Development and characterization of suramin-resistant Chinese hamster fibrosarcoma cells: drug-dependent formation of multicellular spheroids and a greatly enhanced metastatic potential.
Suramin-resistant DC-3F/SU 1,000 Chinese hamster fibrosarcoma cells were obtained by continuous exposure of parental DC-3F cells to increasing concentrations of suramin (1 mg/ml final concentration). These cells are 10-fold more resistant to suramin compared to the parental cell line as determined by colony formation in the continuous presence of drug; the 50% effective dose for DC-3F is 35 micrograms/ml whereas the 50% effective dose for DC-3F/SU 1,000 is 380 micrograms/ml. The resistance is not due to reduced drug accumulation and is stable for at least 10 months in the absence of drug. Sensitive and resistant cells show comparable growth rate, cell size, and DNA content. In the presence of suramin, DC-3F/SU 1,000 cells form big multicellular spheroids which regrow as monolayer cultures when the drug is removed. Similar morphological changes are not observed for sensitive DC-3F cells exposed to isotoxic doses of suramin but appeared early on during the development of resistance. Inoculation of DC-3F or DC-3F/SU 1,000 cells s.c. into nude mice results in 100% tumor take within 1 week for both groups. Although the tumor size increases at the same rate, only animals given injections of DC-3F/SU 1,000 cells show extensive and persistent s.c. hemorrhages around the tumor. By 3 weeks, 30% of DC-3F-injected mice (9 of 30) show approximately 5 metastases/lung compared to -262 metastases/lung in 100% of DC-3F/SU 1,000-inoculated mice (30 of 30). These findings have several important implications: (a) given the fact that suramin is currently used clinically, special precaution may be warranted in patients undergoing suramin treatment; (b) the drug may possess an unusual potential to interfere with processes essential to invasion and metastasis which, when properly used, may result in the development of antimetastatic therapies; and (c) suramin may serve as a model compound for other molecules of the antiangiogenic and/or antimetastatic type.
Department of Molecular Pharmacology, Centre National de la Recherche Scientifique URA 147, Institut Gustave Roussy, Villejuif, France.
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Lelièvre
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Larsen
D000818:Animals; D002448:Cell Adhesion; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004351:Drug Resistance; D005354:Fibrosarcoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D006470:Hemorrhage / Q000209:etiology; D007621:Karyotyping; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D013498:Suramin / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D013498:Suramin