Cytotoxicity and tolerance to DNA adducts of alicyclic mixed amine platinum(II) homologs in tumor models sensitive and resistant to cisplatin or tetraplatin.
Structure-cytotoxicity relationships for six alicyclic cis-(NH3)(R-NH2)Cl2Pt(II) complexes, where R=C3H5, C4H7, C5H9, C6H11, C7H13 and C8H15 (complexes abbreviated C3, C4, C5, C6, C7 and C8, respectively), were evaluated against four sensitive (L1210/0, A2780, FSaIIC and Colon 26), two cisplatin-resistant (L1210/DDP and 2780CP) and two tetraplatin-resistant (L1210/DACH and 2780TP) murine and human tumor cell lines. The studies demonstrated that in general the structure of C6 was optimal within the homologous series for cytotoxic potency against these tumor models. Biochemical pharmacologic studies indicated that the greater sensitivity of cells to C6 could be correlated with their low tolerance to DNA damage induced by this homolog. These results provide evidence for the alicyclic ring size as a structural determinant of DNA damage tolerance and anti-tumor activity in sensitive and resistant tumor cells.
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
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Yoshida
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Khokhar
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Siddik
D000588:Amines; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000633:toxicity*; D003110:Colonic Neoplasms; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007939:Leukemia L1210; D051379:Mice; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000633:toxicity*; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000588:Amines; D009944:Organoplatinum Compounds; D002945:Cisplatin; C049777:ormaplatin