Sigma 24 70
Effect of treatment on doxorubicin-induced cardiotoxicity methimazole
Effect of doxorubicin methimazole more induced cardiotoxicity
Abdel Moneim Osman, Ph.D., Mr. Marwa M.Pharm.Sc Nemnem., A. Amany Emam, T. Ph. D. Wael Mohamed and Abu Daif T. Khayyal Ph.D.
aAuthor for correspondence: Abdel-Moneim Osman M., Department of Pharmacology, Faculty of Medicine, KAAU, Jeddah, PO Box 80202, Saudi Arabia (96626408404 Fax, e-mail. Moneimosman@hotmail.com
Keywords: Methimazole, doxorubicin, cardiotoxicity, the interaction
Operation Title: Protective effect of methimazole
1. Introduction
Doxorubicin is the drug most used in the treatment a variety of human malignancies (1,7). Unfortunately, with the increasing use of doxorubicin, acute and chronic cumulative cardiomyopathy dose-dependent, have been recognized as the main limiting factor of doxorubicin chemotherapy (21, 6).
Several mechanisms cardiovascular toxicity induced by doxorubicin have been proposed, including oxidation of membrane lipids, the formation of free radicals (38.23), damage mitochondrial (19) and oxidative damage to macromolecules iron-dependent (27). Oxygen radicals are apparently involved in the proposed mechanisms. Methimazole is an anti-thyroid, containing the group-SH. Although primarily used in the treatment of hyperthyroidism (9) was found to be effective in reducing the toxicity of some chemotherapeutic drugs by nephrotoxic cephaloridine For example, (32, 3), gentamicin (12) and cisplatin (28). The effect has been attributed to its antioxidant and free radical-scavenging, leading to a reduction oxidative stress damage the kidneys, without affecting the cytotoxic activity of the drug. Since the protective effect of renal function is mainly methimazole based on free radical scavenging and antioxidant effect, and because cardiovascular toxic effects of doxorubicin is mediated by the production of free radicals (34) it was considered interesting to investigate whether the antioxidant effect of methimazole in the kidney can also be extended to its heart. We first examined the cardiovascular toxicity doxorubicin in the presence and absence of methimazole. Second, integration of doxorubicin in the heart and tumor tissue was evaluated in mice. Third, the effect of treatment on methimazole activity antitumor of doxorubicin is determined to answer the question of why the protective effect of methimazole may be at the expense of striking antitumor activity of doxorubicin?
2. Materials and methods
2.1 Drugs
The Doxorubicin was obtained in vials adriablastina Store National Cancer Institute, Cairo, Egypt (Co.SPA Pharmacia & Upjohn, Milan, Italy), was purchased to methimazole Sigma Chemical Co. (St. Louis, MO, USA). All other chemicals included in the study were from Merck (Darmstadt, Germany).
2.2 Animal and tumor
The research was conducted in albino mice 18-20 g in weight of our school inbred stock. The animals were housed in a conditioned atmosphere and followed a standard diet and water ad lip. A line of Ehrlich cites carcinoma cells (EAC) was kindly provided Via the Prof.Dr.AMOsman Dr.C.Benckhuisen, AVL, Amsterdam, Netherlands.
And keep in our laboratory by weekly ip transplantation of 2.5×106 cells / mice.
2.3 The measurement of cardio-toxic effects of doxorubicin
Forty Swiss albino female mice were divided into four groups. Group I, in which mice injected with normal saline (0.2 ml/20 g body weight, ip for 11 days every two days and considered as a control group. Group II, mice were injected with 40 mg methimazole / kg, ip, days 1,7, and 11 since the beginning of treatment (depending serve as a positive control methimazole. Group III mice were injected with doxorubicin at a total dose of 18 mg / kg, ip divided into six doses equal (3 mg / kg each) every two days at The period of two weeks to serve as a positive control doxorubicin. Group IV mice were injected with methimazole at doses of 40 mg / kg, ip, 30 min before the animals were given doxorubicin at doses of 3 mg / kg, ip on the days 1, 7, and 11 since the start of treatment with doxorubicin. After 24 hours of the end of the treatment regime, were collected retro-orbital plexus of animals and serum was separated. Hearts from each group were dissected and immersed in 10% formalin for histopathology research. ISO-LDH CK-MB and tropnin I activities were determined by methods (35, 36 and 13, respectively).
