Abstract
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.
Footnotes
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This work was supported by Spanish Comisión Interministerial de Ciencia y Tecnologica grant SAF00-0029. Support and sponsorship by Cost Actions D20/0001/00 and D20/0003/00 is kindly acknowledged. An institutional grant from Fundación Ramón Areces is also acknowledged.
- Abbreviations:
- cis-DDP
- cisplatin,cis-diamminedichloroplatinum(II)
- trans-DDP
- transplatin,trans-diamminedichloroplatinum(II)
- DMEM
- Dulbecco's modified Eagle's medium
- PI
- propidium iodide
- TXRF
- total reflection X-ray fluorescence
- PBS
- phosphate-buffered saline
- ICL
- interstrand cross-link
- MTD
- maximum tolerated dose
- HSA
- human serum albumin
- RF
- resistance factor
- ri
- input molar ratio of platinum to nucleotide
- dsDNA
- double strand DNA
- Received September 30, 2002.
- Accepted January 14, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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