Overcoming Resistance to Platinum Therapy in Patients with Advanced Cancer

Abstract

The platinum-containing compounds cisplatin and carboplatin represent the mainstay of chemotherapeutic treatment for a variety of solid tumors occurring in adults, especially testicular and ovarian cancers. These drugs confer their antitumor efficacy by binding to DNA, especially to guanine bases, either adjacent on the same DNA strand or across strands. Tumour resistance, either present at the onset of therapy or acquired during successive courses of therapy, represents the significant limiting factor to long-term patient survival. From numerous studies of cancer cell lines in vitro, it is apparent that tumor resistance to cisplatin may arise through two general mechanisms: one preventing sufficient platinum from binding to DNA (reduced membrane transport and cytoplasmic inactivation by thiol-containing species such as glutathione or metallothioneins); and a second whereby platinum-DNA damage does not result in cell death (enhanced DNA nucleotide excision repair, increased tolerance, loss of DNA mismatch repair, failure to undergo apoptotic programmed cell death). It remains largely unclear as to the relative importance of these mechanisms in the clinic or whether additional mechanisms also exist.