Stage of Breast Cancer Screening Adoption; The Role of Cognitive Predictors.

Breast cancer is the most common cancer among women. The present study investigated the stage of breast cancer screening adoption and the role of some of the cognitive predictors in a sample of Iranian married women. There were a total of 334 married women clients of eight health centers in Kermanshah city, the west of Iran, were randomly selected to participate voluntarily. Women filled out a self-report questionnaire. Data were analyzed by SPSS version 20 using One-way ANOVA, χ2-test, Fisher's exact test, and bivariate correlations statistical tests at 95% significant level. The mean age was 39.75 years [SD: 7.73]. Nearly 58.4%, 26.9%, 3%, 9.6%, and 2.1% of the respondents were reported pre-contemplation, contemplation, preparation, action, and maintenance of breast cancer screening adoption, respectively. There was a significant association between age (P=0.005), and positive family history of breast cancer (P=0.037), perceived susceptibility (P=0.005), perceived severity (P=0.001) and knowledge of symptoms (P=0.018) with breast cancer stage of screening adoption. Our findings can provide better knowledge for the development and implementing of stage-targeted breast cancer screening adoption promotion programs. We conclude that it seems that the focus of health planner should be to rise to perceived severity; perceived susceptibility and knowledge of symptoms of breast cancer about the promotion of breast cancer screening adoption an Iranian woman.

The Effect of Religious Psychotherapy Emphasizing the Importance of Prayers on Mental Health and Pain in Cancer Patients.

The religious aspect is the most important aspect of the human nature that helps the human achieve the meaning and purpose of life as well as playing a very important role in the health of patients. This study aimed to determine the effect of religious psychotherapy emphasizing the importance of prayers on mental health and pain in cancer patients. This study is a clinical trial that was conducted in 2017 in Yasuj, Iran. According to the purpose of the study, the patients were randomly assigned into two experimental and control groups. Prayers 15 and 23 of the SahifehSajjadiyeh book were read at the beginning of the treatment sessions, and the patients were asked to pay attention to the meaning of prayer. The data were analyzed using SPSS 16 software. Before implementing the intervention, the mean and standard deviation of mental health score of the patients in the experimental and control groups were equal to 16.40 (2.21) and 16.56 (1.56). But after implementing the intervention, the mean and standard deviation of mental health score were equal to 11.24 (2.93) and 16.82 (1.83) which illustrates a significant statistical increase. Implementing the supportive spiritual intervention has been tested to enhance the mental health and reduce the pain of patients in the experimental group. Regarding this improvement, it is suggested a religious intervention be implemented to increase these patients' health in a participatory way.

Synthesis of [18F]FAZA Using Nosyl and Iodo Precursors for Nucleophilic Radiofluorination.

BACKGROUND: 1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole ([18F]FAZA) is manufactured by nucleophilic radiofluorination of 1-α-D-(2',3'-di-O-acetyl-5'-O-toluenesulfonylarabinofuranosyl)- 2-nitroimidazole (DiAcTosAZA) and alkaline deprotection to afford [18F]FAZA. High yields (>60%) under optimized conditions frequently revert to low yields (<20%) in large scale, automated syntheses. Competing side reactions and concomitant complex reaction mixtures contribute to substantial loss of product during HPLC clean-up. OBJECTIVE: To develop alternative precursors for facile routine clinical manufacture of [18F]FAZA that are compatible with current equipment and automated procedures. METHODS: Two new precursors, 1-α-D-(2',3'-di-O-acetyl-5'-O-(4-nitrobenzene)sulfonyl-arabinofuranosyl)-2- nitroimidazole (DiAcNosAZA) and 1-α-D-(2',3'-di-O-acetyl-5'-iodo-arabinofuranosyl)-2-nitroimidazole (DiAcIAZA), were synthesized from commercially-available 1-α-D-arabinofuranosyl-2-nitroimidazole (AZA). A commercial automated synthesis unit (ASU) was used to condition F-18 for anhydrous radiofluorination, and to radiofluorinate DiAcNosAZA and DiAcIAZA using the local standardized protocol to manufacture [18F]FAZA from AcTosAZA. RESULTS: DiAcNosAZA was synthesized via two pathways, in recovered yields of 29% and 40%, respectively. The nosylation of 1-α-D-(2',3'-di-O-acetyl-arabinofuranosyl)-2-nitroimidazole (DiAcAZA) featured a strong competing reaction that afforded 1-α-D-(2',3'-di-O-acetyl-5'-chloro-arabinofuranosyl)-2- nitroimidazole (DiAcClAZA) in 55% yield. Radiofluorination yields were better from DiAcNosAZA and DiAcIAZA than from DiAcTosAZA, and the presence of fewer side products afforded higher purity [18F]FAZA preparations. Several radioactive and non-radioactive by products of radiofluorination were assigned tentative chemical structures based on co-chromatography with authentic reference compounds. CONCLUSION: DiAcClAZA, a major side-product in the preparation of DiAcNosAZA, and its deprotected analogue (ClAZA), are unproven hypoxic tissue radiosensitizers. DiAcNosAZA and DiAcIAZA provided good radiofluorination yields in comparison to AcTosAZA and could become preferred [18F]FAZA precursors if the cleaner reactions can be exploited to bypass HPLC purification.

