown by the vascular formation of thromboxane B2 (TXB2). Whereas in male SHR the vascular formation of TXB2 was increased by U 46619, the TXB2 formation of female SHR was decreased. The vascular formation of 6-keto-PGF1 alpha of male and female SHR was not influenced by U 46619 alone or a combination of U 46619 and ASA. In conclusion, our results demonstrate that the blood pressure of SHR respond differently to the TXA2 mimetic U 46619 in the two sexes. Furthermore, by modulating blood pressure response to TXA2, vasoactive prostanoids may be significantly involved in the maintenance of hypertension with male SHR.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1993

Different effects of aspirin on blood pressure of spontaneously hypertensive rats (SHR) with high and spontaneously low levels of blood pressure.

Spontaneously hypertensive rats (SHR) of the Okamoto strain with blood pressure above 161 mmHg and SHR with blood pressure levels of less than 160 mmHg were treated with oral doses of aspirin (100 mg kg-1) for three days. Whereas the blood pressure of SHR with blood pressure above 161 mmHg was decreased by aspirin, the blood pressure of SHR below 160 mmHg was increased by aspirin. The extent and direction of blood pressure change by aspirin was strongly correlated with the blood pressure of SHR before treatment (r = -0.88). The effect of aspirin supports an important role for endogenous prostanoids in the regulation of blood pressure of SHR.

Animals↗

PubMed1992

Sexual dimorphism in blood pressure response to thromboxane agonist U 46619 and to endothelin.

The blood pressure rising effect of two vasconstrictoryacting substances (the thromboxan agonist U 46619 and the endothelium-derived peptide endothelin-1) differs in male and in female rats and this fact depends on normotensive or hypertensive levels of blood pressure. Whereas in male rats the drug effect was changed by pretreatment with aspirin, in female rats aspirin was uneffective in changing the blood pressure response to the agents. It could be suggested that the mechanism(s) for blood pressure regulation, especially the vasoconstrictor system, is different in males and females.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1992

The prostacyclin analogue cicaprost inhibits metastasis of tumours of R 3327 MAT Lu prostate carcinoma and SMT 2A mammary carcinoma.

Investigations on mechanisms of metastatic tumour spread revealed a role for compounds that inhibit tumour dissemination at the time of hematogenous dissemination. The platelet aggregation inhibitor prostacyclin and its stable analogues were shown to inhibit tumour-cell-induced platelet interaction as well as tumour cell adhesive mechanisms. This study concentrates on the effect of the stable prostacyclin analogue cicaprost: 5-[(E)-(1S,5S,6S,7R)-7-hydroxy-6-[(3S,4S)-3-hydroxy-4-methylnona-1 ,6- diinyl]-bicyclo[3,3,0]octan-3-ylidene]-3-oxapentanoic acid (Schering AG), as cyclodextrin clathrate, on spontaneous tumour metastases of two different carcinomas of the rat. In Cop rats bearing spontaneously metastasizing R 3327 MAT Lu prostate carcinomas, cicaprost (1.0 mg/kg p.o. daily) inhibited the number of lung metastases by about 80%, whereas the lower doses (0.1 and 0.5 mg/kg) exhibited borderline efficacy. In female Wistar-Furth rats bearing s.c. implanted SMT 2A mammary carcinomas, spontaneously metastasizing into regional lymph nodes and lungs, cicaprost (0.1, 0.5 and 1 mg/kg) p.o. daily exhibited a dose-dependent inhibition of the number of lung metastases. Five out of ten animals treated by 1 mg/kg were free of visible lung metastases. The weight of the axillary lymph node was significantly reduced by the 1 mg/kg dose of cicaprost, whereas lower doses had no effect on the weight of the lymph nodes. The growth of the primary tumour was not influenced by cicaprost in the R 3327 MAT Lu prostate carcinoma nor in the SMT 2A mammary carcinoma in the dose range tested. In conclusion, the stable prostacyclin analogue cicaprost exhibits a strong antimetastatic action in two metastasizing tumours of the rat and interferes with the steps not only of haematogenous, but also of lymphogenous metastasis.

