A. Johnsson et al., METOCLOPRAMIDE AS A MODULATOR OF CISPLATIN - EFFECTS ON PHARMACOKINETICS AND CISPLATIN-DNA ADDUCTS IN TUMOR AND NORMAL TISSUE, Anti-cancer drugs, 7(4), 1996, pp. 483-488
The antiemetic drug metoclopramide (MCA) has previously been shown to
cause DNA damage, to inhibit DNA repair and to enhance the effect of t
he chemotherapeutic agent cisplatin, Cisplatin acts by binding to DNA
and thus forming cisplatin-DNA adducts, The present study was designed
to investigate whether MCA affects the pharmacokinetics of cisplatin
and the levels of cisplatin-DNA adducts in tumor and kidney, The effec
t on kidney is of special interest since cisplatin is highly nephrotox
ic. Nude mice with xenografted squamous cell carcinoma where injected
with cisplatin 5 mg/kg i.p. alone or in combination with MCA 2 mg/kg i
.p. MCA was given 8 h after cisplatin. Total platinum was measured in
serum and cisplatin-DNA adducts were analyzed in tumor and kidney with
quantitative immunohistochemistry at 1, 9 and 24 h after cisplatin ad
ministration, The efficacy after treatment with cisplatin, MCA or cisp
latin + MCA was studied in terms of tumor size measurements during 3 w
eeks following treatment and our previous observation that MCA enhance
s the cisplatin cytotoxicity was confirmed, The addition of MCA to cis
platin resulted in a slight increase in serum-platinum concentrations
at 9 h and in increased levels of adducts in tumors at 24 h, There was
a tendency, however, not statistically significant, for increased add
ucts also in kidney. Thus, our findings may indicate that the sensitiz
ation of MCA on the cytotoxicity of cisplatin is mediated by increased
formation, maybe accompanied by inhibited repair, of cisplatin-DNA ad
ducts.