[Current status of and future perspectives for platinum antitumor drugs].
Cisplatin, a simple inorganic compound, has been one of the leading antitumor drugs for near 30 years. However, cisplatin has several drawbacks such as toxicity and drug resistance. Therefore, much attention has been focused on the development of new platinum complexes with improved pharmacological properties and a broader spectrum of activity to tumors. The recent advance of research on the molecular mechanisms of drug action and the cellular mechanisms of the emergence of resistance to cisplatin assists the rational design of new classes of platinum antitumor drugs, though details of both mechanisms still remain elusive. Information on DNA binding mode of platinum complexes, recognition and repair of DNA damage is instructive. Since several not cis isomers but trans isomers and not neutral complexes but cation complexes have been found active in vitro and in vivo, the early empirical structure-activity relationships of cisplatin analogues should be reevaluated. The hypothesis that platinum complexes which bind to DNA in a different manner will have different pharmacological properties has been tested, and now cationic multi-nuclear complexes and even trans-platinum complexes comprise unique classes of antitumor platinum-based agents with chemical and biological properties different from cisplatin. These new type platinum complexes are often effective to acquired cisplatin resistant tumor cells. In conclusion, the following complexes appear to offer great potential as new antitumor agents: (1) Complexes with distinctively different DNA interaction modes from cisplatin, which may circumvent intrinsic and acquired resistance to cisplatin through eluding the vigilance of DNA repair systems and (2) complexes with different tissue distribution or mechanisms of membrane transport which may exhibit a different spectrum of activity.
Chikuma
Masahiko
M
Osaka University of Pharmaceutical Sciences, Takatsuki City, Japan. chikuma@gly.oups.ac.jp
Sato
Takaji
T
Komeda
Seiji
S
D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis; D002945:Cisplatin / Q000009:adverse effects / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009944:Organoplatinum Compounds; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C081294:satraplatin; C114062:BBR 3464; D002945:Cisplatin