|Ahead of print publication
The relationship between adjuvant chemotherapy and thiol-disulfide compounds
Pınar Akyol1, Didem Şener Dede2, Burak Bilgin3, Arife Ulaş2, Mehmet Ali Nahit Şendur2, Muhammed Bülent Akıncı2, Salih Başer4, Cihan Erol2, Mutlu Hızal2, Bülent Yalçın2
1 Department of Hematology, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
2 Departments of Medical Oncology, Yildirim Beyazit University, Ankara, Turkey
3 Department of Medical Oncology, Ataturk Chest Disease and Chest Surgery Training and Research Hospital, Ankara, Turkey
4 Department of Internal Medicine, Yildirim Beyazit University, Ankara, Turkey
|Date of Submission||07-Jan-2020|
|Date of Decision||28-May-2020|
|Date of Acceptance||16-Jul-2020|
|Date of Web Publication||01-Oct-2021|
Department of Hematology, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara
Source of Support: None, Conflict of Interest: None
Aim: Thiols are the organic compounds of the antioxidant system. There is limited data in the literature concerning chemotherapy (CT) in cancer and thiol balance. In this study, we aimed to evaluate the possible changes of thiol/disulfide levels with the recurrent CT cycles and type of cancer.
Materials and Methods: The 40 healthy individuals and 40 patients who had been newly diagnosed with early-stage breast, ovary and endometrium cancer receiving adjuvant CT. Blood samples were taken from all patients three times as basal and after the first and second CT sessions.
Results: We compared preadjuvant treatment levels of thiol and disulfide parameters in the patients group with the control group. The median of native thiol and total thiol was found to be higher in the control group than in the study group (P < 0.001). In addition, disulfide/native thiol and disulfide/total thiol rates were found to be higher in the patient group (P = 0.001). When we look at the comparison before and after CT in the patient group, disulfide/native thiol and disulfide/total thiol rates, which represent increased oxidative stress (OS) levels were found to be higher after CT than before CT measurement (P < 0.016).
Discussion: This is the first study, which has researched the relationship between cancer type and thiol compounds and changes of thiol compounds during CT therapy, by using the method designed by Erel and Neşelioğlu. In this study, we found that pre-CT thiol disulfide balance in cancer patients shifted toward disulfide direction and OS levels may increase after repetitive CT sessions.
Keywords: Chemotherapy, disulfide, native thiol, oxidative stress, total thiol
|How to cite this URL:|
Akyol P, Dede D&, Bilgin B, Ulaş A, Nahit Şendur MA, Akıncı MB, Başer S, Erol C, Hızal M, Yalçın B. The relationship between adjuvant chemotherapy and thiol-disulfide compounds. J Can Res Ther [Epub ahead of print] [cited 2022 Jun 25]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=327434
| > Introduction|| |
The harmful effects of free oxygen radicals (FOR) on the cells are called oxidative stress (OS). Thiols are the organic compounds that include the sulfydryl group and function as part of the antioxidant system that reacts with FOR to provide protection from cell injury. To demonstrate the OS status of the organism, it is important to evaluate the parameters of plasma thiols. When the thiol levels decrease in serum, the antioxidant function also decreases. Thiol groups are oxidatively reduced in the case of OS by FOR and disulfide bonds are composed. If normal conditions are provided, these disulfide bonding patterns are again reduced in relation to the thiol groups and the thiol/disulfide balance is maintained.
Plasma thiol and disulfide levels can be evaluated separately and totally by a new technique developed by Erel and Neşelioğlu in contrast to current indirect methods. Thiol and disulfide parameters that can be evaluated by this new technique are native thiol levels, dynamic disulfide levels, and total thiol levels. According to this measurement method, native thiols represent the molecules containing unreduced functional thiol groups, total thiol levels represent the sum of oxidized and unoxidized thiols and balanced thiol/disulfide levels.
The latest studies have found evidence that thiol/disulfide balance may have a role in the pathogenesis of several chronic diseases such as cardiovascular disease, cancer, rheumatoid arthritis, chronic kidney disease, and chronic liver disease.,,, There is limited data in the literature concerning chemotherapy (CT) and thiol balance. In this study, we aimed to evaluate the changes of thiol/disulfide levels with the recurrent CT cycles and type of cancer.
| > Materials And Methods|| |
The 40 healthy individuals and 40 patients who had been newly diagnosed with early-stage breast, ovary, and endometrium cancer receiving adjuvant CT following a curative operation were included in this study. They had all been referred to as Ankara Ataturk Training and Research Hospital between December 01, 2015 and January 31, 2016. All patients received adjuvant combined CT with doxorubicin + cyclophosphamide or carboplatin + paclitaxel according to their cancer types. Venous blood samples were taken from all patients three times as basal (2 weeks after operations and before first CT), after the first and second CT sessions. All blood samples evaluated, at Ankara Ataturk Training and Research Hospital Biochemistry Laboratory, using the direct measurement method, which was developed by Erel and Neşelioğlu with Roche Hitachi Cobas c501 automatic analyzer. Any changes in thiol parameters, after recurrent CT cycles, as well as any differences from the control group, were then evaluated.
