Metoclopramide as a modulator of cisplatin: effects on pharmacokinetcs and cisplatin-DNA adducts in tumor and normal tissue.

Abstract

The antiemetic drug metoclopramide (MCA) has previously been shown to cause DNA damage, to inhibit DNA repair and to enhance the effect of the 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 effect on kidney is of special interest since cisplatin is highly nephrotoxic. Nude mice with xenografted squamous cell carcinoma where injected with cisplatin 5 mg/kg i.p. alone or in combination with MCA 2 mg/kp 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 administration. The efficacy after treatment with cisplatin, MCA or cisplatin + MCA was studied in terms of tumor size measurements during 3 weeks following treatment and our previous observation that MCA enhances the cisplatin cytotoxicity was confirmed. The addition of MCA to cisplatin resulted in a slight increase in serum-platinum concentrations at 9 h and increased levels of adducts in tumors at 24 h. There was a tendency, however, not statistically significant, for increased adducts also in kidney. Thus, our findings may indicate that the sensitization of MCA on the cytotoxicity of cisplatin is mediated by increased formation, maybe accompanied by inhibited repair, of cisplatin-DNA adducts.