PLATINUM-INDUCED NEUROPATHY

Platinum-containing cisplatin and oxaliplatin are effective in many cancers but their use is severely compromised by persistent platinum-induced peripheral neuropathy. No treatment has been clinically proven to prevent this toxicity.

Both cisplatin and oxaliplatin bind to DNA and inhibit replication and transcription of DNA, and lead to programmed cell death. However, it is just a small portion that binds to DNA, resulting in a large platinum (Pt) waste that accumulate in the body and cause oppressive peripheral neuropathy.

Like in other form of heavy metal poisoning, chelation therapy represents a viable opportunity, i.e., a drug that binds 

Pt²⁺ with high affinity and forms a non-toxic complex which can be readily excreted through the kidneys. It is, however, not an easy task to determine the affinity of Pt²⁺ for hexa-dentate chelators, which is reflected by the apparent absence of formation constants of Pt²⁺ for common hexa-dentate chelating compounds, such as EDTA, in the literature.

However, Mn²⁺ gives rise to a visible Electron Paramagnetic Resonance (EPR) signal, proportional to the  concentration of free Mn²⁺,  whereas MnDPDP is invisible. Jan-Eric Stehr, Ingemar Lundström and Jan Olof G Karlsson used this method to monitor exchange of Mn²⁺for Zn²⁺and Pt²⁺, respectively, and hereby obtaining a formation constant of PtDPDP relative to that ZnDPDP (see Reference below).

Stehr JE, Lundström I, Karlsson JOG. Evidence that fodipir (DPDP) binds neurotoxic Pt²⁺with a high affinity: An electron paramagnetic resonance study. Sci Rep. 2019 Nov 1;9(1):15813. doi: 10.1038/s41598-019-52248-9. PMID: 31676855; PMCID: PMC6825159