DEVELOPMENT AND CHARACTERIZATION OF SURAMIN-RESISTANT CHINESE-HAMSTERFIBROSARCOMA CELLS - DRUG-DEPENDENT FORMATION OF MULTICELLULAR SPHEROIDS AND A GREATLY ENHANCED METASTATIC POTENTIAL

Suramin-resistant DC-3F/SU 1000 Chinese hamster fibrosarcoma cells wer e obtained by continuous exposure of parental DC-3F cells to increasin g concentrations of suramin (1 mg/ml final concentration). These cells are 10-fold more resistant to suramin compared to the parental cell l ine as determined by colony formation in the continuous presence of dr ug; the 50% effective dose for DC-3F is 35 mu/ml whereas the 50% effec tive dose for DC-3F/SU 1000 is 380 mu g/ml. The resistance is not due to reduced drug accumulation and is stable for at least 10 months in t he absence of drug. Sensitive and resistant cells show comparable grow th rate, cell size, and DNA content. In the presence of suramin, DC-3F /SU 1000 cells form big multicellular spheroids which regrow as monola yer cultures when the drug is removed. Similar morphological changes a re not observed for sensitive DC-3F cells exposed to isotoxic doses of suramin but appeared early on during the development of resistance. I noculation of DC-3F or DC-3F/SU 1000 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-3 F/SU 1000 cells show extensive and persistent s.c. hemorrhages around the tumor. By 3 weeks, 30% of DC-3F-injected mice (9 of 30) show simil ar to 5 metastases/lung compared to -262 metastases/lung in 100% of DC -3F/SU 1000-inoculated mice (30 of 30). These findings have several im portant implications: (a) given the fact that suramin is currently use d clinically, special precaution may be warranted in patients undergoi ng 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 th erapies; and (c) suramin may serve as a model compound for other molec ules of the antiangiogenic and/or antimetastatic type.