2.4 Use of doxorubicin in various tissues.
Swiss albino mice were injected SC in the right rear member with a saline solution containing cells 0.25×106 Ehrlich carcinoma. After 8 days, the animals were divided into 3 groups. Group I received saline and considered as a control group Group II was treated as in group III, Section 2.3 of group III were treated as in group IV of section 2.3 .. Plasma, heart and tumor from each group were dissected and the contents of doxorubicin was determined as mentioned by Bachur et al (2).
2.5Determination thyroid hormones (T3 and T4)
The animals were treated as described in Section 2.3 of the serum was separate and thyroid hormones were determined using the method of Yalow and Berson (37) using the principle of radioimmunoassay.
2.6 Assessment of antitumor activity
Swiss albino male mice were inoculated subcutaneously right hind limb as mentioned in Section 2.4. Only mice with a palpable solid tumor (100 mm3) which were developed in 8 days after inoculation of the tumor were used. They were randomly divided into four groups and drug treatment has been given to Section 2.4.The change in tumor volume was measured every two days with calipers and calculated by the formula according to Papadopoulos et al (30)
4II (A / 2) 2 X (B / 2)
tumor volume (mm3) = —————————————
3
Where A is the minor axis tumor
B is the main axis of the tumor
2.7 Analysis Statistics
Data are presented as mean ± SEM of the different groups were compared using a bilateral t test Student, if applicable. Several groups of comparisons were made using analysis of variance (ANOVA) followed by a Tukey-Kramer analysis post-hoc. Statistical significance was accepted at a level of p <0.05.
3. Results
3.1 Effects of methimazole pretreatment on the toxicity induced by doxorubicin cardio.
Table (1) shows the effect of pretreatment doxorubin with Methimazole-induced changes of cardiac enzymes in normal mice. Treatment of mice with six doses of doxorubicin (3 mg / kg every two x6 days) resulted in 2.6, 3 and 10.5 times increase in the activity of CK-MB, LDH ISO and troponin-I, respectively. Pre-treatment with methimazole (40 mg / kg, ip) 30 minutes before doxorubicin resulted in partial reversal of doxorubicin-induced increase in cardiac enzymes. At the same time methimazole treatment alone showed no significant difference in the serum of the three enzymes tested in comparison with the control group.
Histopathological investigation cardiac tissue after treatment confirmed the biochemical data, when treatment by doxorubicin cardiac muscle fibers showed swelling, edema and interstitial inflammatory infiltrate. Pre-treatment with methimazole showed interstitial edema and minimal inflammatory exudate (Fig. 6).
3.2.Effect methimazole pretreatment on the adoption of doxorubicin in various tissues of animals bearing tumors
treatment with doxorubicin peak plasma concentration of 0.2 ug / ml in half an hour after administration. the drug disappeared rapidly from plasma, falling 60% in the first hours and 90% in two days (Table 2). The drug was rapidly distributed to the heart (11.4 ug / g tissue) and other tissues (liver and kidney data not shown). methimazole pretreatment resulted in an increase of 3 times the plasma levels of doxorubicin and decrease its level in heart tissue (Fig. 1, Table 2). Regarding the level of tumor tissues, pretreatment with methimazole led to an increase slight but not significant in the peak concentration of doxorubicin, after an hour of his administration, but was reduced by about 42% after two days ..
3.3. Effect of pretreatment with methimazole in serum thyroid hormone in mice treated with doxorubicin
methimazole pretreatment did not significantly affect levels of T3 and T4 in the serum of animals treated with doxorubicin (Table 4).
4. Discussion
Doxorubicin is an anti-tumor excellent for the treatment of various types of solid cancers, leukemias and lymphomas.
However, the acute or chronic is the most important complication doxorubicin limited, while the acute toxicity Cardiovascular transient symptoms such as arrhythmia, toxicity can lead to chronic irreversible cardiomyopathy, which affects approximately 30-40% of patients receiving total doses mg/mm2 500 (22).
