Antiplatelet pyrimido-pyrimidines and metastasis

Lichtner, Rosemarie B.; Hutchinson, Gillian; Wedderburn, Nina; Hellmann, K.

doi:10.1016/0305-7372(85)90006-4

Cited by 18 publications

(11 citation statements)

References 32 publications

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“…Another class of drugs that interferes with the organization of the tumor cell cytoskeleton [25,26] and reduces metastases in some animal tumor systems [23,24] are the pyrimido-pyrimidines, which were originally developed as antiplatelet drugs. The antimetastatic effects of the pyrimidopyrimidines have been inconsistent [23,24]. These drugs can inhibit in a dosedependent manner the adherence of circulating tumor cells to the endothelium of mesenteric blood vessels [8,9].…”

Section: Introductionmentioning

confidence: 99%

Effects of the pyrimido-pyrimidine derivative RX-RA 85 on metastatic tumor cell-vascular endothelial cell interactions

Lichtner

Nicolson

1987

Clin Exp Metast

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An important step in the metastatic process is the interaction of blood-borne malignant cells with the vascular endothelium. Among the agents that may interfere with this process are pyrimido-pyrimidines, such as RX-RA 85, developed originally as an antiplatelet agent. Using an endothelial cell momolayer attachment assay we have investigated the effects of RX-RA 85 on tumor cell and endothelial cell properties. Exposure of bovine aortic endothelial cells for 3 h to greater than 4 micrograms/ml RX-RA 85 produced toxic effects, resulting in vacuole formation, retraction and finally rounding up of the cells. Endothelial cells derived from different sources behaved dissimilarly; human brain, human meninges, mouse brain, mouse lung and rat lung endothelial cells were less sensitive to drug treatment than bovine aortic endothelial cells. RX-RA 85 treatment of bovine aortic endothelial cells increased B16-F1 melanoma cell adhesion. When B16-F1 cells were exposed to 4-8 micrograms/ml RX-RA 85, increased adhesion to the subendothelial matrix occurred, whereas exposure to higher drug concentrations (8-16 micrograms/ml RX-RA 85) decreased adhesion. Indirect immunofluorescence staining of cytoskeletal structures in B16-F1 cells adhering to and spreading on matrix revealed that the differential effects of RX-RA 85 on the organization of microtubules and microfilaments might explain the dose-dependent differences in adhesion kinetics.

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Section: Introductionmentioning

confidence: 99%

Effects of the pyrimido-pyrimidine derivative RX-RA 85 on metastatic tumor cell-vascular endothelial cell interactions

Lichtner

Nicolson

1987

Clin Exp Metast

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“…As Lichtner et aI. [29] have demonstrated, the median number of lung metastases in animals bearing mammary fat pad implanted MTLn3 cell clone was decreased by the use of RA 233, although this decrease was not statistically significant. Since the primary tumour was, however, removed 14 days after implantation (mean tumour weight about 50 rag), it is difficult to compare the effects of RA 233 with those of Cicaprost reported in this study.…”

Section: Discussionmentioning

confidence: 67%

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

Schirner¹,

Lichtner²,

Schneider³

1994

Clin Exp Metast

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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.

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“…However, correlations have been reported in a rat renal sarcoma [23], a mouse fibrosarcoma [3,9,10], and in some independently derived B16 melanoma cell lines platelet aggregation appeared to play an important role, as an inverse relationship was found between metastasis and the production of prostaglandin D2, an inhibitor of platelet aggregation [27]. Conflicting results have been reported on the effect of another inhibitor of platelet aggregation, RA233, tested in different assays on a panel of rodent tumours [19]. Conflicting results have been reported on the effect of another inhibitor of platelet aggregation, RA233, tested in different assays on a panel of rodent tumours [19].…”

Section: Discussionmentioning

confidence: 99%

Comparison of metastatic cell lines derived from a murine mammary tumour, and reduction of metastasis by heparin

et al. 1988

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A murine mammary carcinoma, which had a high potential for metastasis to the lungs, was established in culture, and from the parent line several clonally derived variants were isolated, showing different characteristics including metastatic potential. C1, a high metastatic clone, and C2, a low one, were selected for further study. When tumour cells were injected s.c. the growth rates of the resulting tumours were higher when they developed from the parent line (P2) or C1 cells, than from C2 cells. The numbers of lung colonies seen following i.v. inoculation of tumour cells also varied, C2 cells yielding the lowest score. In vitro C1 cells were more efficient at aggregating platelets than C2, an effect reduced by the addition of heparin. In vivo heparin reduced the number of tumour cells arrested in the lungs after i.v. injection, and also the number lung colonies which subsequently became established. The number of metastases which developed following s.c. injection of tumour cells was also reduced by heparin.

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Antiplatelet pyrimido-pyrimidines and metastasis

Cited by 18 publications

References 32 publications

Effects of the pyrimido-pyrimidine derivative RX-RA 85 on metastatic tumor cell-vascular endothelial cell interactions

Effects of the pyrimido-pyrimidine derivative RX-RA 85 on metastatic tumor cell-vascular endothelial cell interactions

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

Comparison of metastatic cell lines derived from a murine mammary tumour, and reduction of metastasis by heparin

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