Effects of the modulating agent WR2721 on myelotoxicity and antitumour activity in carboplatin-treated mice.
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).
Treskes
M
M
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Boven
E
E
van de Loosdrecht
A A
AA
Wijffels
J F
JF
Cloos
J
J
Peters
G J
GJ
Pinedo
H M
HM
van der Vijgh
W J
WJ
D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D016190:Carboplatin / Q000627:therapeutic use* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy
D016190:Carboplatin; D004999:Amifostine