EFFECTS OF THE MODULATING AGENT WR2721 ON MYELOTOXICITY AND ANTITUMOR-ACTIVITY IN CARBOPLATIN-TREATED MICE

The selective modulation of carboplatin 1,1-cyclo-butanedicarboxylato) platinum(II)-induced myelotoxicity was investigated in mice, using the protective agent WR2721 [S-2-(3-aminopropylamino)ethyl-phosphorothioi c acid, ethiofos]. In female BALB/c mice, WR2721 (200 mg/kg intraperit oneally, i.p.) partly prevented the reduction of in vitro proliferatio n of whole bone marrow cells and non-adherent cells when administered at different time points relative to 90 mg/kg carboplatin (i.p.). Prot ection was highest when WR2721 was administered 5 min prior to carbopl atin. In vitro proliferation of whole bone marrow cells and non-adhere nt cells in liquid culture increased from 15% of control for carboplat in alone to 45% when WR2721 was administered 5 min prior to carboplati n. However, WR2721 did not significantly prevent the loss in clonogeni c capacity of early hematopoietic progenitors in the bone marrow, as d etermined by a bilayered soft agar colony forming units assay. In nude mice, bearing well-established subcutaneous human ovarian carcinoma x enografts OVCAR-3, WR2721 (200 mg/kg i.p.) 5 min prior to intravenous carboplatin allowed a 1.5-fold increase in the maximum tolerated dose of carboplatin as determined by overall weight loss. WR2721 alone did not affect tumour growth. However, WR2721 had a potentiating effect on the tumour growth inhibition of a standard dose of carboplatin in thi s model. Minimal tumour volume compared to control (T/C) decreased fro m 9.4% with carboplatin alone to 2.2% with WR2721 5 min prior to the s ame dose of carboplatin. Specific growth delay (SGD) increased from 7. 4 to 10.3. With the 1,5-fold increased, equitoxic dose of carboplatin in combination with WR2721, the antitumour activity was only slightly further increased (T/C = 1.4%, SGD = 10.5).