International Journal of Molecular Sciences

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Dr. Jan Olof G Karlsson

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Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology, Linköping University, 581 83 Linköping, Sweden
Interests: oxidative and nitrosative stress; chemotherapy; dose limiting toxicity; superoxide dismutase (SOD) mimetics; chelation therapy

Special Issue Information

Dear Colleagues,

When it comes to the dose-limiting toxicity of chemotherapy, Platinum-Associated Chemotherapy-Induced Peripheral Neuropathy (PA-CIPN) represents one of the most troublesome obstacles in achieving the optimal tumoricidal efficacy of cisplatin and oxaliplatin.

Various approaches for preventing/treating this dose-limiting toxicity caused by cisplatin and oxaliplatin have failed. However, recent clinical studies have shown that Sodium ThioSulfate (STS) may reduce ototoxicity without lowering the tumoricidal efficacy of cisplatin in pediatric patients with localized solid tumors, renewing the possibilities of using a similar approach when it comes to PA-CIPN.

The obstacles that need to be overcome for finding an effective treatment of PA-CIPN apparently involve a lack of consensus around how to quantify CIPN and the use of mainly subjective measures, i.e., various physician- and patient-judged quantifications. Therefore, it is essential to develop objective methods to quantify CIPN.

The exact mechanism behind PA-CIPN is poorly understood. However, it seems reasonable to assume that it is the uptake and the retention of Pt2+ in the peripheral sensory nerve system that cause the toxicity. This system lacks a blood–brain barrier, a draining lymph system, and cerebrospinal fluid. This causes potentially dangerous substances, such as chemotherapy drugs, to accumulate in the peripheral nerve system, leading to oxidative stress and detrimental nerve injuries.

A better mechanistic understanding of PA-CIPN would of course increase the possibility of preventing/treating this bothersome toxicity, without lowering the tumoricidal efficacy of the drugs. We welcome submissions involving studies on key molecules and updates on treatments to avoid or to reduce Chemotherapy-Induced Peripheral Neuropathy.

Dr. Jan Olof G Karlsson
Guest Editor

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Keywords

Platinum-Associated Chemotherapy-Induced Peripheral Neuropathy (PA-CIPN)
molecular mechanisms
pharmacological approach
objective quantification measures

Published Papers (1 paper)

Review

12 pages, 2219 KiB

Open AccessReview

Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca₄Mn(DPDP)₅, MnDPDP and DPDP

by Jan Olof G. Karlsson and Per Jynge

Int. J. Mol. Sci. 2024, 25(8), 4347; https://doi.org/10.3390/ijms25084347 - 15 Apr 2024

Viewed by 347

Abstract

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative–nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca₄Mn(DPDP)₅; PledOx^®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca₄Mn(DPDP)₅ in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca₄Mn(DPDP)₅, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca₄Mn(DPDP)₅. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca₄Mn(DPDP)₅ may be explained by redox interactions between Pt²⁺ and Mn²⁺ and subtle oxidative–nitrosative chain reactions. In peripheral sensory nerves, Pt²⁺ presumably leads to oxidation of the Mn²⁺ from Ca₄Mn(DPDP)₅ as well as from Mn²⁺ in MnSOD and other endogenous sources. Thereafter, Mn³⁺ may be oxidized by peroxynitrite (ONOO⁻) into Mn⁴⁺, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O₂^•−) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt²⁺-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca₄Mn(DPDP)₅ mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt²⁺-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt²⁺ outcompetes Mn²⁺ and endogenous Zn²⁺ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt²⁺ by DPDP, which in turn suggests that Mn²⁺ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN. Full article

(This article belongs to the Special Issue Molecular Mechanism behind Platinum Associated Chemotherapy-Induced Peripheral Neuropathy (CIPN))

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