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M R Schneider

Publications and source records attributed to M R Schneider.

At least 19 recordsLinked to original sources
PubMed2004

Insulin-like growth factor-binding protein-4 inhibits growth of the thymus in transgenic mice.

Numerous in vitro studies have demonstrated that IGF-binding protein (IGFBP)-4 is a consistent inhibitor of IGF actions. In order to investigate the functions of IGFBP-4 in vivo, transgenic mice were generated by microinjection of a transgene, in which the murine Igfbp4 cDNA is driven by the H-2K(b) promoter, and followed by a splicing cassette and polyadenylation signal of the human beta-globin gene. Transgene mRNA was expressed ubiquitously, and elevated IGFBP-4 protein was detected in the spleen, thymus, kidney and lung of transgenic mice. The activities of serum IGFBPs were not changed in transgenic mice. Immunohistochemical studies revealed transgene expression predominantly in the thymic medulla and red pulp of the spleen. Body weight and the weights of the spleen, kidney and lung of transgenic mice were not different from controls. In contrast, the thymus of transgenic mice showed a significantly reduced weight and cortex volume. In transgenic thymus and spleen, cell proliferation was inhibited and apoptosis was stimulated. Transgenic mice showed normal T- and B-cell development and normal basal plasma immunoglobulin levels. In conclusion, overexpression of IGFBP-4 inhibits growth of the thymus. IGFBP-4 excess inhibits cell proliferation and stimulates apoptosis in lymphoid tissues, but does not affect lymphocyte development. These findings suggest that IGFBP-4 is a potential growth inhibitor of lymphoid tissues.

Animals↗
PubMed2002

IGF-binding protein-5: flexible player in the IGF system and effector on its own.

The multiple activities of IGF-I and -II are modulated by a family of IGF-binding proteins (IGFBP-1 to -6). Although structurally related, each IGFBP has unique properties and exerts specific functions. IGFBP-5 is the most conserved IGFBP across species and was identified as an essential regulator of physiological processes in bone, kidney and mammary gland. In addition, IGFBP-5 appears to play a decisive role in the control of proliferation of specific tumour cell types. In many situations IGFBP5 exerts biological activities in the absence of IGFs, indicating the existence of IGF-independent actions. This concept was supported by the unexpected localisation of IGFBP-5 in the nucleus and the description of IGFBP-5-specific membrane-bound IGFBP-5 receptor(s). The scope of this review is to summarise the available information about the structure of IGFBP-5 and the regulation of its expression. Furthermore, the potential significance of IGFBP-5 in the regulation of physiological processes will be critically analysed in the light of recent experimental data.

Animals↗
PubMed2001

Insulin-like growth factor-binding protein-5 inhibits growth and induces differentiation of mouse osteosarcoma cells.

The precise role of insulin-like growth factor-binding protein-5 (IGFBP-5) in regulating the growth of tumor cells, especially of bone-derived malignant cells, is not well understood. We have investigated the biological activity of IGFBP-5 by transfecting OS/50-K8 mouse osteosarcoma cells with an expression vector containing the osteocalcin promoter and the complete mouse IGFBP-5 cDNA (OC-IGFBP-5). Overexpression of IGFBP-5 mRNA and secretion of increased amounts of bioactive protein in conditioned media were demonstrated in different clones. For the analysis of cell proliferation, three clones exhibiting high levels of IGFBP-5 expression were selected and compared to a mock clone and to nontransfected parental cells. IGFBP-5-secreting clones displayed reduced proliferation under both anchorage-dependent and -independent conditions (P < 0.05). The increase in proliferation observed in IGFBP-5-secreting clones after addition of exogenous IGF was significantly lower than that observed in mock-transfected or parental cells. A similar result was obtained with long[R3]IGF-I which has a low affinity for all IGFBPs, suggesting that the inhibitory effect of IGFBP-5 is only partially IGF-dependent. OC-IGFBP-5-transfected clones expressed significantly higher amounts of osteocalcin mRNA (P < 0.05) and secreted more osteocalcin protein than a mock clone or parental OS-50/K8 cells. Thus, part of the growth-inhibiting effect of IGFBP-5 may be due to an induction of differentiation in these cells.

Animals↗
PubMed2001

Signaling-inactive epidermal growth factor receptor/ligand complexes in intact carcinoma cells by quinazoline tyrosine kinase inhibitors.

