Possible role of P-glycoprotein in cyclophosphamide resistance of transplanted mouse RLS lymphosarcoma

The causes of different sensitivity of mouse LS lymphosarcoma and its resistant RLS variant to cyclophosphamide were studied. Division of LS and RLS cells stops in the G2/M phase 24 h after cyclophosphamide treatment, but this stop lasts for more than 48 h in LS cells and less than 24 h in RLS cells. DNA fragmentation, a marker of apoptosis, is observed only in LS cells starting from 24 h after cyclophosphamide treatment. LS and RLS strains do not differ by the expression of bcl-2, bcl-6, bax, bad, mdr1a, mdr1b genes and P-glycoprotein protein. The strains differ by transport activity of P-glycoprotein, tested by SYTO 16 substrate release from cells: activity of P-glycoprotein in RLS cells was 2-fold higher than in LS cells. Presumably, the resistance of RLS tumor to cyclophosphamide-induced apoptosis is a result of inhibition of the apoptotic cascade by P-glycoprotein which is functionally more active in these cells than in LS cells.