CHEM 4344

Diamminedichloroplatin(II) (cisplatin) is one of the most effective oncoytic agents against cancers of the ovaries, bladder , and head and neck. It is also an important adjunct for cancers of cervix, lung and breast. Its most specacular success has been in the treatment of testicular cancer, a form of cancer previously resistant to any therapy but now considered to be curable in most cases.

However, cisplatin has three drawbacks which limit its usefulness: its severe toxicities, it only affects a narrow range of tumors and it causes the development of resistance in the tumor cell.

Recent studies by Stephen J. Lippard at MIT points to the complexation of HMG 1 proteins to the cisplatin-DNA adduct as the molecular basis for the therapeutic effect.

It has long been known that cisplatin forms covalent adducts with DNA ( click here ) which inhibit DNA replication and induce apoptosis. These complexes result in a distortion of the double helix through the introduction of a bend.

HMG proteins are high mobility group proteins that are non-histone components of chromatin and play roles in the specific regulation of transcription and cell differentiation. Common properties of HMG domain proteins include interaction with DNA via the minor groove of the helix, binding to irregular DNA structures and the capacity to modulate DNA structure by bending.