ABSTRACT
BACKGROUND: In this study, it was aimed to investigate the relationship between diabetes and breast cancer and the detection of enzymes and ornithine levels in polyamine synthesis pathway in diabetes, breast cancer and diabetic breast cancer patients. METHODS: Ornithine, arginine decarboxylase, ornithine decarboxylase and agmatinase levels have been measured in serum of all groups. Ornithine levels were measured spectrophotometrically. Arginine decarboxylase, ornithine decarboxylase and agmatinase levels were determined by ELISA kits. RESULTS: Except for the diabetic group, the levels of enzymes in the polyamine synthesis pathway were increased in all and statistically significant (P < 0.05). The increase in the levels of agmatinase was very important among the enzymes (P < 0.001). CONCLUSIONS: Decreased levels of polyamine synthase enzymes in diabetes mellitus were found to be increased patients with breast cancer. Whether and how diabetes-based breast cancer development relates to increase activity of enzymes responsible for polyamine synthesis requires further mechanistic and prospective monitoring studies in larger patient cohorts.
ABSTRACT
OBJECTIVE: Currently, medical and surgical treatment options for endometriosis are limited due to suboptimal efficacy, and also safety and tolerance issues. Long-term use of gonadotrophin-releasing hormone analogs, androgenes, and the danazol, which are widely used drugs for endometriosis, is usually not possible due to their suboptimal safety and tolerance profile. The lack of an effective, tolerable and safe treatment option for endometriosis makes animal models of experimental endometriosis necessary to study candidate drugs. The aim of this study was to investigate the efficacy of imatinib on the experimental endometriosis in a rat model. STUDY DESIGN: Endometriosis was induced by autotransplantation of uterine tissue into the peritoneal cavity. Twenty-four rats, which had visually confirmed endometriotic implants on subsequent laparotomy, were randomized into three groups to receive imatinib (25mg/kg/day, p.o.), anastrozole (0.004 mg/day, p.o.), or normal saline (0.1 mL, i.p.) for 14 days. After removal of endometriotic tissue and H & E staining, endometriosis score was determined according to a semiquantitative histological classification. Also, immunostaining with primary antibodies including VEGF, CD117, and Bax were used for immunohistochemical (IHC) examination. RESULTS: Both anastrozole and imatinib suppressed the growth of endometriotic tissue and reduced the number of ovarian follicles. Although the difference was not statistically significant, imatinib was less effective than anastrozole for treatment of endometriosis. CONCLUSION: Imatinib effectively treats experimental endometriosis by its inhibitor effects on angiogenesis and cell proliferation.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Aromatase Inhibitors/pharmacology , Cell Proliferation/drug effects , Endometriosis , Endometrium/drug effects , Imatinib Mesylate/pharmacology , Nitriles/pharmacology , Peritoneal Diseases , Peritoneum/drug effects , Triazoles/pharmacology , Anastrozole , Animals , Disease Models, Animal , Endometriosis/metabolism , Endometrium/metabolism , Endometrium/transplantation , Female , Ovarian Follicle/drug effects , Peritoneal Diseases/metabolism , Peritoneum/metabolism , Proto-Oncogene Proteins c-kit/drug effects , Proto-Oncogene Proteins c-kit/metabolism , Rats , Transplantation, Autologous , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/metabolism , bcl-2-Associated X Protein/drug effects , bcl-2-Associated X Protein/metabolismABSTRACT
We aimed to compare the effects of pazopanib, sunitinib, and sorafenib on endometriotic tissue morphology and histological characteristics as well as ovarian reserve in a rat model. Experimental endometriosis was established in 32 rats. They were randomly divided into 4 groups (8 rats for each group) to administer study drugs: pazopanib, sunitinib, sorafenib, and normal saline. Histological examination with hematoxylin and eosin staining to determine endometriosis score and immunostaining with primary vascular endothelial growth factor (VEGF), CD117, and Bax antibodies were performed. Bilateral ovaries excised to determine the ovarian follicle number. The endometriosis score was significantly reduced by pazopanib compared to other study drugs and by sunitinib compared to sorafenib and normal saline (P < .05). Sorafenib did not affect endometriosis score (P > .05). The VEGF score was significantly decreased similarly by pazopanib, sunitinib, and sorafenib compared to normal saline (P < .05). The CD117 score was reduced by pazopanib and sunitinib similarly compared to both sorafenib and normal saline that provided similar effect on the score (P < .05). The Bax scores of all the groups were found similar (P > .05). No study drugs caused meaningful change in the ovarian follicle number (P > .05). Pazopanib reduces the growth of endometriotic implants. This effect may be related to the suppressive effect of pazopanib on the endometriotic tissue expressions of VEGF and CD117 but not Bax. The study drugs do not affect ovarian reserve. The inconsistent effects of study drugs regarding study parameters require further studies to elucidate the molecular bases of their effects on the growth of endometriotic implants.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Endometriosis/drug therapy , Endometrium/drug effects , Indoles/pharmacology , Niacinamide/analogs & derivatives , Phenylurea Compounds/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Sulfonamides/pharmacology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Endometriosis/metabolism , Endometriosis/pathology , Endometriosis/physiopathology , Endometrium/metabolism , Endometrium/pathology , Endometrium/physiopathology , Female , Indazoles , Niacinamide/pharmacology , Ovarian Reserve , Proto-Oncogene Proteins c-kit/metabolism , Rats, Wistar , Signal Transduction/drug effects , Sorafenib , Sunitinib , Vascular Endothelial Growth Factor A/metabolism , bcl-2-Associated X Protein/metabolismABSTRACT
BACKGROUND: Breast cancer evolution and tumor progression are controlled by complex interactions between steroid receptors and growth factor receptor signaling. Aberrant growth factor receptor signaling can augment or suppress estrogen receptor function in hormone-dependent breast cancer cells. Thus, we aimed to investigate antitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells. MATERIALS AND METHODS: Cytotoxicity of the sorafenib and lapatinib was tested in MCF-7 cells by XTT assays. 50, 25, 12.5 and 6.25µM concentrations of sorafenib and 200, 100, 50 and 25µM concentrations of lapatinib were administered alone and in combination. Results were evaluated as absorbance at 450nM and IC50 values are calculated according to the absorbance data RESULTS: Both sorafenib and lapatinib showed concentration dependent cytotoxic effects on MCF-7 cells. Sorafenib exerted cytotoxic effects with an IC50 value of 32.0µM; in contrast with lapatinib the IC50 was 136.6µM. When sorafenib and lapatinib combined, lapatinib increased cytotoxic effects of sorafenib at its ineffective concentrations. Also at the concentrations where both drugs had cytotoxic effects, combination show strong anticancer effects and killed approximately 70 percent of breast cancer cells. CONCLUSIONS: Combinations of tyrosine kinase inhibitors and cytotoxic agents or molecular targeted therapy has been successful for many types of cancer. The present study shows that both sorafenib and lapatinib alone are effective in the treatment of breast cancer. Also a combination of these two agents may be a promising therapeutic option in treatment of breast cancer.
