Vol. 63, Issue 4, 933-944, April 2003

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

José M. Pérez, Lloyd R. Kelland, Eva I. Montero, Frances E. Boxall, Miguel A. Fuertes, Carlos Alonso, and Carmen Navarro-Ranninger

Departamento de Química Inorgánica (J.M.P., E.I.M., C.N.R.) and Centro de Biología Molecular "Severo Ochoa" Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid (M.A.F., C.A.), Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain; and CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Belmont, Sutton, United Kingdom (L.R.K., F.B.)

The antitumor and cellular pharmacological properties of the trans-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 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.