Effects of the modulating agent WR2721 on myelotoxicity and antitumour activity in carboplatin-treated mice

Abstract

The selective modulation of carboplatin [diammine(1,1-cyclo-butanedicarboxylato)platinum(II)]-induced myelotoxicity was investigated in mice, using the protective agent WR2721 [ S-2-(3-aminopropylamino)ethyl-phosphorothioic acid, ethiofos]. In female BALB c mice, WR2721 (200 mg/kg intraperitoneally, i.p.) partly prevented the reduction of in vitro proliferation of whole bone marrow cells and non-adherent cells when administered at different time points relative to 90 mg/kg carboplatin (i.p.). Protection was highest when WR2721 was administered 5 min prior to carboplatin. In vitro proliferation of whole bone marrow cells and non-adherent cells in liquid culture increased from 15% of control for carboplatin alone to 45% when WR2721 was administered 5 min prior to carboplatin. However, WR2721 did not significantly prevent the loss in clonogenic capacity of early hematopoietic progenitors in the bone marrow, as determined by a bilayered soft agar colony forming units assay. In nude mice, bearing well-established subcutaneous human ovarian carcinoma xenografts 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 this model. Minimal tumour volume compared to control ( T C ) decreased from 9.4% with carboplatin alone to 2.2% with WR2721 5 min prior to the same 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).