PT - JOURNAL ARTICLE AU - José M. Pérez AU - Lloyd R. Kelland AU - Eva I. Montero AU - Frances E. Boxall AU - Miguel A. Fuertes AU - Carlos Alonso AU - Carmen Navarro-Ranninger TI - Antitumor and Cellular Pharmacological Properties of a Novel Platinum(IV) Complex:<em>trans</em>-[PtCl<sub>2</sub>(OH)<sub>2</sub>(Dimethylamine) (Isopropylamine)] AID - 10.1124/mol.63.4.933 DP - 2003 Apr 01 TA - Molecular Pharmacology PG - 933--944 VI - 63 IP - 4 4099 - http://molpharm.aspetjournals.org/content/63/4/933.short 4100 - http://molpharm.aspetjournals.org/content/63/4/933.full SO - Mol Pharmacol2003 Apr 01; 63 AB - The antitumor and cellular pharmacological properties of thetrans-Pt(IV) complex,trans-[PtCl2(OH)2(dimethylamine)(isopropylamine)] (compound 2) has been evaluated in comparison with its corresponding trans-Pt(II) counterpart,trans-[PtCl2(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 and2 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 1might be related to its extracellular inactivation before reaching the tumor site because of its high rate of binding to plasma proteins. The American Society for Pharmacology and Experimental Therapeutics