Animals↗

PubMed1991

Cicaprost inhibits metastases of animal tumors.

Since an involvement of platelet aggregation in the metastatic process has been found, platelet activation inhibitors were investigated for their potential to reduce tumor metastases. Recent in-vitro and in-vivo investigations showed an antimetastatic effect of prostacyclin (PGI2) and stable prostacyclin analogues. This study concentrates on the effect of the stable prostacyclin analogue Cicaprost (Schering AG) on tumor metastases in two metastasizing tumors of rodents. C57BL/6 mice bearing s.c.-implanted M5076 reticulum sarcoma were treated with Cicaprost in doses of 0.1-1.0 mg/kg throughout the experiment. Cicaprost in all doses tested reduced the number of liver metastases in a statistically significant manner. The 1.0 mg/kg dose, which decreases the median number of liver metastases to more than 93% compared to the control, was most effective. Cicaprost in the 0.5 mg/kg dose reduced the number of liver metastases in mice bearing i.v.-implanted M5076 reticulum sarcoma. In Cop-Fisher rats bearing s.c.-implanted spontaneously metastasizing R3327 MAT Lu prostate carcinoma, Cicaprost in a dose of 1.0 mg/kg p.o. daily strongly reduced the number of lung metastases. These results indicate that Cicaprost is a potent inhibitor of tumor metastases in different tumor models in rodents.

Animals↗

PubMed1991

Effects of prostacyclin analogues in in vivo tumor models.

Much attention has recently focused on the role of tumor cell-platelet interaction in the metastatic cascade. Prostacyclin and stable prostacyclin analogues have been shown to inhibit specifically the formation of metastases in experimental tumor models. This action is based on their ability to reduce the attachment of tumor cells to platelets and to inhibit adhesion of tumor cells-platelet aggregates to the endothelial lining. To investigate the antimetastatic potential of two prostacyclin analogues (Iloprost and Eptaloprost, Schering AG), we have tested these compounds in the spontaneously metastasizing R 3327 MAT Lu prostate carcinoma of the Cop rat in two types of experiments. Treatment was performed for 33 days, starting one day before s.c. implantation of the tumor. The primary s.c.-implanted tumor remained in situ throughout the experiment. In the first test, Iloprost (0.3 micrograms/kg/min) and Eptaloprost (0.1 micrograms/kg/min) were administered via Alzet mini pumps s.c.. There was a considerable reduction of the number of visible lung metastases by Eptaloprost. In the second test, Eptaloprost was administered p.o. in doses of 0.1 and 0.5 mg/kg daily. The number of lung metastases was significantly reduced. Both compounds had no effect on the growth of the primary tumor in the first as well as in the second test. These data show that the prostacyclin analogue Eptaloprost has a significant antimetastatic activity in a spontaneously metastasizing tumor model and thus merits further investigation.

Animals↗

PubMedDate not supplied

Cicaprost does not affect tumor inhibitory potential of cytostatic drugs.

Cicaprost, a stable prostacyclin analogue with antimetastatic potential, was investigated as regards its effect on the tumor inhibitory potential of cytostatic drugs exhibiting different modes of action in the MXT-OVEX mouse mammary carcinoma. Cicaprost itself in doses of 0.5 mg/Kg and 1.0 mg/Kg po. daily had no effect on the growth of the sc.-implanted tumor. cis-Platinum at a dose of 1.5 mg/Kg sc. strongly inhibited tumor growth, while at a dose of 0.75 mg/Kg only a weak effect was seen. The efficacy of both treatments was not altered by cicaprost (0.5 mg/Kg; po.) administered in two different schedules. Whereas cyclophosphamide (400 mg/Kg; sc) completely inhibited the growth of the MXT-OVEX tumor, doxorubicin (2.5 mg/kg; sc.) and 5-FU (10 mg/Kg; sc.) had only a weak effect. The combination of cicaprost with either cyclophosphamide, doxorubicin or 5-FU did not alter the inhibition of tumor growth. On the basis of these data, we anticipate that the antimetastatic agent cicaprost can be used in combination with cytostatic regimens without interfering with their clinical effectiveness.

Animals↗