Nadia I. Zakhary

A study on the aetiological factors of bilharzial bladder cancer in Egypt--1. Nitrosamines and their precursors in urine.

Abstract Endogenous nitrosamines and nitrosamines formed by deliberate chemical nitrosation of urine have been found to be much higher in urine of bilharzial infested and bladder cancer patients when compared with that of normal or cancer patients other than bladder cancer. Thiocyanate had been detected in all different types of urine samples. Nitrite was not found in normal urine but it had been detected in the urine of 3 out of 10 bilharzial patients. 7 out of 15 bladder cancer patients and 1 out of 14 non-bladder cancer patients.

In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs

Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents.

Impact of PIVKA-II in diagnosis of hepatocellular carcinoma.

Liver cancer grows silently with mild or no symptoms until advanced. In the absence of an effective treatment for advanced stage of hepatic cancer hope lies in early detection, and screening for high-risk population. Among Egyptians viral hepatitis is the most common risk factor for hepatocellular carcinoma (HCC). The current work was designed to determine the level of prothrombin induced by vitamin K absence-II (PIVKA-II) in sera of patients suffering from HCC and hepatitis C virus (HCV) patients being the most common predisposing factor for HCC. Our ultimate goal is diagnosis of HCC at its early stage. The current study was carried out on 83 individuals within three groups; Normal control, HCV and HCC groups. Patients were subdivided into cirrhotic and non-cirrhotic. Complete clinicopathological examination was carried out for each individual to confirm diagnosis. Individuals’ sera were subjected to quantitative determination of alpha-fetoprotein (AFP), PIVKA-II and other parameters. PIVKA-II proved to be superior to AFP for early detection of HCC patients being highly sensitive and specific. Furthermore it has the ability to discriminate between different histopathological grades of HCC and It has a powerful diagnostic validity to evaluate the thrombosis of portal vein and to differentiate between early and late stages of HCC. The direct relation between the level of PIVKA-II and the size of tumor makes it an attractive tool for early HCC diagnosis and surveillance. Using the best cut-off value of AFP (>28), showed a sensitivity of (44%) and specificity of (73.3%). While cut-off value of PIVKA-II (>53.7) showed 100% sensitivity and specificity.

Effect of Vicia faba and bran feeding on nitrosamine carcinogenesis and formation

The goal of this work was to study the effect of the most common Egyptian food items, Vicia faba beans (VF) and bran, on the carcinogenicity of dibutylnitrosamine (DBN) precursors (dibutylamine and nitrite). Mice receiving DBN precursors showed a delayed gain in body weight as well as decreased protein level and 5-nucleotidase activity. Acid ribonuclease, alkaline phosphatase, and DNA level and rate of synthesis were significantly increased compared with corresponding controls. Hepatomas and bladder papillomas developed in 60% and 40% of mice, respectively, after nine months of treatment. On the other hand, administration of VF or bran, in addition to DBN precursors, lessened the damage caused by DBN precursors alone, except DNA level and rate of synthesis were elevated. Alkaline phosphatase was also elevated when bran was administered with DBN precursors. However, these elevations were still less than corresponding elevations in mice receiving DBN precursors alone. The incidence of hepatoma was also reduced to only 20% for both groups. Meanwhile, incidence of bladder papillomas was only 20% in mice receiving VF in addition to DBN precursors, and bladder papillomas were completely absent in mice receiving bran in addition to DBN precursors. In vitro studies were also performed to clarify the effect of VF or bran on diphenylnitrosamine (DPhNA) and its formation from its precursors (diphenylamine and nitrite). The study revealed that VF and bran have the ability to eliminate nitrite and DPhNA from the reaction media and to reduce the rate of formation of DPhNA from its precursors. This reaction depends on the concentration and form of VF or bran and the duration of the reaction. Thus it is concluded that some naturally occurring food items, such as VF and bran, could protect humans against the hazardous effect of nitrosamines and their precursors.

A study on the aetiological factors of bilharzial bladder cancer in Egypt—2 Nitrosamines and their precursors in Egyptian dairy products

Abstract Milk, yoghourt and four types of cheese consumed by Egyptians have been analysed for the presence of nitrosamines, and that formed after deliberate chemical nitrosation. Two, three, seven out of ten samples of milk, cottage cheese, white cheese and six out of 9 samples of salted cheese respectively were contaminated with nitrosamines at g × 10 −9 level. Deliberate chemical nitrosation produced increasing amounts of both volatile and nonvolatile nitrosamines especially in blue cheese and salted cheese (cottage cheese stored in high concentrations of sodium chloride). The daily consumption of salted cheese and drinking water with high nitrate content, beside a heavily infected urinary bladder due to bilharzial infestation, may contribute to the observed high incidence of bladder cancer among Egyptian farmers.

Copper (II)-Surfactant Complex and Its Nano Analog as Potential Antitumor Agents

The in vitro anticancer activity of copper cetyl trimethyl ammonium bromide (Cu-CTAB)-loaded cyclodextrin nanoparticles on Ehrlich ascites carcinoma (EAC), colon cancer cells (HCT 116), liver cancer cells (HepG-2), breast cancer cells (MCF-7), and cervix cancer cells (Hela) was investigated using MTT due assay. Cyclodextrin nanoparticles loaded with Cu-CTAB exerted in vitro anticancer activity against the previous human cancer cell lines comparable to the activity of free non-entrapped in nanoparticles macro-particle Cu-CTAB. The nano analog was synthesized by physical loading using grinding with ball mill. The ratio between Cu-CTAB and cyclodextrin oligosaccharide was 1 Cu-CTAB: 3 cyclodextrin. The particle size of the nano derivative was determined using the transmitted electron microscope (TEM).