Statistical Package for the Social Sciences (SPSS) software for Windows 20 program (IBM SPSS Inc., Chicago, USA) was used for analyses. Mean ± standard deviation was used for normally distributed variables, median value, and minimum-maximum values were used for nonnormally distributed variables. Nominal values are presented by percentage (%), and Chi-square test was used for comparisons. The variables were investigated using visual (Histogram, Probability Plots) and analytic methods (Kolmogorov–Smirnov/Shapiro Wilk's test) to determine whether or not they are normally distributed. According to these tests, WBC, hemoglobin, albumin, native thiol, disülphide parameters are normally distributed, platelet count, total thioldisülfide/native thiol are not normally distributed. Student's t-test was used to compare the measurement of normally distributed variables. Mann–Whitney U-Test was used to compare nonnormally distributed variables between independent groups. The Wilcoxon test was used to compare the change in not normally distributed thiol parameters. Kruskal–Wallis tests were conducted to compare the not normally distributed parameters and the ordinal variables. Post hoc tests were used to determine the difference between multiple variants analysis. Statistical significance was accepted as P < 0.05.
Ethical approval and informed consent
All procedures performed in this study were conducted in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. Patient records from Ankara Ataturk Training and Research Hospital confirmed the all patients gave informed consent before hospitalization and before CT and for other relevant diagnostics/therapeutic procedures.
| > Results|| |
We enrolled 40 patients in the patient group and 40 healthy individuals in the control group. Some statistically significant differences were existed between patient and control group characteristics. The mean age of the patient group was 54.3 ± 11.8 and 37.9 ± 11.4 in the patient and control groups, subsequently. All individuals in the patient group were female, whereas 80% and 20% of cases in the control group were female and male, subsequently. The detailed characteristics of the patient group and the control group are shown in [Table 1].
|Table 1: The clinical and demographic characteristics of patients and control group (*)|
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In the patient group, there were 28 patients (70%) with breast cancer, seven patients (17.5%) with endometrium cancer and five patients (12.5%) with ovary cancer. The-28 patients (70%) received adjuvant CT with adriamycin + cyclophosphamide and 12 (30%) patients received adjuvant CT with carboplatin + paclitaxel. The detailed characteristics of disease in the patient's group are shown in [Table 2].
We compared preadjuvant treatment levels of thiol and disulfide parameters in the patients group with the control group. In this anaylsis, the median of native thiol and total thiol was found to be higher in the control group than in the study group (P < 0.001). In addition, disulfide/native thiol and disulfide/total thiol rates were found to be higher in the patient group compared with the control group (P = 0.001). However, there was no statistically significant difference in disulfide level and native thiol/total thiol ratio (P > 0.05). Comparisons of the thiol parameters of the patient and the control group before CT are shown in [Table 3].
|Table 3: Comparisons of thiol parameters of the patients and control group before chemotherapy|
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When we look at the comparison before and after CT in the patient group, disulfide/native thiol and disulfide/total thiol rates, which represent increased OS levels were found to be higher after CT than before CT measurement (P < 0.016).
When we used post hoc tests, it was observed that disulfide/native thiol and disulfide/total thiol rates were significantly different between before and the first cycle of CT. However, the other parameters of thiol and disulfide levels had no change with CT administration. The detailed alteration of thiol and disulfide parameters with repetitive CT administration are shown in [Table 4].
|Table 4: The alteration of thiol and disulfide parameters with repetitive chemotherapy|
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There was no significant difference between thiol and disulfide parameters in preadjuvant treatment and after 1 and 2 cycles CT administration between the type of cancer, stage of cancer, and type of CT regimens. When we looked at the breast cancer group, we found a significant difference between the three CT cycles in total thiol and disulfide levels (before CT, after the first and second CT sessions). The measurement that performs after the second CT cycle was found to be higher than the first two measurements (P = 0.01). There was no significant difference between recurrent CT and thiol parameters in the ovary cancer and endometrium cancer groups.
| > Discussion|| |
To the best of our knowledge, this is the first trial that measured the effect of CT on OS by using direct methods. In the past, the relationship between thiol parameters and different disease have been researched in several studies. However, in these studies, thiol levels were measured by indirect methods. Thiol-disulfide balance can be measured by single-sided indirect methods since 1979. Now both variable levels can be measured separately and totally by the new method developed by Erel and Neselioglu.
