Activity and DNA binding of new organoamidoplatinum (II) complexes
Two series of organoamidoplatinum (II) complexes were synthesized [Class 1, Pt(NRCH2)2L2 and Class 2, Pt(NRCH2CH2NR2')L(X)] and their antitumour activity examined by a range of in vitro, cellular and animal studies. All Class 1 compounds exhibited activity comparable to cisplatin in mouse leuke...
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| Veröffentlicht in: | Investigational new drugs 1999-02, Vol.17 (1), p.1-15 |
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| creator | TALARICO, T PHILLIPS, D. R DEACON, G. B RAINONE, S WEBSTER, L. K |
| description | Two series of organoamidoplatinum (II) complexes were synthesized [Class 1, Pt(NRCH2)2L2 and Class 2, Pt(NRCH2CH2NR2')L(X)] and their antitumour activity examined by a range of in vitro, cellular and animal studies. All Class 1 compounds exhibited activity comparable to cisplatin in mouse leukemia L1210 cells, but were at least 8-fold more active against the cisplatin-resistant L1210/R line. The lead compound 1a (R=p-HC6F4) caused nearly complete tumour regression in the ADJ/PC6 mouse tumour model. Compound 1a exhibited similar DNA reactivity to cisplatin, resulting in virtually identical DNA sequence specificity as cisplatin, and had similar time and concentration dependency of interstrand crosslinks. Compared with cisplatin, la showed 3-fold greater cellular uptake into human ovarian carcinoma 2008 cells, and this was dramatically enhanced to 17-fold in the cisplatin-resistant 2008/R line. The activity of 1a, therefore, appears to be due at least in part to a greater cellular uptake into tumour cells, particularly cisplatin-resistant cells, and once in the cell it reacts with DNA in a similar manner to that of cisplatin. The enhanced uptake and enhanced cytotoxicity of Class 1 compounds, and 1a in particular, may be due to a greater hydrophobicity compared with cisplatin. The activity of the Class 2 compounds, especially in the cisplatin-resistant cell lines, is unusual because they have trans amine ligands, and further study of both classes of compounds is warranted. |
| doi_str_mv | 10.1023/A:1006263917610 |
| format | Article |
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Compared with cisplatin, la showed 3-fold greater cellular uptake into human ovarian carcinoma 2008 cells, and this was dramatically enhanced to 17-fold in the cisplatin-resistant 2008/R line. The activity of 1a, therefore, appears to be due at least in part to a greater cellular uptake into tumour cells, particularly cisplatin-resistant cells, and once in the cell it reacts with DNA in a similar manner to that of cisplatin. The enhanced uptake and enhanced cytotoxicity of Class 1 compounds, and 1a in particular, may be due to a greater hydrophobicity compared with cisplatin. The activity of the Class 2 compounds, especially in the cisplatin-resistant cell lines, is unusual because they have trans amine ligands, and further study of both classes of compounds is warranted.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1023/A:1006263917610</identifier><identifier>PMID: 10555118</identifier><identifier>CODEN: INNDDK</identifier><language>eng</language><publisher>Dordrecht: Kluwer</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Autoradiography ; Binding Sites ; Biological and medical sciences ; Cancer therapies ; Cell growth ; Chemotherapy ; Cisplatin - analogs & derivatives ; Cisplatin - metabolism ; Cross-Linking Reagents ; DNA Adducts - metabolism ; DNA Adducts - pharmacology ; Drug Screening Assays, Antitumor ; Drugs ; Drugs, Investigational - pharmacokinetics ; Drugs, Investigational - pharmacology ; Ethanol ; Female ; Humans ; In Vitro Techniques ; Leukemia ; Leukemia L1210 - drug therapy ; Leukemia L1210 - metabolism ; Ligands ; Medical research ; Medical sciences ; Mice ; Ovaries ; Pharmacology. 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Compound 1a exhibited similar DNA reactivity to cisplatin, resulting in virtually identical DNA sequence specificity as cisplatin, and had similar time and concentration dependency of interstrand crosslinks. Compared with cisplatin, la showed 3-fold greater cellular uptake into human ovarian carcinoma 2008 cells, and this was dramatically enhanced to 17-fold in the cisplatin-resistant 2008/R line. The activity of 1a, therefore, appears to be due at least in part to a greater cellular uptake into tumour cells, particularly cisplatin-resistant cells, and once in the cell it reacts with DNA in a similar manner to that of cisplatin. The enhanced uptake and enhanced cytotoxicity of Class 1 compounds, and 1a in particular, may be due to a greater hydrophobicity compared with cisplatin. 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R</au><au>DEACON, G. B</au><au>RAINONE, S</au><au>WEBSTER, L. K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activity and DNA binding of new organoamidoplatinum (II) complexes</atitle><jtitle>Investigational new drugs</jtitle><addtitle>Invest New Drugs</addtitle><date>1999-02-01</date><risdate>1999</risdate><volume>17</volume><issue>1</issue><spage>1</spage><epage>15</epage><pages>1-15</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><coden>INNDDK</coden><abstract>Two series of organoamidoplatinum (II) complexes were synthesized [Class 1, Pt(NRCH2)2L2 and Class 2, Pt(NRCH2CH2NR2')L(X)] and their antitumour activity examined by a range of in vitro, cellular and animal studies. All Class 1 compounds exhibited activity comparable to cisplatin in mouse leukemia L1210 cells, but were at least 8-fold more active against the cisplatin-resistant L1210/R line. The lead compound 1a (R=p-HC6F4) caused nearly complete tumour regression in the ADJ/PC6 mouse tumour model. Compound 1a exhibited similar DNA reactivity to cisplatin, resulting in virtually identical DNA sequence specificity as cisplatin, and had similar time and concentration dependency of interstrand crosslinks. Compared with cisplatin, la showed 3-fold greater cellular uptake into human ovarian carcinoma 2008 cells, and this was dramatically enhanced to 17-fold in the cisplatin-resistant 2008/R line. The activity of 1a, therefore, appears to be due at least in part to a greater cellular uptake into tumour cells, particularly cisplatin-resistant cells, and once in the cell it reacts with DNA in a similar manner to that of cisplatin. The enhanced uptake and enhanced cytotoxicity of Class 1 compounds, and 1a in particular, may be due to a greater hydrophobicity compared with cisplatin. The activity of the Class 2 compounds, especially in the cisplatin-resistant cell lines, is unusual because they have trans amine ligands, and further study of both classes of compounds is warranted.</abstract><cop>Dordrecht</cop><pub>Kluwer</pub><pmid>10555118</pmid><doi>10.1023/A:1006263917610</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0167-6997 |
| ispartof | Investigational new drugs, 1999-02, Vol.17 (1), p.1-15 |
| issn | 0167-6997 1573-0646 |
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| subjects | Animals Antineoplastic agents Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Autoradiography Binding Sites Biological and medical sciences Cancer therapies Cell growth Chemotherapy Cisplatin - analogs & derivatives Cisplatin - metabolism Cross-Linking Reagents DNA Adducts - metabolism DNA Adducts - pharmacology Drug Screening Assays, Antitumor Drugs Drugs, Investigational - pharmacokinetics Drugs, Investigational - pharmacology Ethanol Female Humans In Vitro Techniques Leukemia Leukemia L1210 - drug therapy Leukemia L1210 - metabolism Ligands Medical research Medical sciences Mice Ovaries Pharmacology. Drug treatments Tumor Cells, Cultured - drug effects Tumor Cells, Cultured - metabolism Tumors |
| title | Activity and DNA binding of new organoamidoplatinum (II) complexes |
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