Several inhibitors of EGF receptor (EGFR) tyrosine kinase activity have been developed that compete with ATP at its binding site such as the quinazolines PD 153035 and ZD 1839 or the 4,5-dianilino-phthalimides DAPH1 and DAPH2. When tested on human A431 cells, the quinazolines completely blocked EGF-induced receptor phosphorylation at 100 nM, whereas it was inhibited by DAPH1 and DAPH2 by only 20% at 3 microM. Quinazoline-treated A431 as well as tumor cells expressing less EGFR (A549, MDA MB 231, and T47D) bound 3- to 6-fold more (125)I-labeled EGF than untreated intact control cells. Scatchard analysis revealed the disappearance of low- and high-affinity EGFR on A431 cells upon PD 153035 treatment. A single receptor class of intermediate ligand binding affinity emerged and its number corresponded to the sum of the two classes. DAPH1 and DAPH2 did not change ligand binding properties of EGFR. PD 153035 exerted the most potent effects on EGF binding to A431 or on inhibiting EGF-stimulated growth of rat MTLn3 cells at low ligand concentrations. Cross-linking of EGFR on PD 153035-treated A431 cells indicated the formation of inactive dimers that further increased upon addition of EGF. Chemical cross-linking of (125)I-labeled EGF to PD 153035-treated A431 cells revealed increased binding to monomeric and dimeric EGFR. Thus, the quinazolines sequestered EGFR plus the ligand into inactive receptor/ligand complexes. This novel mode of action of quinazoline tyrosine kinase inhibitors may be the basis for their extraordinary potency especially in conditions when the ligand is present in limiting amounts.

Animals↗
PubMed2000

PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.

PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

Angiogenesis Inhibitors↗
PubMed2000

Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon carcinoma cells.

Interleukin-6 (IL-6) is a pleiotropic cytokine which exerts biological activities on various cell types including neoplastic cells. We have investigated the biological effect of IL-6 and the expression of IL-6 receptors (IL-6R) on human colorectal carcinoma cell lines. Isreco-1 was derived from the primary site of a colon cancer while Isreco-2 and Isreco-3 were established from a liver and peritoneal metastasis of the same patient. IL-6 stimulated colony formation in methylcellulose of Isreco-1 cells to 150% (P < 0.05). The effect was even more pronounced on the metastatic Isreco-2 line where colony numbers in the presence of IL-6 were enhanced up to four-fold (P < 0.0001) in a dose-dependent fashion. An anti-IL-6 antibody completely abolished this growth stimulatory effect of IL-6. RT-PCR analysis revealed transcripts for IL-6Ralpha and gp 130 in these cell lines. Experiments with additional cell lines confirmed the general expression of gp130 but showed limited expression of the IL-6Ralpha chain. Surprisingly, about half of the cell lines tested expressed IL-6 mRNA at low levels which was not translated into protein. Our results suggest that IL-6 can potently stimulate anchorage-independent growth of some colorectal carcinoma cells. This stimulation appears to occur through a paracrine mechanism.

Cell Division↗
PubMed2000

Transgenic mouse models for studying the functions of insulin-like growth factor-binding proteins.

The insulin-like growth factor-binding proteins (IGFBPs) comprise a family of six related peptides that interact with high affinity with IGFs. IGFBPs compete with IGF receptors for IGF binding, and as a consequence of this competition they can affect cell growth. In addition, IGF-independent regulatory mechanisms of IGFBPs have been described. Despite their common property to interact with IGFs every IGFBP is expressed in a tightly regulated time- and tissue-specific manner suggesting that each protein may have its own distinct functions. Several transgenic mouse models overexpressing IGFBP-1, -2, -3, or -4 were developed in the past few years. Brain abnormalities were a common feature of IGFBP-1 transgenic models. Individual strains showed alterations in glucose homeostasis, reproductive performance, and a reduction of somatic growth as the most prominent phenotypes. The latter was also the main effect observed in IGFBP-2 transgenic mice. The overexpression of IGFBP-3 under the control of an ubiquitous promoter resulted in selective organomegaly, whereas mammary gland-targeted expression of this protein caused an altered involution after pregnancy in this organ. Tissue-specific overexpression of IGFBP-4 resulted in hypoplasia and reduced weight of smooth muscle-rich tissues such as bladder, aorta, and stomach. This review summarizes the current knowledge about the actions of IGFBPs in vivo based on the presently established transgenic mice.

Animals↗
PubMed1999

Differential cross-talk of estrogen and growth factor receptors in two human mammary tumor cell lines.

