مقایسه روشهای درمانی شامل: شیمی درمانی با دوکسوروبیسین، اولتراسونوگرافی 150KHzو ترکیب این دو روش در ایجاد مناطق نکروزه با روش هیستوپاتولوژی درتومور ادنوکارسینومای پستان موش

نویسندگان

1 بخشپاتولوژی،دانشکدهدامپزشکیدانشگاهتهران،تهران،ایران

2 بخشفیزیکپزشکی،دانشکدهفیزیکپزشکیوفیزیولوژی،دانشگاهعلومپزشکیاراک،اراک،ایران

3 بخشپاتولوژی،دانشکدهدامپزشکیدانشگاهسمنان،سمنان،ایران

چکیده

زمینه مطالعه: سرطان پستان به تنهایی 28% از همه موارد سرطان را در میان زنان تشکیل داده است. اگرچه شیمی درمانی نقش بسیار مهمی در درمان سرطان دارد،با این حال استفاده ازداروهای ضد سرطان اثر نامطلوب خود را بر روی بافت نرمال هم می‌گذارد. لذا همواره دانشمندان به دنبال روشی برای کاهش دوز مصرفی این داروها بوده اند. هدف: این مطالعه با هدف بررسی اثرهم افزایی امواج فراصوت kHz 150 با شدت کم در ترکیب با داروی شیمی درمانی دوکسوروبیسین با دوز کاهش یافته در درمان رایج ترین سرطان پستان (ادنوکارسینوما) انجام شد. روش کار: در این مطالعه  25 موش ماده نژاد BALB/c انتخاب وتومور ادنوکارسینوما با روش جراحی در زیر پوست پستان آن‌ها کاشته شد. موش‌های دارای تومور به پنج گروه شامل شاهد، شم، تزریق وریدی دوکسوروبیسین (mg/kg 2)،امواج فراصوت (150kHz) و امواج + دارو (در غلظت 1mg/kg) تقسیم و تحت درمان قرارگرفتند. نتایج درمان تومور بین گروه‌ها با استفاده از آنالیز ANOVA در محیط نرم افزار نسخه 13 SPSS و تست تکمیلی توکی مورد بررسی قرار گرفت. نتایج: پس از تزریق دوکسوروبیسین و قرار گرفتن در معرض امواج فراصوت به مدت 15 دقیقه مناطق نکروزه در تومور ادنوکارسینوم در مقایسه با گروه کنترل وشم افزایش معنی‌داری را نشان داد (0.001>p). همچنین در مقایسه بین گروه دارو + امواج با گروهی که تنها دارو دریافت کرده بودند گروه دریافت کننده امواج رشد مناطق نکروزه بیشتری را نسبت به حجم کل تومور نشان داد (0.05>p). نتیجهگیرینهایی: نتایج این مطالعه حاکی از این است که استفاده ازامواج فراصوت با شدت کم می‌تواند در کاهش دوز داروی دوکسوروبیسین در درمان ادنوکارسینومای پستانی مؤثر واقع گردد.

کلیدواژه‌ها


عنوان مقاله [English]

Histopathological findings in necrotic spaces developed with doxorubicin and 150 kHz ultrasound at low intensity and a combination of these two methods on adenocarcinoma tumor breast cancer in BALB/c mice

نویسندگان [English]

  • Sahar Ghaffari Khaligh 1
  • abas tavasoli 2
  • Seyed Hossein Marjanmehr 1
  • Homa Soleimani 2
  • Abbas Javaheri Vayghan 3
1 Department of Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
2 Department of Medical Physics and Physiology, School of Medical Science, Arak university of Medical Science, Arak, Iran
3 Department of Pathology, Faculty of Veterinary Medicine, Semnan University, Semnan, Iran
چکیده [English]

BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women. One in eight women will be diagnosed with breast cancer in their lifetime. Chemotherapy works on active cells. Active cells are cells that are growing and dividing into more of the same type of cell. Cancer cells are active, but so are some healthy cells. Also, scientists work constantly to develop ways of providing treatment with fewer chemotherapy side effects. Objectives: The aim of this study was antitumor effect of simultaneous low-intensity, 150 kHz ultrasound, in combination with the reduced dose of anticancer drug Doxorubicin (DOX) on breast adenocarcinoma using murine model (BALB/c). Methods: Twenty-five female BALB/c mice were used in this study. The tumor was implanted under the breast skin of mice. Mice were divided into five groups, namely control, sham, drug (IV injected of 2 mg/kg of DOX), drug (IV injected of 1 mg/kg of DOX) + US (150 kHz for 15 minutes) and exposure to ultrasound (150 kHz for 15 minutes) alone. The data were analyzed employing ANOVA using SPSS software V.13 and complementary test of Tooki was done. Results: It was shown that, after injection of DOX, exposure to ultrasound at 150 kHz the necrotic spaces in adenocarcinoma tumors compared to control and sham groups have meaningful variance (p<0.001). There was also a significant difference (the bigger the necrotic spaces) between the drug+US group and drug treated group (p<0.05), It should be mentioned that the dose of DOX in drug+US group was reduced to 1mg/kg. Conclusions: The co-administration of DOX and low-intensity ultrasound provided a more effective treatment than the drug alone in murine adenocarcinoma breast cancer. The combined treatment appeared to produce synergistic effects that could prove potentially useful in reducing the side effects of DOX by lowering the required effective dose of the drug while increasing the efficiency of the therapy as a whole.

کلیدواژه‌ها [English]

