title: Effects of AGM-1470 and pentosan polysulphate on tumorigenicity and metastasis of FGF-transfected MCF-7 cells.
abstract: Previously, we described FGF-1- or FGF-4-transfected MCF-7 breast carcinoma cells which are tumorigenic and metastatic in untreated or tamoxifen-treated ovariectomised nude mice. In this study, we have assessed the effects of AGM-1470, an antiangiogenic agent, and pentosan polysulphate (PPS), an agent that abrogates the effects of FGFs, on tumour growth and metastasis produced by these FGF-transfected MCF-7 cells. Untreated or tamoxifen-treated ovariectomised mice were injected with FGF-transfected cells, treated with AGM-1470 or PPS, and tumour growth and metastasis analysed. The sensitivity of FGF-transfected and parental MCF-7 cells to AGM-1470 or PPS was also determined in vitro. Both AGM-1470 and PPS inhibited tumour growth in otherwise untreated or tamoxifen-treated mice injected with either FGF- or FGF-4-transfected MCF-7 cells. This effect was more reliably seen in tamoxifen-treated animals. AGM-1470 was about 10(5) times less potent in inhibiting the anchorage-dependent growth of parental MCF-7 or FGF-transfected MCF-7 cells than in inhibiting the growth of human umbilical vein endothelial cells. PPS did not affect the in vitro growth of the transfectants or parental cells. Thus, the growth-inhibitory effect on tumours was in excess of the effect of either drug on the same cells in tissue culture, implying that stromal elements are important determinants of the effects of these drugs. There was a positive correlation between tumour size and the extent of proximal lymph node metastasis. However, neither drug had a significant effect on the extent of metastasis to proximal or distal lymph nodes or lungs. AGM-1470 or PPS may be helpful in cases of breast carcinoma in which angiogenesis is due to expression of FGFs by the tumour cells and may be more effective when combined with tamoxifen.
authors.affiliation: Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: McLeskey
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: B J
authors.initials: BJ
authors.lastname: Trock
authors.forename: S
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: M M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: M E
authors.initials: ME
authors.lastname: Lippman
authors.forename: F G
authors.initials: FG
authors.lastname: Kern
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003510:Cyclohexanes; D004343:Drug Implants; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000096:biosynthesis / Q000502:physiology*; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013629:Tamoxifen / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D003510:Cyclohexanes; D004343:Drug Implants; C496445:FGF4 protein, human; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D013629:Tamoxifen; D016220:Fibroblast Growth Factor 1; D010426:Pentosan Sulfuric Polyester; D005346:Fibroblast Growth Factors; D000077609:O-(Chloroacetylcarbamoyl)fumagillol