Evaluation of cytotoxicity of some Mannich bases of various aryl and arylidene ketones and their corresponding arylhydrazones.

Mannich bases were synthesized and converted to the corresponding arylhydrazones. X-ray analysis of a ketone (1a) and a hydrazone (4d) revealed structural features of interest. All of the compounds showed cytotoxicity toward murine lymphocytic leukemia L1210 cells in the 4.9-25.0-microM range. The correlation coefficients generated by plotting the IC50 values (the concentrations of compounds that inhibit the growth of tumors by 50%) of some hydrazones against certain electronic, hydrophobic, and steric constants of the aryl substituents indicated only weak correlations. A few ketones and hydrazones displayed significant cytotoxicity to the WiDr human colon cancer cells, and these derivatives, especially the ketones, may serve as prototypes for future drug development. The KB tumor (a human epidermoid carcinoma of the nasopharynx) was somewhat refractory to selected compounds. In an in vitro assay conducted by the National Cancer Institute and involving approximately 53 tumor cell lines originating from eight neoplastic diseases, 65% of the compounds showed some selectivity toward one or more groups of cancers, principally leukemia, melanoma, and colon cancer. The bioevaluation of the ketones and hydrazones against the L1210, WiDr, and KB tumors, as well as evidence from proton nuclear magnetic resonance studies did not support the suggestion that hydrazones may be prodrugs of the corresponding ketones.     

The genetic aetiology of somatic distress

BACKGROUND: Somatoform disorders such as neurasthenia and chronic fatigue syndrome are characterized by a combination of prolonged mental and physical fatigue. This study aimed to investigate the heritability of somatic distress and determine whether this dimension is aetiologically distinct from measures of depression and anxiety. METHOD: Measures of anxiety, depression, phobic anxiety, somatic distress and sleep difficulty were administered in a self-report questionnaire to a community-based sample of 3469 Australian twin individuals aged 18 to 28 years. Factor analysis using a Promax rotation, produced four factors: depression, phobic anxiety, somatic distress and sleep disturbance. Multivariate and univariate genetic analyses of the raw categorical data scores for depression, phobic anxiety and depression were then analysed in Mx1.47. RESULTS: Univariate genetic analysis revealed that an additive genetic and non-shared environmental (AE) model best explained individual differences in depression and phobic anxiety scores, for male and female twins alike, but could not resolve whether additive genes or shared environment were responsible for significant familial aggregation in somatic distress. However, multivariate genetic analysis showed that an additive genetic and non-shared environment (AE) model best explained the covariation between the three factors. Furthermore, 33 % of the genetic variance in somatic distress was due to specific gene action unrelated to depression or phobic anxiety. In addition, 74% of the individual environmental influence on somatic distress was also unrelated to depression or phobic anxiety. CONCLUSION: These results support previous findings that somatic symptoms are relatively aetiologically distinct both genetically and environmentally from symptoms of anxiety and depression.     

Cognitive function in depression: a distinct pattern of frontal impairment in melancholia?

BACKGROUND: Although depressed patients demonstrate impaired performance on a range of neuropsychological tests, there is little research that examines either frontal cognitive deficits or possible differences in test performance between melancholic and non-melancholic subtypes. METHODS: Depressed subjects were administered a broad neuropsychological battery. In an overall analysis, 77 depressed subjects were compared with 28 controls. In a second set of analyses, the depressed sample was divided into melancholic and non-melancholic subsets according to DSM-III-R, the CORE system and the Newcastle scale. These depressed subsets were contrasted to controls and with each other using ANCOVA controlling for age, IQ, simple reaction time and Hamilton Depression scores where appropriate. RESULTS: The total depressed sample was impaired on most mnemonic tasks, simple reaction time and Trails B. Similar findings applied to DSM-III-R melancholic and non-melancholic subjects. When defined by the CORE and Newcastle (narrower definitions of melancholia), melancholic patients were additionally impaired on WCST (perseverative response) and (for Newcastle) digit symbol substitution. In contrast, the cognitive performance of the CORE and Newcastle-defined non-melancholic patients was largely unimpaired. CONCLUSIONS: Using narrower definitions of melancholia, i.e. CORE and (in particular) Newcastle, melancholic patients were impaired on mnemonic tasks and tasks of selective attention, and set-shifting while non-melancholic subjects were largely unimpaired in their cognitive performance. These differences may be due to impairment of specific neuroanatomical regions in narrowly defined melancholic patients, in particular the anterior cingulate.     

Angiogenesis is an early event in the development of chemically induced skin tumors

In this study we have analyzed the vascular response induced in the two- stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g. colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model.