Antitumor and Cellular Pharmacological Properties of a Novel Platinum(IV) Complex:trans-[PtCl2(OH)2(Dimethylamine) (Isopropylamine)]
| Autor: | Carmen Navarro-Ranninger, Lloyd R. Kelland, F. E. Boxall, Eva I. Montero, Carlos Alonso, Miguel Fuertes, José M. Pérez |
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| Rok vydání: | 2003 |
| Předmět: |
Organoplatinum Compounds
Serum albumin Mice Nude Antineoplastic Agents Apoptosis DNA Adducts Mice chemistry.chemical_compound In vivo Tumor Cells Cultured medicine Animals Humans Isopropylamine Dimethylamine Serum Albumin Platinum Pharmacology Cisplatin Binding Sites biology Chemistry DNA Neoplasms Experimental Xenograft Model Antitumor Assays Blood proteins Disease Models Animal Biochemistry Cell culture biology.protein Molecular Medicine Female Cell Division Neoplasm Transplantation Plasmids medicine.drug |
| Zdroj: | Molecular Pharmacology. 63:933-944 |
| ISSN: | 1521-0111 0026-895X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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