In this study, doxorubicin was injected 6 times at 3 mg / kg, which is a cumulative dose of 18 mg / kg more or less equivalent to 500 mg/mm2 of doxorubicin in a 50 kg man (20).
Our experimental design mimics the state clinic in multiple doses of anthracycline are given to patients. Administration of doxorubicin showed increased cardiac enzyme activities, Iso-LDH, CK-MB and troponin-I. The increased level of enzymes different from doxorubicin is probably a reflection that the drug induced cardiac toxicity, where LDH-Iso, CK-MB and troponin I are highly specific to myocardial damage (8, 18 and 10, respectively).
The present biochemical data were confirmed by histopathological changes induced by doxorubicin, where inflated heart tissue of heart muscle fibers, edema interstitial inflammatory infiltration (Fig. 5).
Several hypotheses have been advanced to explain the mechanism of toxicity induced by doxorubicin cardio including the production of reactive oxygen (33). For this reason, methimazole has nucleophilic sulfur in their structure, showed protective role against doxorubicin-induced renal failure (data not shown) and cardiotoxicty (Table 1 and Figure 6).
Although Methimazole has not already been reported to reduce cardiovascular toxicity, has shown that control of tachycardia and arrhythmia associated with high levels of circulating thyroid hormones (15).
Recently it was reported that methimazole may improve cardiac arrhythmias in clinical hyperthyroidism (5). These results are supported indirectly by reducing the concentration of doxorubicin in heart tissue by pretreatment with methimazole (Fig. 1). This is partly protects the myocardium of the accumulation of doxorubicin in cardiac cells and consequently may prevent the accumulation of free radicals. Our results also showed that treatment methimazole induced by an increase of nearly 3 folds of the plasma concentration of doxorubicin (Table 2). This is consistent with that reported by Gerweck et al. (17) Rancia et.al (31), and Frezard et al. (16), where they found a decrease in the accumulation of doxorubicin in the tissues and increases in plasma may be a function of pH gradient or the overexpression of P-glycoprotein. Knowing that doxorubicin is a weak base, its accumulation and toxicity in tissues was studied as a function of extracellular pH. Therefore, its level in tissues increases with the increase in extracellular pH and therefore any drug that lowers the extracellular pH can reduce the accumulation of doxorubicin in tissues (17, 31, 16)
On the other hand, the toxicity chronic doxorubicin has been reported that it is more likely related to reactive oxygen species are not (29, 24). This reflects the absence of certain antioxidants to show a protective effect against chronic cardiomyopathy (4, 25). In addition, Ferreira et al (14) suggests an antioxidant role of doxorubicin rather than acting as a pro-oxidant in experimental animals. This difference could be due to the nature of the treatment protocol system experimental design, the method to determine oxidative stress in different systems.
In certain circumstances, the administration compounds with antioxidant properties may reduce the antitumor activity of doxorubicin OD (11, 26). Therefore, it was necessary to check if methimazole may interfere with the cytotoxic activity of doxorubicin?. In this study, methimazole pretreatment does not interfere with the cytotoxic activity of doxorubicin (Fig. 2). This is evident from data showing that the uptake of doxorubicin in cells tumor was not affected by pretreatment with methimazole (Table 3) and percent survival of tumor-bearing animals treated with doxorubicin Fron different are not treated with the combination of methimazole and doxorubicin.
In conclusion, methimazole has proved as a promising drug against toxicity induced by cardiprotective doxorubicin cardio without affecting its experimental antitumor activity.
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Figure captions:
Figure 1: Effect of methimazole pretreatment on the adoption of the doxorubicin cardiac tissue of mice bearing Ehrlich carcinoma. Each column represents the mean ± sem of 5 mice
* Indicates a change important in the group treated with doxorubicin with p <0.05, statistical analysis was performed by students t test for paired data.
Figure 2: Effect of doxorubicin, methimazole and their combination on the growth of Ehrlich's letter mice.Each solid cancer support represents the average tumor volume (mm3) of 11 mice ± SEM. Statistical analysis was performed by Student unpaired t-test.
