Amifostine Has Chemopreventive Effects in a Mouse Skin Carcinogenesis Model

Abstract

PURPOSE: Amifostine (WR-2721) is dephosphorylated and converted into an active free radical scavenger (WR-1065) by the enzyme alkaline phosphatase, which is found at high levels in normal tissues but at low levels in tumor cells. However, although there are studies on the fibrosis-healing effect of Amifostine, there is no study on preventing secondary cancerization. We aimed to investigate the chemopreventive properties of WR-1065, the active metabolite of WR-2721 by using Amifostine at different stages of carcinogenesis in the skin carcinogenesis model to shed light on the question of whether it will protect only the normal cells and prevent the formation of secondary cancers. MATERIAL AND METHODS: 5-6week old female, 160 CD-1 mice weighing 22-24 g were purchased from the laboratory of Charles River Breeding, Germany. Forty CD-1 mice were used twice weekly for the toxicity study to find the practicable dose. Skin carcinogenesis control and experimental groups were formed with 120 CD-1 mice. Control group; DMBA (100 nmol) day 0. TPA (10nmol twice a week, 22 weeks), Experiment 1; to measure the promotional effect, it was applied twice a week for 22 weeks before TPA application, Experiment 2; To measure the effect of initiation, Amifostine was applied 2 days before and 5 days after the DMBA application, Experiment 3; Amifostine was administered before both DMBA and TPA to measure the effect of both initiation and promotion. The number of tumors per week (incidence) and the number of mice with tumors (multiplicity) were noted up to week 33rd. Tumor samples were stored in formalin solution for histopathological analysis. Statistical comparisons for normal data among groups were performed using the one-way ANOVA test, then the Dunnet test was used for non-normal data among groups was performed by using the Kruskal Walls test and then Bonferroni correction was used for comparison of the experimental groups with the control group (p<0.016 was considered as statistically significant for Bonferroni correction).  RESULTS: Papillomas were first seen during the 6th week in the control group. Incidence and multiplicity values ​​for the week recorded for the control group were compared with each group of Experiment-1, Experiment-2, and Experiment-3. At the end of the 22nd week, tumor mean values ​​for control and experimental groups were 40.81±18.26, 13.00 ± 11.99, 18.04 ±20.94, 4.82 ± 5.93 (*p<;.001,*p<;.000*, p<;.001 ), tumor multiplicity respectively; 26 (100%), Experimental-1; 22 (91.7%), Odds Ratio (OR): 2.18, Experimental-2; 25 (100%), OR:1, Experimental-3; 17 (77.3%), OR:2.52, (*p=.225*, p=1, p=.015) were found. As a result, Amifostine showed the most chemoprevention properties in both tumor number and tumor multiplicity when used together before initiation and promotion. CONCLUSIONS: Amifostine was shown to have chemoprevention properties in the chemical carcinogenesis model. Amifostine is abandoned due to its side effects such as nausea, vomiting, and hypotension. However, as we used in our experiment, studies for clinical use at low doses can be triggered. The ability to prevent secondary malignancies, especially from late effects that may develop due to chemo-radiotherapy, should not be ignored.