Abstract
Peripheral neurotoxicity is the dose-limiting factor for clinical use of platinum derivatives, a class of anticancer drugs which includes cisplatin, carboplatin, and oxaliplatin. In particular cisplatin and oxaliplatin induce a severe peripheral neurotoxicity while carboplatin is less neurotoxic. The mechanisms proposed to explain these drugs’ neurotoxicity are dorsal root ganglia alteration, oxidative stress involvement, and mitochondrial dysfunction. Oxaliplatin also causes an acute and reversible neuropathy, supposed to be due by transient dysfunction of the voltage-gated sodium channels of sensory neurons. Recent studies suggest that individual genetic variation may play a role in the pathogenesis of platinum drug neurotoxicity. Even though all these mechanisms have been investigated, the pathogenesis is far from clearly defined. In this review we will summarize the current knowledge and the most up-to-date hypotheses on the mechanisms of platinum drug-induced peripheral neurotoxicity.
Highlights
Since biological activity of cisplatin (CDDP) as anticancer drug was discovered in the 1970s and approved by FDA for the treatment of testicular and ovarian cancer in 1978, the use of this drug has become more diffuse overtime [1].In the following years many other platinum drugs were synthesized and evaluated in clinical trials in order to overcome side effects and cases of CDDP resistance
One of the major side-effects limiting the clinical use of platinum drugs, as of several other anticancer drugs, is peripheral neurotoxicity, due to the fact that these drugs have easy access to the peripheral nervous system, which is less effectively protected from toxic substances compared to the central nervous system, where blood brain barrier is present
NER plays a dual role in modulating the CDDP cytotoxicity: its inability to remove the DNA-Pt adducts from nucleosomes and to repair intra-strand cross-links 1,2 is the basis of the cytotoxic effect of platinum drugs, on the other hand an increasing expression of genes encoding proteins involved in this repair mechanism may make it more effective, causing the onset of drug resistance [21]
Summary
Since biological activity of cisplatin (CDDP) as anticancer drug was discovered in the 1970s and approved by FDA for the treatment of testicular and ovarian cancer in 1978, the use of this drug has become more diffuse overtime [1]. Carboplatin shows reduced side-effects and less effectiveness as an anticancer drug if compared to CDDP It is used in combination therapy as first line treatment of ovarian, lung, and breast cancer. One of the major side-effects limiting the clinical use of platinum drugs, as of several other anticancer drugs, is peripheral neurotoxicity, due to the fact that these drugs have easy access to the peripheral nervous system, which is less effectively protected from toxic substances compared to the central nervous system, where blood brain barrier is present. This represents a major clinical problem for the extensive use of these drugs in chemotherapy. We will consider the issue of ion-channel involvement in the pathogenesis of the acute form of OHP neurotoxicity
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