New Cisplatin Analogues—On the Way to Better Antitumor Agents

Abstract

The clinical success of cisplatin (cis-diamminedichloroplatinum(1r)) in antitumor chemotherapy has encouraged an all-out search for analogues with lower toxicity, improved therapeutic index and increased activity. Literally thousands of analogues, obtained by replacement of the ammine-and chloro-ligands by other amines and anionic ligands, respectively, have been systematically screened for activity in experimental tumor models. Some of these analogues have been selected for clinical evaluation, but only very few of them appear to be promising antitumor agents. More recently, cisplatin analogues have been designed and synthesized on the basis of, inter alia, the following considerations: 1) platinum complexes with carrier molecules as ligands should prove useful for achieving increasing drug concentration in tumor tissues; 2) platinum complexes with chemotherapeutic agents as ligands could afford polyfunctional drugs with synergistic action; 3 ) complexes containing more than one platinum atom might be more effective than complexes containing only one platinum atom; 4) platinum complexes could be used as sensitizers in radiation therapy. In this paper, we shall give a brief account of the "traditional" analogues, and then critically discuss what we believe could be the new trends in the design of cisplatin analogues.

Synthesis and Cytotoxicity of Platinum(II) Complexes of a Physiologically Active Carrier Histamine

“…The order of cytotoxic activity of histamine platinum(II) complexes is 1 A 2 L 3 L 4 L 5. This is in good agreement with the previous finding that the complexes with Cl -as the leaving group have greater antitumor activity than the corresponding dicarboxylatocomplexes [26].…”

Novel platinum(II) complexes of long chain aliphatic diamine ligands with oxalato as the leaving group: comparative cytotoxic activity relative to chloride precursors

“…The IC 50 values, calculated from the dose survival curves obtained after 120 h of drug exposure (MTT test), are shown in We observed that, in all cell lines assessed, the cytotoxicity was influenced by the leaving group, with oxalato complexes showing decreased activity compared to chloride precursors. Especially with the B16-F10 cell line, IC 50 values vary from 6.3 to 3.6 µmol L -1 for chloride complexes (1-4) and from 38.0 to 16.6 µmol L -1 for the oxalato analogues (5)(6)(7)(8). With the A 549 cell line, while the IC 50 value for chloride complexes is around 10 µmol L -1 , those for the oxalatos vary from 60.6 to 13.5 µmol L -1 .…”

“…[1][2][3] However, their clinical usefulness has frequently been limited by severe side effects, such as nephrotoxicity, ototoxicity and neurotoxicity, and by the emergence of cancer cells resistant to cisplatin. [4][5][6] Carboplatin was designed to overcome the severe side effects of cisplatin, and, indeed, the replacement of the labile chloride ligands by a comparatively more stable bidentate O-O leaving group resulted in a modified pharmacodynamic behavior and a more tolerable toxicological profile. 7 However, the cross-resistance between cisplatin and carboplatin makes them both ineffective in the treatment of patients who fail to respond to therapy.…”

Synthesis of Polyamines from Ethylenediamine and Their Platinum(II) Complexes, Potential Antitumor Agents

“…[14][15][16] It is also an important adjunct for cancers of the lung, cervix, and breast. [16] However, its clinical usefulness has frequently been limited by severe side effects, [17][18][19] such as nephrotoxicity, ototoxicity, and neurotoxicity, and by the emergence of cancer cells resistant to cisplatin.…”