Cultured human mammary MCF7 and T47D tumor cell lines were used to test the interference of the partial antiestrogen 4'-hydroxytamoxifen (4-OH-TAM) and the pure antiestrogen ZM 182780 with growth factor (IGF-I, heregulin) signaling pathways. Growth of both cell lines was stimulated by IGF-I (20 ng/ml) or heregulin (3 nM). ZM 182780 effectively blocked growth factor induced as well as basal proliferation of MCF7 cells while the compound was ineffective in interfering with growth factor mitogenic activity in T47D cells. On both cell lines the IGF-I or heregulin- induced proliferation was enhanced further by 4-OH-TAM. This synergism could be inhibited dose-dependently by ZM 182780. When cells were grown in the presence of estradiol plus growth factors, the antiestrogenic potencies of both compounds and the efficacy of ZM 182780 were unaffected, while the efficacy of 4-OH-TAM was reduced. Our data show cell type specific cross-talk between the receptor for estrogen and that for IGF-I or heregulin, which is different in MCF7 and T47D cells, respectively. In MCF7 cells with demonstrable cross-talk, a clear superiority exists for a pure antiestrogen over a partial agonist in interfering with growth factor mitogenic activity.

Breast Neoplasms↗
PubMed1999

Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system.

Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R1881), whereas 0.01 nM of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the first time that the nonsteroidal anti-androgen bicalutamide acquires agonistic properties during long-term androgen ablation. These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention.

Androgen Antagonists↗
PubMed1998

Estrogenic regulation of clusterin mRNA in normal and malignant endometrial tissue.

Clusterin is a heterodimeric, 80kDa, glycoprotein that is synthesized in a wide variety of tissues in response to a number of diverse stimuli, including hormone ablation. We have investigated the regulation of clusterin expression by estradiol and anti-estrogens in RUCA-I rat endometrial adenocarcinoma cells in vitro and in vivo. We have also compared clusterin expression in endometrial tumors and in normal uterine tissue. Estradiol treatment significantly increases the steady state mRNA levels of clusterin in RUCA-I cells cultured on a reconstituted basement membrane, with a maximal induction 24 hr after estradiol treatment. The inductive effects of estrogen on clusterin mRNA steady state levels in vitro are significantly more pronounced than the effects on fibronectin mRNA levels, an estrogen-repressed gene in RUCA-I. In vivo, induction of clusterin expression in primary and metastatic endometrial adenocarcinoma is also dependent on the presence of estradiol, in marked contrast to expression of clusterin in the normal endometrium of the same animals. These data suggest that clusterin mRNA expression in rat endometrial adenocarcinoma cells is tightly regulated by estrogens and anti-estrogens in vitro and in vivo, and that there is a complex mechanism of regulation of clusterin expression in the normal and cancerous endometrium.

Adenocarcinoma↗
PubMed1998

Negative cooperativity between alpha 3 beta 1 and alpha 2 beta 1 integrins in human mammary carcinoma MDA MB 231 cells.

The alpha 3 beta 1 integrin has been implicated as a receptor for several matrix components, including collagen, fibronectin, and laminins. The function of alpha 3 beta 1 seems to be very versatile involving cell adhesion to or migration on ECM, establishment of cell-cell contacts in aggregates, as well as linkage to intracellular tyrosine phosphorylation cascades. Here we report a strong induction of attachment of alpha 3 beta 1 integrin expressing human breast carcinoma cell line MDA MB 231 to matrix proteins by two alpha 3 integrin subunit function-blocking monoclonal antibodies (P1B5 and ASC-1). In contrast, stimulation of adhesion to ECM by inhibitory alpha 3 integrin-specific antibodies was not observed in the alpha 3 beta 1 integrin-expressing nonmalignant human mammary epithelial cell line MCF-10A or the human breast carcinoma cell line MDA MB 468 that expressed relatively low amounts of alpha 3 beta 1 integrin at the cell surface. This increase was specific for collagens and not observed on fibronectin or laminin. Physiological concentrations of bivalent cations were not required. MAb P1B5 did not induce homotypic aggregation of MDA MB 231 cells. The P1B5-induced increase in cell attachment to collagens could be prevented but not reduced below control levels by blocking mAb to the alpha 2 integrin subunit. Function blocking anti-alpha 5 integrin subunit mAb was without effect while anti-beta 1-mAb completely abolished adhesion. Our data indicate that negative cooperativity between integrins results in transdominant inhibition of alpha 2 beta 1 function by alpha 3 beta 1 in human MDA MB 231 but not MDA MB 468 tumor cells or nonmalignant MCF-10A cells.

Antibodies, Monoclonal↗
PubMed1998

Tumor metastasis inhibition with the prostacyclin analogue cicaprost depends on discontinuous plasma peak levels.

