BIOCHEMICAL-MECHANISMS OF RESISTANCE TO A NEW ANTITUMOR DRUG AMINE(CYCLOPENTYLAMINE)-S-(-)-MALATOPLATINUM (II) (CYCLOPLATAM)

The in vivo effect of cycloplatam on DNA synthesis was studied in P388/o (parent strain) and P388/c (cycloplatam-resistant strain) leukemia cells and in some organs of tumor-bearing mice (e.g., spleen, kidney, small intestine epithelium, and bone marrow). Cycloplatam induced a profound-and stable inhibition of DNA synthesis in leukemia cells and kidney. DNA synthesis in normal dividing cells (small intestine epithelium, bone marrow, spleen) recovered more rapidly than in leukemia cells and kidney after cycloplatam treatment. The glutathione level was increased tenfold in P388/c versus P388/o leukemia cells. Glutathione peroxidase and glutathione reductase activities were increased twofold in resistant versus parent strain, while the activity of glutathione-S-transferase showed a 1.5-fold increase. Cycloplatam administration to tumor-bearing mice markedly increased the glutathione level in tumor cells of both strains. Changes in glutathione-dependent enzymes following cycloplatam therapy were less expressed. The data suggest that glutathione and glutathione-dependent enzymes may play an important role in resistance of P388 leukemia cells to cycloplatam.