A study on the etiological factors of bilharzial bladder cancer in Egypt: 5-urinary nitrite in a rural population.

Urinary nitrite was present in 5.6 % of 2379 individuals from a rural population infested with « Schistosoma haematobium ». A higher frequency was observed in symptomatic patients with active bilharzial cystitis (25 %) and patients with bladder cancer associated with schistosomiasis (66.2 %); conversely, urinary nitrite was absent in normal urban individuals. The frequency of urinary nitrite was higher in females (6.4%) than males (4.6%), and was more frequent in adults than extremes of age. The presence of urinary nitrite was associated with urinary infection and was commonly accompaned by cellular atypia in urine, in the form of dysplasia. Under these circumstances, carcinogenic nitrosamines are liable to be produced in the bladder from urinary nitrite and amines. These observation support the possible role of urinary bacterial infection, commonly associated with bilharzial cystitis, in bladder carcinogenesis.

Effect of soybean, Vicia faba, and vitamin C on the carcinogenicity of DMBA.

A single dose of 10 mg of 7,12-dimethylbenz[a]anthracene (DMBA), administered to rats through intragastric intubation, was sufficient to induce many biochemical and histopathological changes in their mammary tissue. Significant increases were observed in the activity levels of the enzymes acid ribonuclease, 5-nucleotidase, alkaline phosphatase, and beta-glucuronidase in mammary tissue homogenates of DMBA-treated rats after an experimental period of five months. Histopathological studies of the mammary tissue also revealed malignant epithelial tumors (cribriform carcinoma) induced among 85% of the treated rats, with an incidence of 4 tumors in 12 mammary glands. Nevertheless, administration of 30% soybean in the diet of rats or 5,000 ppm ascorbic acid in their drinking water in addition to DMBA revealed a significant chemoprotective effect against the carcinogenesis induced by DMBA alone. This chemoprotective effect was demonstrated by the normalization of the activity levels of the enzymes studied in mammary tissue homogenates, because most of the enzymes were maintained at near the levels in the control animals. The incidence and number of tumors were also decreased. Cribriform carcinoma was observed in 50% of the rats, and the incidence of the affected glands was 2 in 12 mammary glands among both groups. On the other hand, a less chemoprotective effect was observed due to Vicia faba administration.

Aging, Metabolic, and Degenerative Disorders: Biomedical Value of Antioxidants

Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt Chrono-Environment Laboratory, Bourgogne Franche-Comté University, UMR CNRS 6249, 25030 Besançon Cedex, France Pharmacy Department, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania Centre for Interdisciplinary Research, D. Y. Patil University, Kolhapur 416006, India Department of Biochemistry, College of Science, King Saud University, Riyadh 11495, Saudi Arabia

Prognostic significance of plasma osteopontin level in breast cancer patients

Abstract Many studies have demonstrated that osteopontin (OPN) contributes functionally to aggressive behaviour in many tumours including breast cancer. This study aims to investigate its role as a simple biochemical marker easily measured in plasma of breast cancer patients to give an early signal for metastases and to detect its relationship to clinicopathological findings and survival. We measured plasma OPN, CA15.3 and serum alkaline phosphatase (ALP) activity in 55 patients, 28 with early stage breast cancer and 27 with bone metastasis out of whom 20 had metastasis in other sites. The median age at diagnosis for non-metastatic cases was 60 years (range 35-85) and for metastatic cases was 45.5 years (range 32-59). In the non-metastatic group, 78.57% of the patients were histologically graded as grades I and II and 21.43% as grade III tumours. In the metastatic group, 81.48% of the patients had grades I and II and 18.52% had grade III tumours; 54% of patients in the non-metastatic group were at stage II and 46% were at stage III at presentation. All patients of group II had bone metastasis, 33% had liver metastases, 25.9% had lung metastasis and 14.8% had lymph node metastasis. Patients with non-metastatic disease had a median OPN level of 55 ng/ml (range 54-150 ng/l), while those in the metastatic group had a median of 148.0 ng/l (range 56.0-156.0 ng/l), a difference which was statistically significant (P = 0.001). There was no statistically significant difference in the median levels of CA15.3 and ALP between both groups. The median OPN level was significantly higher with serum ALP level above 90, progesterone receptor (PR) status, bone and visceral metastasis. Median OPN was not affected significantly by menopausal status (P-value 0.3), tumour grade (P-value 0.3), estrogen receptor (ER) status (P-value 0.7), pathological type (P-value 0.42) or serum CA15.3 level (P-value 0.6). At the end of 12-year follow-up, 83% of the patients survived (92.3% in the non-metastatic versus 74.1% in the metastatic group). The estimated median survival for the whole study population at 12 years was 13 years (95% CI 8.144-17.856). The estimated median survival was 13 years (95% CI 0) and 12 years (95% CI 4.893-19.11) in patients with median OPN levels of <142 and ≥142, respectively, a difference which was not statistically significant (P = 0.343). No statistically significant difference in overall survival OS was noticed in relation to menopausal status (P = 0.7), pathological type (P = 0.4) and hormone receptor status (P = 0.3). At 6-year follow-up, it was found that OS was affected by the presence of visceral metastasis, tumour grade, serum plasma level of ALP and the serum level of CA15.3 (P = 0.0006, 0.007, 0.001 and 0.03, respectively). However, the presence of bone metastasis did not affect OS (P = 0.6). Osteopontin level can be a simple biochemical marker easily measured in plasma of breast cancer patients to give early signals for metastases, but not a prognostic factor for survival.