Abstract
The cytotoxic effects in vivo of hydroxyurea (HU) on murine fibrosarcoma (FSa) cells grown as pulmonary tumours were determined. Tumour cells from 13-day-old nodules were made into suspension and separated on the basis of cell size by centrifugal elutriation. Flow microfluorometry (FMF) was used to determine the cell-cycle parameters and the relative synchrony of the separated populations, as well as the degree of contamination by normal diploid cells in each of the tumour-cell populations. HU cytotoxicity was tested by administering both a single 1 mg/g i.p. dose into mice that had been injected i.v. 20 min earlier with known numbers of synchronized viable FSa cells, and i.p. doses of 1 mg/g each into mice bearing 13-day-old pulmonary nodules. In the latter experiments, animals were killed 1 h after the last dose, and the tumour nodules were excised and made into a single-cell suspension and elutriated. Known numbers of cells from each fraction were injected into recipient mice to determine survival. In both sets of experiments, cell killing by HU correlated with the percentage of S-phase cells. The treatment of 13-day-old pulmonary nodules with 3 doses of HU also depleted the (G2+M) phase tumour cells and increased the heterogeneity between tumour subpopulations, as determined by FMF analysis.
Highlights
Summary.-The cytotoxic effects in vivo of hydroxyurea (HU) on murine fibrosarcoma (FSa) cells grown as pulmonary tumours were determined
The method of centrifugal elutriation has been applied to separate murine fibrosarcoma (FSa) cells from pulmonary tumour nodules grown in C3H mice
Centrifugal elutriation has been successfully used to separate and isolate populations of FSa tumour cells enriched in G1, S or (G2 + M) phases following growth in vitro (Grdina et al, 1978b, 1979) it has not been effective for synchronizing FSa cells derived directly from solid tumours growing in vivo (Grdina et al, 1977, 1978b)
Summary
Summary.-The cytotoxic effects in vivo of hydroxyurea (HU) on murine fibrosarcoma (FSa) cells grown as pulmonary tumours were determined. HU cytotoxicity was tested by administering both a single 1 mg/g i.p. dose into mice that had been injected i.v. 20 min earlier with known numbers of synchronized viable FSa cells, and i.p. doses of 1 mg/g each into mice bearing 13-day-old pulmonary nodules In the latter experiments, animals were killed 1 h after the last dose, and the tumour nodules were excised and made into a single-cell suspension and elutriated. This was accomplished by a 48h in vitro incubation (Grdina et al, 1978a) To avoid this limitation, the method of centrifugal elutriation has been applied to separate murine fibrosarcoma (FSa) cells from pulmonary tumour nodules grown in C3H mice. Hydroxyurea (HU), because of its well characterized S-phase-specific cytotoxicity (Kim et al, 1967; Sinclair, 1967), was chosen to demonstrate the applicability of this procedure to characterizing the in vivo effectiveness of phasespecific chemotherapeutic agents on advanced metastatic disease
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