Cytotoxicity, cellular accumulation and DNA binding of oxaliplatin isomers

• Published in: Cancer letters Vol. 97; no. 2; pp. 177 - 184
• Main Authors: Pendyala, L., Kidani, Y., Perez, R., Wilkes, J., Bernacki, R.J., Creaven, P.J.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 06.11.1995; Elsevier
• Subjects: Accumulation; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemotherapy; Cytotoxicity; DNA - metabolism; DNA binding; Drug Resistance; Humans; Medical sciences; Mice; Organoplatinum Compounds - metabolism; Organoplatinum Compounds - pharmacology; Oxaliplatin; Pharmacology. Drug treatments; Tumor Cells, Cultured; Cytotoxicity; Oxaliplatin; Accumulation; DNA binding; Antineoplastic agent; Human; Metabolism; In vitro; Biological activity; Isomer; Biological fixation; Cell line; Structure activity relation; Analog; DNA; Tumor cell; Platinum II Complexes
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/0304-3835(95)03974-2

Oxaliplatin ( trans-l-1,2-diaminocyclohexane oxalato Pt(II); 1 R,2 R-dach, l-OHP), its trans-d isomer (1 S,2 S-dach) and cis-dach (1 R,2 S-dach) isomers were compared in in vitro testing against human ovarian carcinoma cell lines A2780, A2780/CP (cisplatin resistant), A2780/ l-OHP (oxaliplatin resistant), colon carcinoma cell line HT-29, and murine leukemia cell lines L1210, L1210/CP (cisplatin resistant), and L1210/dach (tetraplatin resistant). The relative molar potency of the three complexes in all the cell lines except A2780/ l-OHP and L1210/dach are trans-l > trans-d > cis-dach; in A2780/ l-OHP they are trans-l = trans-d > cis-dach; in L1210/dach trans-l > trans-d = cis-dach. The A2780/ l-OHP selected for trans-l resistance is 3.6-fold resistant to oxaliplatin, showed no resistance to trans-d isomer and is 6-fold resistant to cis-dach. However, L1210/dach which is selected for carboxyphthalato 1,2-dach ( trans-dl) platinum(II) is 140-fold resistant to oxaliplatin, 73-fold resistant to trans-d, and 41-fold resistant to cis-OHP. The accumulation and DNA binding of platinum following a 2-h treatment of A2780 cells with each of the isomers (60 μM) is in the order of trans-l > cis-dach > trans-d which corresponded to the cytotoxicity of trans-l, but not the others. The data suggest that other processes, such as differential formation of specific adducts and/or repair may be involved. Of the three isomers l-OHP is the superior and its accumulation and DNA binding are consistent with its cytotoxicity.