ß -[18F]Fluoro Azomycin Arabinoside (ß -[18F]FAZA): Synthesis, Radiofluorination and Preliminary PET Imaging of Murine A431 Tumors.

BACKGROUND: 1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole([18F] FAZA) is a PET radiotracer that demonstrates excellent potential in imaging regional hypoxia, and is clinically used in diagnosing a wide range of solid tumors in cancer patients. [18F]FAZA, however, is radiofluorinated in only moderate recovered radiochemical yield (rRCY, ~12%). It is postulated that the relative stability of the C1' ß-anomeric bond at C5' will make 1-ß-D-(5-fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole (ß-FAZA), the ß-conformer of FAZA, an attractive candidate for clinical hypoxia imaging. OBJECTIVES: The principle goals were to synthesize ß-FAZA and ß-Ac2TsAZA, the radiofluorination precursor, to establish the radiofluorination chemistry leading to ß-[18F]FAZA, and to investigate the biodistribution of ß-[18F]FAZA in an animal tumor-bearing model using PET imaging. METHODS: The appropriately-protected furanose sugar was coupled with 2-nitroimidazole to afford 1-ß-D-(2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (ß-Ac2AZA). Fluorination of ß-Ac2AZA with DAST, followed by alkaline hydrolysis, afforded ß-FAZA (21%). The radiolabeling synthon, 1-ß-D-(5-O-toluenesulfonyl-2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (ß-Ac2TsAZA), on radiofluorination using the 18F/K222 complex under various reaction conditions, followed by base-catalyzed deacetylation, afforded ß-[18F]FAZA. ß-[18F]FAZA was radiochemically stable for at least 8 h when stored in aqueous ethanol (8%) at 22 °C. A preliminary PET imaging-based biodistribution study of ß-[18F]FAZA was performed in A431 tumor-bearing nude mice. RESULTS: ß-FAZA and ß-Ac2TsAZA were synthesized in satisfactory yield. Radiochemistry of [18F]FAZA was established. PET images showed strong uptake in hypoxic regions of the tumor. CONCLUSION: The synthesis of ß-FAZA and ß-[18F]FAZA are reported. Radiofluorination of ß-Ac2TsAZA and the deprotection of ß-Ac2[18F]FAZA were facile, but led to a more complex mixture of radiofluorinated by-products than observed with the corresponding precursor of α-[18F]FAZA. PET images were indicative of hypoxia-selective accumulation of ß-[18F]FAZA in tumor.

Synthesis, radiofluorination, and hypoxia-selective studies of FRAZ: A configurational and positional analogue of the clinical hypoxia marker, [18F]-FAZA.

The current work evaluates 1-alpha-d-(2-deoxy-2-fluororibofuranosyl)-2-nitroimidazole (FRAZ), a novel azomycin nucleoside that is a potential radiosensitizer of tumor hypoxia. FRAZ is a ribose analogue of 1-alpha-d-(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole ([(18)F]-FAZA), a clinically used hypoxia marker. Preliminary assessment of the cytotoxicity and hypoxia-specific in vitro binding in HCT-110 colorectal cancer cells indicate that the radiosensitization properties of FRAZ are similar to that of FAZA, with a sensitizer enhancement ratio (SER) of approximately 1.8. An automated radiosynthesis of [(18)F]-FRAZ using a commercial automated synthesis unit (ASU) was established (synthesis time approximately 32 min; radiochemical yield (decay uncorrecetd) approximately 22%) to facilitate its application in PET-based diagnosis of hypoxic tumors.

A one-pot synthesis of 1-alpha- and 1-beta-D-arabinofuranosyl-2-nitroimidazoles: synthons to the markers of tumor hypoxia.

1-alpha- and 1-beta-D-Arabinofuranosyl-2-nitroimidazole (alpha-AZA and beta-AZ A) are synthons for a number of potential markers of tissue hypoxia. A one pot synthesis in which 2-nitroimidazole is coupled with a mixture of alpha- and beta-1-O-acetyl-2,3,5-tri-O-benzoyl-D-arabinofuranose in the presence of stannic chloride, followed by deprotection using ammonia/methanol, is described Previously reported conditions for coupling 2-nitroimidazole to 1-alpha-bromoarabinofuranose protected by base-hydrolyzable groups afforded alpha-AZA almost exclusively.