Figure 3: Heart of albino mice controls treated with saline showing normal myocardial histology (H & E stain 200x)
Figure (4) Heart of albino mice treated with methimazole 40 mg / kg for 3 doses on day 1, 7, 11 since the start of treatment. No damage is apparent myocardial (200x H & E Stain)
Figure (5). Heart of albino mice treated with doxorubicin for 6 doses of 3 mg / kg each, divided about two weeks, showing a swelling of cardiac muscle fibers, interstitial edema and inflammatory infiltration (H & E stain 200x).
Figure (6). heart of mice treated with methimazole Albino 30 minutes before administration of doxorubicin on days 1, 7, 11, the start of treatment with doxorubicin, which shows minimal interstitial edema and inflammatory exudate (H & E stainx400)
Tables (1): rate of cardiovascular toxicity after different doses of doxorubicin in mice pretreated with methimazole
Treatment groups Seum cardiac enzymes levels
LDH iso-CK-MB (U / L), Troponin-I (ng / ml)
Control 903 ± 71 328 ± 25 1.25 ± 0.08
Doxorubicin 2361 3447 ± 79 * 530 * 3.6 ± 0.60 *
Methimazole ± 0.42 1141 ± 161 # 868 # # 1.45 ± 0.20
Methimazole + Dox 1869 ± 2041 ± 76 * 267 * #, # # 1.87 ± 0.27
A six equal doses of doxorubicin (3 mg / kg) every two days have been administered in normal mice treated with methimazole (40 mg / kg, IP 30 minutes before doxorubicin) on days 1, 7 and 11
All values presented as means ± sem of 10 mice
* Indicates significant change compared to respective control values with p <0.05.
# Indicates significant change methimazole treated groups (with or without doxorubicin) in the group treated with doxorubicin at p <0.05. Statistical analysis was performed
With an ANOVA followed by Tukey-Kramer multiple comparison test.
Table (2) Effect of pretreatment with methimazole on plasma doxorubicin mice bearing Ehrlich carcinoma
concentration of doxorubicin (ug / ml plasma)
Time (hours) doxorubicin gp. Methimazole doxorubicin + gp
0.5 0.20 ± 0.05 0.66 ± 0.06 *
1 0.08 ± 0.01 0.14 ± 0.009 *
3 0.06 ± 0.02 0.12 ± 0.012
24 0.03 0.01 ± 0.096 ± 0.015 *
0.02 ± .0.007 48 0.062 ± 0.003 *
Legends as in a table (1)
All values are presented as mean ± SEM of 5 animals
* Indicates a significant change in the group treated with doxorubicin in the p <0.05.Statistical analysis was by Student t test for paired data.
Table (3) Effect of methimazole pretreatment on the adoption of doxorubicin in mice Ehrlich tumor with carcinoma.
the concentration of doxorubicin (ug / g protein of the tumor)
Time (hours) gp doxorubicin. methimazole doxorubicin + gp.
0.5 ± 0.01 ± 0.01 0.040 0.068
1 0.070 + 0.077 0.01 ± 0.008
3 0.060 ± 0.017 0.58 ± 0.001
24 0.058 ± 0.004 0.55 ± 0.007
48 0.056 ± 0.004 0.45 ± 0.003
alegends in Table (1)
All values are presented as means ± sem of 5 mice
Analysis Statistics was performed by Student t test for paired data.
Table (4) Effect of doxorubicin and methimazole in serum thyroid hormones in normal mice.
The treatment groups in serum hormone levels
T3 (ng / dl) T4 (ug / dl)
Control 100 ± 6.8 5.38 ± 0.22
Methimazole 98.9 ± 8.8 5.7 ± 0.3
Doxorubicin 95.5 ± 3 4.98 ± 0.24
+ Methimazole
Doxorubicin 104.6 ± 8.7 4.38 ± 0.11 *
aLegends in Table (1)
All values are presented as mean ± SEM of 12 animals
* Indicates a significant change from control to doxorubicin methimazole + p <0.05.
Statistical analysis was performed by ANOVA followed by Tukey-Kamer multiple comparison test.
About the Author
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