  • Breast Cancer
  • doxorubicin
  • Ultrasound
  • necrotic space
  • acoustic cavitation
Alter, A., Rozenszajn, L.A., Miller, H.I., Rosenschein, U. (1998) Ultrasound inhibits the adhesion and migration of smooth muscle cells in vitro. Ultrasound Med Biol. 24: 711-721.
Barati, A.H., Mokhtari-Dizaji, M., Mozdarani, H., Bathaie, S.Z., Hassan, Z.M. (2009) Treatment of murine tumors using dual-frequency ultrasound in an experimental in vivo models. Ultrasound Med Biol. 35: 756-763.
Barnett, S.B., Ter Haar, G.R., Ziskin, M.C., Nyborg, W.L., Maeda, K., Bang, J. (1994) Current status of research on biophysical effects of ultrasound. Ultrasound Med Biol. 20: 205-218.
Bernard, V., Skorpikova, J., Mornstein, V., Slaninova, I. (2010) Biological effects of combined ultrasound and cisplatin treatment on ovarian carcinoma cells. Ultrasonics. 50: 357-362.
Bouma, J., Beijnen, J.H., Bult, A., Underberg, W.J.M. (1986) Anthracycline antitumor agents. A review of physicochemical, analytical and stability properties. Pharm world Sci. 8: 109-133.
Colombo, T., Donelli, M.G., Urso, R., Dallarda, S., Bartosek, I., Guaitani, A. (1989)  Doxorubicin toxicity and pharmacokinetics in old and young rats. Exp Gerontol. 24: 159-171.
Doan, N., Reber, P., Meghji, S., Harris, M. (1999)  In vitro effects of therapeutic ultrasound on cell proliferation, protein synthesis, and cytokine production by human fibroblasts, osteroblasts, and monocytes. J Oral Maxillofac Surg. 57: 409-419.
Gustafson, D.L., Lond, M.E. (2001)  Alterations in p-glycoprotein expression in mouse tissues by doxorubicin: implications for pharmacokinetics in multiple dosing regiments. Chem Biol Interact. 138: 43-57.
Guzman, H.R., Nguyen, D.X., Khan, S., Prausnitz, M.R. (2001) Ultrasound-mediated disruption of cell membranes-I. Quantification of molecular uptake and cell validity. J Acoust Soc Am. 110: 588-596.
Harrison, GH., Balcer-Kubiczek, E.K., Gutierrez, P.L. (1996) In vitro mechanisms of chemopotentitation by tone-burst ultrasound. Ultrasound Med Biol. 22: 355-362.
Hrazdira, I., Skorikova, J., Dolnikova, M. (1999) ultrasonically induced alterations of Cultured tumor cells. Eur J Ultrasound. 8: 43-49.
Jemal, A., Siegel, R., Xu, J., Ward, E. (2010) Cancer statistics, 2010. CA Cancer J Clin. 61: 133-4.
Jin, C.B., Wu, F., Wang, Z.B., Chen, W.Z. (2003)  High intensity focused ultrasound therapy in combination with trans catheter arterial chemo embolism for advanced hepatocellular carcinoma. Chinese Journal of Oncology. 25: 401-3.
Lejbkowicz, F., Zwiran, M., Salzberg, S. (1993)  The response of normal and malignant cells to ultrasound in vitro. Ultrasound Med Biol. 19: 75-82.
Liu, Y., Yang, H., Sakanishi, A. (2006) Ultrasound: mechanical gene transfer into plant cells by sonoporation. Biotechnol Adv. 24: 1-16.
Luna, L.G. (1968) Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology. (3rd ed.) McGraw-Hill. NewYork, USA.
Minchinton, A.I., Tannock, I.F. (2006) Drug penetration in solid tumors. Nat Rev Cancer. 6: 583-592.
Saad, A.H., Hahn, G.M. (1992) Ultrasound-enhanced effects of Adriamycin against murine tumors. Ultrasound Med Biol. 18: 715-723.
Sartiano, G.P., Lynch, W.E., Bullington, W.D. (1979) Mechanism of action of the anthracycline anti-tumor antibiotics, doxorubicin, daunomycin and rubidazone: preferential inhibition of DNA polymerase alpha. J Antibiot. 32: 1038-45.
Soleimani, H., Abdolmaleki, P., Mokhtari-Dijazi, M., Toliat, T., Tavasoli, A. (2011) The synergistic effect of Doxorobicin and 150 kHz ultrasound in low intensity on tumor growth of adenocarcinoma breast cancer in BALB/c mice. Ofogh-e- Danesh. GMUHS J. 17: 5-14.
Tachibana, K., Uchida, T., Tamura, K., Eguchi, H., Yamashita, N., Ogava, K. (2000) Enhanced cytotoxic effect of  Ara.C by low intensity ultrasound to HL. 60 cells. Cancer Lett. 149: 189-194.
Wang, S., Konorev, E.A., Kotamraju, S., Joseph, J., Kalivendi, S., Kalyanaraman, B. (2004) Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms. Intermediacy of H(2)O(2)- and p53-dependent pathways. J Biol Chem. 279: 25535-43.
Wang, X.B., Liu, Q.H., Wang, P., Wang, Z.Z., Tong, W.Y., Zhu, B., Wang, Y. (2009) Comparisons among sensitivities of different tumor cells to focused ultrasound in vitro. Ultrasonics. 49: 558-564.
Wu, F., Wang, Z.B., Chen, W.Z., Zou, J.Z. (2004)  extracorporeal high intensity focused ultrasound for treatment of solid carcinomas: four-year Chinese clinical experience. Ultrasound Med Biol. 30: 245-60.
Young, R.C.,Ozols, R.F., Myers, C.E. (1981) The anthracycline antineoplastic drugs. N EngI J Med. 305: 139-153.
Yu, T., Wang, Z., Jiang, S. (2001) Potentiation of cytotoxicity of adriamycin on human ovarian carcinoma cell line AO3 by low-level ultrasound. Ultrasonics. 39: 307-309.
Yu, T., Wang, Z., Mason, T.J., (2004)  A review of research in to uses of low level ultrasound in cancer therapy. Ultrason Sonochem. 11: 95-103.