Enhancement of the nuclear reactivity of alkylating agents by prednisolone

We have compared the nuclear reactions of the alkylating agents chlorambucil, melphalan, and cyclophosphamide used alone, with those produced when the same drugs were used in combination with the corticosteroid prednisolone. Studies were performed in vivo in Wistar rats bearing ascites forms of either the Yoshida sarcoma or the Walker carcinosarcoma. Strains of both tumor lines, which were sensitive to alkylating agents, showed loss of condensed chromatin, increased phosphorylation of nuclear proteins, and increased DNA cross-linking after exposure to the alkylating agents alone; these changes were generally enhanced in the presence of prednisolone. When paired tumor lines which exhibited acquired resistance to alkylating agents were studied, no nuclear changes were detected when individual alkylating agents were given alone. However, in combination with prednisolone, each of the three alkylating agents produced loss of condensed chromatin, increased nuclear protein phosphorylation, and DNA cross-linking. These chromatin changes were associated with tumor cell death and may determine drug sensitivity in the tumors studied.