Potentiation of vincristine by vitamin A against drug-resistant mouse leukaemia cells.

I Nogae,M Kuwano,N Shiraishi,T Yamaguchi,M Nakagawa,J Kikuchi

doi:10.1038/bjc.1987.188

Abstract

Vitamin A has been shown to potentiate the cytotoxic action of anticancer agents like vincristine (VCR) against drug resistant mouse P388 leukaemia cells. In vitro tests showed enhancement by retinyl acetate of cytocidal activities of VCR against drug-sensitive leukaemia (P388/S) and VCR-resistant leukaemia (P388/VCR) cells in culture; retinyl acetate rather specifically potentiated VCR against cultured P388/VCR cells than P388/S cells. The cellular accumulation of radioactive VCR was significantly enhanced in cultured P388/VCR cells when retinyl acetate was present. The efflux of VCR from drug-resistant cells was blocked by retinyl acetate. The effect of the combination of vitamin A and VCR was also tested in vivo on the life-span of mice bearing P388/S or P388/VCR. Intraperitoneal administration of retinyl palmitate at 41.75 or 83.5 mg kg-1 was effective to potentiate the antileukaemic activity of VCR against P388/S bearing mice, and it also overcame vincristine-resistance in P388/VCR bearing mice.

Highlights

P388/VCR is established by repeated administration of VCR to P388 leukaemia cells (P388/S) leukaemia bearing mice (Inaba & Johnson, 1978)
We examined the effect of VCR alone or with retinyl acetate (RA) on growth of P388/S and P388/VCR when treatment for 3 h with drugs was performed in the presence of serum
Differences in drug sensitivity to VCR was observed between P388/S and P388/VCR: P388/S cell growth was inhibited 50% by 50 ng VCR ml-1, whereas growth of P388/VCR was inhibited by 50% at 2,000 ng VCR ml- 1 (Figure la)

Summary

Methods

Cell line and cell cultureP388/S, and its resistant subline P388/VCR, were obtained from Dr M. Inaba (Cancer Chemotherapy Cancer, Japanese Foundation for Cancer Research, Tokyo, Japan). This resistant subline was developed by in vivo treatment of drugsensitive P388 leukaemia cells (P388/S) with VCR (Inaba et al, 1979). Both sublines were passaged weekly by i.p. inoculation in BALB/c x DBA/2 (CDFl) mice The relative resistance of each cell line to anticancer agents was confirmed for each assay because the phenotype of resistance is relatively unstable under in vitro conditions. Kuwano Received 27 November 1986; and in revised form, 14 April 1987

Results

Discussion

Conclusion