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    Evaluation of morphine effect on tumour angiogenesis in mouse breast tumour model, EATC
    (Humana Press Inc, 2011) Ustun, Funda; Durmus-Altun, Gulay; Altaner, Semsi; Tuncbilek, Nermin; Uzal, Cem; Berkarda, Sakir
    Breast cancer is the leading cause of death among women, and morphine is used to relieve the pain of patients with cancer. The data on the effects of morphine on tumour growth and angiogenesis are contradictory. We determined in mouse breast cancer model whether analgesic doses of morphine would affect tumour angiogenesis, and then the correlation between microvessel density (MVD), Doppler sonography (DS) and Tc-99m-Tetrofosmin (TF) uptake. Ehrlich ascites tumour cell xenografts, Pgp-negative tumour were divided into two groups: (a) Morphine sulphate [0.714 mg/kg/day (equivalent to 50 mg per day for a 70 kg human)], (b) no-morphine. For the determination of angiogenesis in mice tumour tissue, TF scintigraphy, microvessel density and DS were done. MVD was significantly different between groups (49.4 +/- 1.8 vs. 41.8 +/- 1.9, morphine and no-morphine groups, respectively, P < 0.001). A strong correlation was found between late uptakes of mass at scintigraphy and degree of angiogenesis in histopathologic examination (r = 0.52, P < 0.01). There was statistically significant inverse correlation between degree of angiogenesis in histopathologic examination and washout ratio of TF (r = 0.40, P < 0.05). The higher values for angiogenesis are related to higher TF reuptake. There was no statistically significant correlation between DS and TF. A strong correlation was found between MVD and grade of DS (r = 0.51, P < 0.01). Our preclinical mice study indicates that morphine at clinically relevant doses stimulates angiogenesis, and angiogenesis triggered of morphine is demonstrated with MVD and DS, but not TF. However, uptake and washout of TF are compared with immunohistochemically assessed morphine-stimulated angiogenesis in tumour tissue.
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    Glucose-Induced Alteration of Accumulation of Organotechnetium Complexes Accumulation in Pgp-Negative Tumor-Bearing Mice
    (Mary Ann Liebert Inc, 2009) Ustun, Funda; Durmus-Altun, Gulay; Cukur, Ziya; Altaner, Semsi; Berkarda, Sakir
    The biologic and microenvironmental factors determining (99m)Tc sestamibi (MIBI) and (99m)Tc tetrofosmin (TF) uptake in breast tumors are incompletely understood, especially in P-glycoprotein (Pgp)-negative tumors. We analyzed the influence of glucose administration on the uptake and retention of MIBI and TF in Pgp-negative tumor-bearing mice in vivo. Twenty (20) mice bearing Ehrlich ascites tumor cell (EATC) xenografts were divided into four groups: (1) MIBI, (2) MIBI+glucose, (3) TF, and (4) TF+glucose. Glucose was administered (5.0 g/kg body weight) intraperitoreally (i.p.) 1 hour before scintigraphy. There were significant differences between the E-UPR MIBI and MIBI+glucose groups (p = 0.009) and minor differences in L-UPR between these groups (p = 0.04). There was a significant inverse correlation between E-UPR of MIBI and glucose levels (r = 0.71, p = 0.02). Comparing the four groups, the highest E-UPR was obtained in the MIBI group (p = 0.006). Other parameters were not different in the MIBI and MIBI+glucose groups and in the TF and TF+glucose groups. Increased blood glucose level affected the MIBI uptake of tumor tissue, particularly for E-UPR. We suggest that these findings were due to basically decreased blood flow and secondarily decreased extracellular pH. However, glucose administration did not affect TF.
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    HISTOPATHOLOGICAL AND SCINTIGRAPHIC COMPARISONS OF THE PROTECTIVE EFFECTS OF l-CARNITINE AND AMIFOSTINE AGAINST RADIATION-INDUCED LATE RENAL TOXICITY IN RATS
    (Wiley-Blackwell Publishing, Inc, 2009) Caloglu, Murat; Yurut-Caloglu, Vuslat; Durmus-Altun, Gulay; Oz-Puyan, Fulya; Ustun, Funda; Cosar-Alas, Rusen; Saynak, Mert
    The aim of the present study was to compare the protective effects of l-carnitine and amifostine against radiation-induced late nephrotoxicity using technetium-99m diethylenetriaminepentaacetic acid scintigraphy and histopathological examination. Seventy-one Albino rats were randomly divided into six groups as follows: (i) AMI + RAD (n = 15), 200 mg/kg, i.p., amifostine 30 min prior to irradiation (a single dose of 9 Gy); (ii) LC + RAD (n = 15), 300 mg/kg, i.p., l-carnitine 30 min prior to irradiation; (iii) LC (n = 10), 300 mg/kg, i.p., l-carnitine 30 min prior to sham irradiation; (iv) AMI (n = 10), 200 mg/kg, i.p., amifostine 30 min prior to sham irradiation; RAD (n = 11), 1 mL/kg, i.p., normal saline 30 min prior to irradiation; and (vi) control (n = 10), 1 mL/kg, i.p., normal saline 30 min prior to sham irradiation. Scintigraphy was performed before treatment and again 6 months after treatment. Kidneys were examined by light microscopy and a histopathological scoring system was used to assess the degree of renal damage. The main histopathological findings were proximal tubular damage and interstitial fibrosis. Glomerular injury was similar in all groups. Tubular degeneration and atrophy were less common in the AMI + RAD group than in the RAD group (P = 0.011 and P = 0.015, respectively), as well as in the LC + RAD group compared with the RAD group (P = 0.028 and P = 0.036, respectively). Interstitial fibrosis in the AMI + RAD and LC + RAD groups was significantly less than that in the RAD group (P = 0.015 and P = 0.015, respectively). The highest total renal injury score (9) was seen in the RAD group. On scintigraphy, there were significant differences in post-treatment time to peak count (T(max)) and time from peak count to half count (T(1/2)) values (P = 0.01 and 0.02, respectively) between groups in the right kidney. In the control and RAD groups, the T(1/2) of the right kidney was 8 +/- 2 and 21 +/- 2 min, respectively. The T(max) values for the AMI + RAD and LC + RAD groups (2.8 +/- 0.2 and 3.2 +/- 0.2 min, respectively) were similar to those in the control group (2.5 +/- 0.3 min). Based on the results of the present study, l-carnitine and amifostine have comparable and significant protective effects against radiation-induced late nephrotoxicity.