Cisplatin is a highly active anticancer agent with an important role in clinical chemotherapy. Cisplatin has limitations, however, as its use is accompanied by significant toxicity, and it is subject to natural and acquired tumor resistance. The discovery of platinum complexes for clinical use complementary or superior to cisplatin is a realistic, yet unfulfilled, research objective. Of a series of 1,2-diaminocyclohexaneiminodiacetatoplatinum(II) complexes synthesized as a part of continuing research at the Vermont Regional Cancer Center, two complexes have been selected for further development on the basis of preclinical evidence for favorable antitumor activity, toxicity, and chemical characteristics in comparison with cisplatin. Preclinical investigations are proposed to characterize the activity, toxicity mechanisms of activation and action, and pharmacokinetics and distribution of these complexes and to compare them in these features to cisplatin and CBDCA. Results of these studies will (1) facilitate introduction of these promising new complexes into clinical investigation, and (2) elucidate structure-activity relations for this class of agents. Activity will be studied with the in vitro and in vivo use of tumor cell lines sensitive and resistant to cisplatin and other platinum complexes. Toxicity studies will evaluate for end-organ effects. Mechanisms of activation will be studied with HPLC, FAAS, and radioisotopic analytic methods applied to complexes in chemical and biologic systems. Mechanisms of action will be studied by analysis of DNA-platinum interactions using FAAS, the DNA alkaline elution technique, and an ELISA for platinum-DNA adducts. The pharmacokinetics of parent drug and, potentially, of important metabolites, and distribution of platinum adducts will be studied using animal and cellular systems. Comparative studies with cisplatin and CBDCA in sensitive and resistant tumor systems will address specific issues of structure-activity relations for this class of agents using methodologies developed. Similar comparative studies of end-organ toxic effects will be performed.
| Roberts, J D; Van Houten, B; Qu, Y et al. (1989) Interaction of novel bis(platinum) complexes with DNA. Nucleic Acids Res 17:9719-33 |