It is known that free radicals have several negative effects on DNA. These effects may cause DNA damages that may cause mutations, activation in oncogenes, or inhibition of tumor suppressor genes. There are several studies that show that FOR plays a role in the variable steps of carcinogenesis. Serum malondialdehyde (MDA) is an indirect marker of OS, and it occurs as a result of lipid peroxidation and had highly cytotoxic features. In the literature, the MDA level was found significantly high in various cancer types, including colon, gastric, esophagus, and nonsmall cell lung cancers, while comparing with benign conditions.,,, Hydrogen peroxide (H2O2) is another marker that indirectly reflects OS. The previous trials showed that H2O2 was also found highly in melanoma, breast, colon, lung, and pancreas cancers compare with normal patient populations., As we mentioned above, MDA and H2O2 as indirect methods reflect only oxidative condition rather than both the antioxidant condition and balance between oxidation and anti-oxidation. However, the new method developed by Erel and Neselioglu can measure serum thiol and disulfide levels that reflect directly oxidant and antioxidant conditions and also balance of these.
In the literature, there are limited trials that evaluated oxidant and antioxidant conditions in cancer by using this new direct and automated method. In these trials, plasma disulfide level was found low in malign disease, including colon cancer, renal cell carcinoma, and bladder cancer compared with the benign disease as a consequence of consumption of the sulfide compounds by cancer. Another trial that investigated plasma thiol levels in advanced gastric cancer, plasma thiol level, was found significantly low in cancer patients than the control group. Dirican et al. were also evaluated thiol and disulfide levels in advanced lung cancer. In this trial, total thiol, native thiol, and disulfide levels were found lower in the patient group compared with the control group. In our study, native and total thiol measurements (before CT) were found to be lower in the patient group than in the control group. In addition, disulfide/native thiol and disulfide/total thiol rates were found to be higher. However, the comparison of thiol parameters in the patient group and the control group could not reflect clear results in our study, since there were several differences between our control group and the patient group that may affect OS such as age, comorbidity and smoking. Because many studies have shown that aging, smoking, comorbid diseases, thiol-disulfide disrupt homeostasis in favor of disulfide.,
When we assessed pre-CT thiol parameters according to the type and stage of cancer, we did not find any differences between the patients with breast, ovary, and endometrium cancer. One of the reasons for this is that the study has been done on patients in an adjuvant setting. The same parameters may be found to be different in patients who have metastasis or different tumor volume.
We also evaluated the alteration of thiol parameters before, after the first and second CT cycles in the patient group. We found a significant difference between before CT, after the first and second CT measurement of disulfide/native thiol and disulfide/total thiol ratios. When analyzed in detail, these rates showing the increase of OS decreased after 1st CT but increased with 2nd CT. This is an important indicator of the cumulative increase of oxidative damage resulting from CT. It is known that platins, alkylating agents, and anthracyclines can cause high FOR production and some chemotherapeutic such as taxane, vinca alkaloids can also cause low FOR production. A current study also determined that the baseline level of native thiol-disulfide compounds were strong predictors for anthracycline-induced cardiac toxicity. In that study, the baseline thiol level was found to be lower and disulfide and the disulfide/total thiol ratio were found to be higher in the patients with cardiotoxicity. In addition, there were no clinical trials that investigate the difference between the thiol and disulfide levels with repetitive CT administration. Thus, our study is the first trial that investigates the difference between the thiol and disulfide levels with repetitive CT administration.
If the results are evaluated according to the adjuvant CT type, it was found that there were no differences in any thiol parameters between before and after CT administrations in the patient group who were receiving carboplatin + paclitaxel. However, it was found that total thiol and disulfide levels after the second CT administration were higher than the first two measurements (before CT and subsequent to the first CT session) in the patient group who were receiving doxorubicin + cyclophosphamide. This finding supports those results which show increased OS after doxorubicin therapy. However, the limited number of patients in the carboplatin + paclitaxel group may be caused not to show a possible relationship with the thiol and disulfide levels and CT administration.
The major limitations of our study were a limited number of patients and several differences in demographic features between patient and control groups. However, we do not know that these differences influence the results or not, due to there is not enough data about the difference in the level of thiol and disulfide compounds between age and sex groups.
This is the first study, which has researched the relationship between cancer type and thiol compounds and changes of thiol compounds during CT therapy, by using the method designed by Erel and Neselioglu. In this study, we found that pre-CT thiol disulfide balance in cancer patients shifted toward disulfide direction, and OS levels may increase after repetitive CT sessions. Further studies with larger homogeneous groups are needed to demonstrate any changes in thiol-disulfide homeostasis as a result of cancer and CT.
Financial support and sponsorship
There is no financial support or sponsorship.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]