Antitumor and Cellular Pharmacological Properties of a Novel Platinum(IV) Complex:trans-[PtCl2(OH)2(Dimethylamine) (Isopropylamine)]

The antitumor and cellular pharmacological properties of the trans -Pt(IV) complex, trans -[PtCl 2 (OH) 2 (dimethylamine)(isopropylamine)] (compound 2 ) has been evaluated in comparison with its corresponding trans -Pt(II) counterpart, trans -[PtCl 2 (dimethylamine)(isopropylamine)] (compound 1 ). The results reported here indicate that compound 2 markedly circumvents cisplatin resistance in 41McisR and CH1cisR ovarian tumor cell lines endowed with different mechanisms of resistance (decreased platinum accumulation and enhanced DNA repair/tolerance, respectively). However, compound 1 is able to circumvent cisplatin resistance only in CH1cisR cells. Interestingly, at equitoxic concentrations, compounds 1 and 2 induce a higher amount of apoptotic cells than cisplatin in CH1cisR cells. Moreover, the number of apoptotic cells induced by compounds 1 and 2 correlates with their ability to form DNA interstrand cross-links in CH1cisR cells. Although compounds 1 and 2 showed remarkable cytotoxic activity, only compound 2 was able to inhibit the growth of CH1 human ovarian carcinoma xenografts in mice. Binding studies with serum albumin indicate that compound 1 possesses a much higher reactivity against albumin than compound 2 . Moreover, the level of binding of compound 1 to plasma proteins during the period 15 min to 1 h after administration to mice (15 mg/kg, i.p.) is 2.5-fold higher than that of compound 2. Therefore, the lack of in vivo antitumor activity shown by compound 1 might be related to its extracellular inactivation before reaching the tumor site because of its high rate of binding to plasma proteins.