Dose-dependent pharmacokinetics of 1-(2-deoxy-beta-D- ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2'-deoxyuridine.

The dose-range pharmacokinetics of l-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR), a C-aryl nucleoside mimic of IUdR, were studied in male Sprague-Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from approximately 32 ml/min/kg at a dose of 15 mg/kg, to approximately 19 ml/min/kg when dosed at 54 mg/kg, and the elimination half-life increased from 8.4 min to 21.5 min, for the respective doses. While the dose-normalized area under the concentration-time curve (AUCnorm) remained practically unchanged (0.132 kg min ml(-1)) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% ( approximately 0.19 kg min ml(-1)) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose-dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half-life increased from 24.5 min to 176 min, while blood clearance was reduced from approximately 37 ml/min/kg to approximately 17 ml/min/kg. The urinary recoveries of unchanged 5-IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5-IDFPdR (as percent of the dose) was, however, decreased with increasing doses. The overall kinetic profile of 5-IDFPdR based on these data is suggestive of dose-dependent pharmacokinetics. Decreased elimination of 5-IDFPdR with increasing dose, as supported by longer elimination half-lives at higher doses, is one likely mechanism contributing to the dose-dependent behaviour of this compound. Saturable non-renal metabolism might explain the reduced total body clearance of 5-IDFPdR at higher doses, despite the unchanged or increased urinary clearance. For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5-IDFPdR, which may be of therapeutic relevance, warrants extended dose-range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens.

Biochemical and pharmacokinetic evaluation of a novel pyrimidine nucleoside nitric oxide donor as a potential anticancer/antiviral agent.

The objective of this study was to determine the physiochemical, biochemical and pharmacokinetic properties of 5-iodo-3'-O-nitro-2'-deoxyuridine (INUdR), a novel prodrug releasing both nitric oxide (NO) and 5-iodo-2'-deoxyuridine. The INUdR partition coefficient (log P=1.12) was determined by both the shake-flask method and by calculation using Interactive Analysis Log P Program. In vitro binding of INUdR to bovine serum albumin (BSA) was estimated using an ultrafiltration method to be 65 to 77%, depending on the INUdR concentration. INUdR was stable in phosphate buffer (pH 7.4) and in water, at both ambient temperature and at 37 degrees C. INUdR was resistant to phosphorolysis when incubated with thymidine phosphorylase. Plasma, L-cysteine and glutathione catalyzed release of NO from INUdR, as determined using the Griess reaction. In all three systems, the release of NO by INUdR was equal to or greater than that of the reference drug isosorbide dinitrate. The pharmacokinetics of INUdR following single intravenous bolus and oral doses of INUdR (40 mg/kg) to male Sprague-Dawley rats were characterized by a short elimination half-life (T(1/2) 0.27 h), a large steady-state volume of distribution (V(ss) 0.89 l/kg) and high oral bioavailability (F=0.95). In conclusion, INUdR lipophilicity, shelf-stability, and resistance towards catabolic breakdown by thymidine phosphorylase, together with its non-spontaneous, yet considerable NO release, constitute favorable characteristics of a potential anticancer/antiviral agent.

Synthesis of 3'- and 5'-nitrooxy pyrimidine nucleoside nitrate esters: "nitric oxide donor" agents for evaluation as anticancer and antiviral agents.

A group of 3'-O-nitro-2'-deoxyuridines, 3'-O-nitro-2'-deoxycytidines, and 5'-O-nitro-2'-deoxyuridines possessing a variety of substituents (H, Me, F, I) at the C-5 position were synthesized for evaluation as anticancer/antiviral agents that have the ability to concomitantly release cytotoxic nitric oxide (*NO). Although these compounds generally released a greater percent of *NO than the reference drug isosorbide dinitrate upon incubation in the presence of l-cysteine, or serum, their cytotoxicity (CC(50) = 10(-3) to 10(-6) M range) was comparable to 5-iodo-2'-deoxyuridine, but weaker than 5-fluoro-2'-deoxyuridine, against a variety of cancer cell lines. No differences in cytotoxicity against nontransfected (KBALB, 143B), and the corresponding transfected (KBALB-STK, 143B-LTK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK(+)) were observed, indicating that expression of the viral TK enzyme did not provide a gene therapeutic effect. These nitrate esters were inactive antiviral agents except for 5-iodo-3'-O-nitro-2'-deoxyuridine that showed modest activity against HSV-1, HSV-2, and vaccinia virus.

