Antitumor and cellular pharmacological properties of a novel platinum(IV) complex: trans-[PtCl(2)(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.
Pérez
José M
JM
Departamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
Kelland
Lloyd R
LR
Montero
Eva I
EI
Boxall
Frances E
FE
Fuertes
Miguel A
MA
Alonso
Carlos
C
Navarro-Ranninger
Carmen
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010957:Plasmids / Q000235:genetics; D010984:Platinum / Q000378:metabolism*; D012709:Serum Albumin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; C472803:PtCl(2)(OH)(2)(dimethylamine) (isopropylamine); D012709:Serum Albumin; D010984:Platinum; D004247:DNA