Stable prostacyclin analogues exert a strong inhibitory effect on lymphogenous as well as haematogenous tumor metastasis in a series of tumor lines. The strong inhibition of metastasis was achieved by repeated once-daily i.g. applications. The mechanism of antimetastatic action is related to the expression of functional IP-receptors (PGI-receptors). As cellular assay systems indicated that the IP-receptor mediated signalling is down-regulated upon continuous exposure to prostacyclin or stable derivatives, it has been questioned whether a mode of drug application with constant plasma drug levels may potentially result in a decrease of the antimetastatic effect. We addressed this question using the stable prostacyclin analogue cicaprost in a disease model by comparing i.g. applications given once daily with a continuous administration of equivalent doses via drinking water. Very similar to our previous investigations in the 13762NF MTLn3 rat mammary carcinoma model, cicaprost administered by i.g. application strongly reduced lung and lymph node metastasis. In contrast, administration of equivalent doses via drinking water leading to lower but constant steady-state plasma levels failed to exert inhibitory effects. Plasma and urine levels of cicaprost were measured with a sensitive radioimmunoassay on the last treatment day. Pharmacokinetic evaluation demonstrated a similar bioavailability of cicaprost in both groups. This result first demonstrates a treatment failure of a prostacyclin derivative in a chronic disease model in association with a continuous drug administration leading to constant plasma levels. A desensitization of receptor signalling by constant plasma levels may be a possible mechanism for treatment failure.

Administration, Oral↗
PubMed1998

Antiangiogenic chemotherapeutic agents: characterization in comparison to their tumor growth inhibition in human renal cell carcinoma models.

The mechanism of action of anticancer chemotherapeutic agents is mainly thought to be due to a direct inhibition of tumor cell proliferation. The enhanced endothelial cell proliferation rate in tumor specimens raised the question of whether therapeutic effects of chemotherapeutic agents might be at least partially attributed to inhibition of tumor angiogenesis. In the present study, we investigated the potential effects of chemotherapeutic agents on human renal carcinoma angiogenesis with the alginate implantation model in mice. For the first time, we also compared results from the angiogenesis model with the inhibitory effects on growth of s.c. xenografts in nude mice. Vincristine and bleomycin exerted strong inhibition of tumor angiogenesis in both carcinoma lines close to the level of the standard antiangiogenic agent O-chloroacetyl-carbamyl-fumagillol (AGM-1470; T/C 22%). Adriamycin reduced angiogenesis of Caki-2 cells (T/C 33%) but had no effect on Caki-1 angiogenesis (T/C 137%). Etoposide and 5-fluorouracil reduced Caki-1 tumor angiogenesis but had no effect on Caki-2. Despite antiangiogenic effects in both carcinoma lines, vincristine, bleomycin, and AGM-1470 significantly reduced only the growth of fast-growing Caki-1 s.c. xenografts but not the slow-growing Caki-2. Antivascular effects by bleomycin and AGM-1470 were also shown by a decrease of microvessel density in nude mouse xenografts. Our findings suggest that chemotherapeutic agents may exert inhibition of tumor angiogenesis, which could be exploitable by combination therapy of fast-growing tumors. The resistance of the slow-growing Caki-2 carcinoma against acute angiogenesis inhibition indicates a need for well-tolerated angiogenesis inhibitors. Our results also suggest the use of fast-growing s.c. xenografts for demonstrating growth inhibition by antiangiogenic compounds. Further characterization of antiangiogenic compounds considered for clinical application should, however, have its focus on slow-growing tumors, which are not accessible for most therapeutic strategies.

Animals↗
PubMed1998

Novel steroid-linked conjugates of 17 beta-[N-[N'-(2-chloroethyl)-N'-nitroso]carbamoyl]amino acids and their antineoplastic activity against Noble Nb prostate carcinoma model in rats.

The novel steroid conjugates 17 beta-[N-[N'-(2-chloroethyl)-N'-nitroso] carbamoyl]-glycyl-19-nortestosterone (1) and 17 beta-[N-[N'-(2-chloroethyl)-N'-nitroso]carbamoyl]-L-alyanyl-19- nortestosterone (2) were synthesized and characterized with respect to affinity for steroid receptors and for androgenic efficacy. At an i.p. dosage of 50 mg/kg, conjugates 1 and 2 induced strong tumor inhibition of Nobel Nb prostate carcinoma in rats, but also a marked loss of body weight. In two further experiments, treatment with conjugate 2 at a dosage of 25 mg/kg demonstrated high antitumor activity without indication of toxicity. Conjugate 2 achieved the same tumor growth inhibition as a nearly twofold molar dose of cyclophosphamide. The results indicate reproducibly high antitumor activity of 2 in the Noble Nb model at a well tolerated dosage. A low dose equimolar mixture of unlinked N-(2-chloroethyl)-N-nitrosocarbamoyl (CNC)-alanine and 19-nortestosterone was significantly more toxic than conjugate 2, showing about the same adverse effect on the body weight as the conjugate at high dosage. CNC-L-alanine at equimolar dosage was highly toxic, causing early death of all animals.

Amino Acids↗
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↗