Imaging expression of adenoviral HSV1-tk suicide gene transfer using the nucleoside analogue FIRU.

Substrates for monitoring HSV1-tk gene expression include uracil and acycloguanosine derivatives. The most commonly used uracil derivative to monitor HSV1-tk gene transfer is 1-(2-fluoro-2-deoxy--D-arabinofuranosyl)-5-[*I]iodouracil (fialuridine; I*-FIAU), where the asterisk denotes any of the radioactive iodine isotopes that can be used. We have previously studied other nucleosides with imaging properties as good as or better than FIAU, including 1-(2-fluoro-2-deoxy--D-ribofuranosyl)-5-[*I]iodouracil (FIRU). The first aim of this study was to extend the biodistribution data of 123I-labelled FIRU. Secondly, we assessed the feasibility of detecting differences in HSV1-tk gene expression levels following adenoviral gene transfer in vivo with 123I-FIRU. 9L rat gliosarcoma cells were stably transfected with the HSV1-tk gene (9L-tk+). 123I-FIRU was prepared by radioiodination of 1-(2-fluoro-2-deoxy--D-ribofuranosyl)-5-tributylstannyl uracil (FTMRSU; precursor compound) and purified using an activated Sep-Pak column. Incubation of 9L-tk+ cells and the parental 9L cells with 123I-FIRU resulted in a 100-fold higher accumulation of radioactivity in the 9L-tk+ cells after an optimum incubation time of 4 h. NIH-bg-nu-xid mice were then inoculated subcutaneously with HSV1-tk (-) 9L cells or HSV1-tk (+) 9L-tk+ cells into both flanks. Biodistribution studies and gamma camera imaging were performed at 15 min and 1, 2, 4 and 24 h p.i. At 15 min, the tumour/muscle, tumour/blood and tumour/brain ratios were 5.2, 1.0 and 30.3 respectively. Rapid renal clearance of the tracer from the body resulted in increasing tumour/muscle, tumour/blood and tumour/brain ratios, reaching values of 32.2, 12.5 and 171.6 at 4 h p.i. A maximum specific activity of 22%ID/g tissue was reached in the 9L-tk+ tumours 4 h after 123I-FIRU injection. Two Ad5-based adenoviral vectors containing the HSV1-tk gene were constructed: a replication-incompetent vector with the transgene in the former E1 region, driven by a modified CMV promoter, and a novel replication-competent vector with the HSV1-tk gene in E3 driven by the natural E3 promoter. The human glioma cell lines U87MG and T98G were infected with a multiplicity of infection (m.o.i.) of 10. Forty-eight hours later the cells were incubated with 123I-FIRU and radioactivity was measured in a gamma counter. We found significantly higher levels of radioactivity in both cell lines following infection with the replication-competent vector (P<0.001). NIH-bg-nu-xid mice were then inoculated subcutaneously with U87MG cells. Tumours (approximately 1,000 mm3) were injected with 108 and 109 Infectious Units (I.U.) of either vector. After 48 h, the tracer was injected, followed by gamma camera imaging and direct measurement of radioactivity in the tumours at 4 h p.i. Images and direct measurements indicated increased uptake of tracer with higher I.U. and also demonstrated increased accumulation of tracer in the tumours treated with the replication-competent adenoviral vector (P=0.03). These results demonstrate that 123I-FIRU in combination with HSV1-tk is a valuable tracer for in vivo monitoring of adenoviral gene transfer.

Pharmacokinetics and metabolism of the novel synthetic C-nucleoside, 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2'-deoxyuridine.

1-(2-Deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR) is one of the several unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzenes recently synthesized for evaluation as anticancer, antiviral and diagnostic imaging agents. This class of C-nucleosides was designed to exploit several potential advantages relative to classical 5-substituted-2'-deoxyuridines, including stability towards phosphorolysis by pyrimidine phosphorylase, increased lipophilicity that may alter their ability to cross the blood-brain-barrier, and a greater resistance towards catabolism and deiodination. The physiochemical evaluation of 5-IDFPdR showed high lipophilicity (log P = 2.8), moderately high protein binding (70-75%), stability towards phosphorolysis (e.g. no evidence of metabolic deglycosylation) by thymidine phosphorylase, and minimal microsomal metabolism in vitro. Pharmacokinetic studies of 5-IDFPdR in rat were characterized by a short elimination half-life (9-12 min), modest urinary elimination in pooled 0-24 h urine specimens (10-14%, including 2% as unconjugated drug) and high oral bioavailability (F = 0.96). Both glucuronide and sulfate metabolites were present in urine. Glucuronidation was the predominant conjugation pathway.