Molecular mechanisms of resistance and toxicity associated with platinating agents

Abstract

Platinating agents, including cisplatin, carboplatin, and oxaliplatin, have been used clinically for nearly 30years as part of the treatment of many types of cancers, including head and neck, testicular, ovarian, cervical, lung, colorectal and relapsed lymphoma. The cytotoxic lesion of platinating agents is thought to be the platinum intrastrand crosslink that forms on DNA, although treatment activates a number of signal transduction pathways. Treatment with these agents is characterized by resistance, both acquired and intrinsic. This resistance can be caused by a number of cellular adaptations, including reduced uptake, inactivation by glutathione and other anti-oxidants, and increased levels of DNA repair or DNA tolerance. Here we investigate the pathways that treatment with platinating agents activate, the mechanisms of resistance, potential candidate genes involved in the development of resistance, and associated clinical toxicities. Although the purpose of this review is to provide an overview of cisplatin, carboplatin, and oxaliplatin, we have focused primarily on preclinical data that has clinical relevance generated over the past five years.

Figure 1

The chemical structures of cisplatin, transplatin, carboplatin, oxaliplatin, and satraplatin.

Figure 2

Platinating agent adducts on DNA. Platinating agents are able to interact with DNA to form monoadducts, intrastrand crosslinks (1,2-d(GpG), 1,2-d(ApG), 1,3-d(GpXpGp)), interstrand crosslinks (G-G), and DNA-protein crosslinks.

Figure 3

Mechanism of cisplatin activity and mechanisms of resistance to platinating agents, as exemplified here by cisplatin. Cisplatin can act in the cell either by causing DNA damage, or by activating the ER stress pathway, both of which can lead to cellular apoptosis. In addition, many mechanisms of resistance (italics) are present, including transport, cellular antioxidants, increased DNA damage repair, and DNA tolerance.

Figure 4

Toxicities associated with treatment with platinating agents. A. The most common side effects associated with cisplatin treatment are ototoxicity, peripheral neuropathy, myelosuppression, and nephrotoxicity. Ototoxicity is notably higher in pediatric patients, while neuropathy is relatively more common in adult patients. B. The most common toxicity associated with carboplatin is myelosuppression, with rare cases of neurotoxicity and nephrotoxicity. Oxaliplatin most commonly causes neurotoxicity.