Can acetylcysteine ameliorate cisplatin‐induced toxicities and oxidative stress without decreasing antitumor efficacy? A randomized, double‐blind, placebo‐controlled trial involving patients with head and neck cancer

Abstract

The protective antioxidant activity of acetylcysteine (NAC) against toxicity due to cisplatin has been reported in experimental models; however, its efficacy in patients has not been elucidated. The aim of this study was to investigate the possible protective effect of NAC on cisplatin‐induced toxicity and the effect of NAC on clinical response and oxidative stress in patients treated for head and neck cancer. This was a randomized, double‐blind, placebo‐controlled trial conducted in patients receiving high‐dose cisplatin chemotherapy concomitant to radiotherapy. Patients were randomly assigned to groups and received: (a) 600 mg NAC syrup, orally once daily at night for 7 consecutive days or (b) placebo, administered similarly to NAC. Nephro‐, oto‐, hepato‐, myelo‐, and gastrointestinal toxicities, clinical responses, and plasma and cellular markers of oxidative stress were evaluated. Fifty‐seven patients were included (n = 28, NAC arm; and n = 29, placebo arm). A high prevalence of most types of toxicities was observed after cisplatin chemotherapy; however, the parameters were similar between the two groups. There was a predominance of partial response to treatment. In the cellular and plasmatic oxidative stress analyses, minor differences were observed. Overall, there was no statistically significant difference between the groups for all outcomes. These findings show that low‐dose oral NAC does not protect patients with head and neck cancer from cisplatin‐induced toxicities and oxidative stress. The antitumor efficacy of cisplatin was apparently not impaired by NAC.

Chrysophanol Relieves Cisplatin-Induced Nephrotoxicity via Concomitant Inhibition of Oxidative Stress, Apoptosis, and Inflammation

“…As an example, NAC prevents both the death receptor and the mitochondrial apoptotic pathways induced by CDDP in preclinical studies ( Wu et al, 2005 ). At the clinical level, however, the use of NAC was not effective in attenuating the toxicity of CDDP in patients with head and neck cancer ( Visacri et al, 2019 ). This means that exploration of alternative candidates is still urgently needed.…”

Preventive Effect of Muscone against Cisplatin Nephrotoxicity in LLC-PK1 Cells

“…The protective effect of muscone against cisplatin-induced kidney proximal tubule LLC-PK1 cell death was examined using cell viability assay. The NAC, a medication primarily is used as a mucolytic agent and in treatment of paracetamol overdose proved the effectiveness in reduction of cisplatin nephrotoxicity in both in vitro and in animal models, which was chosen as the reference drug [ 23 , 24 ]. As indicated in Figure 2 , the viability of cells reduced to 53.3 ± 2.3% ( N = 3, p = 0.05) in cisplatin only-treated cells and was restored in a concentration-dependent manner in the presence of compounds.…”

Regression Modeling of the Antioxidant-to-Nephroprotective Relation Shows the Pivotal Role of Oxidative Stress in Cisplatin Nephrotoxicity

“…In agreement, a recent meta-analysis identified antioxidants as the most effective protectants of cisplatin nephrotoxicity in clinical studies [ 159 ]. Interestingly, several antioxidants have shown, in animal models, nephroprotective properties without interfering with the antitumor effect of cisplatin [ 160 , 161 , 162 , 163 , 164 ], a critical issue for clinical application. This might be attributed to cisplatin genotoxicity mostly impacting on proliferating cells, such as tumor cells.…”