A novel 9-aza-anthrapyrazole effective against human prostatic carcinoma xenografts

OBJECTIVES: Systematic investigation of a novel series of intercalating agents, 9-aza-anthrapyrazoles, has led to the identification of a promising analogue, BBR 3438. This study describes the antitumour efficacy of the novel compound in human prostate carcinoma models and the molecular/cellular basis of its activity. METHODS AND RESULTS: The novel 9-aza-anthrapyrazole BBR 3438 was significantly more effective than doxorubicin and losoxantrone (DuP-941) in two of the three tested prostate carcinoma models. The superior activity was more evident in PC3 tumour, since BBR 3438 produced an appreciable rate of complete tumour regressions. Under these conditions, the drug-induced antiproliferative activity paralleled delayed apoptosis. Tumour response to in vivo drug treatment was associated with an early down-regulation of Bcl-2, which was somewhat more marked for the aza compound. In fact, the 9-aza-anthrapyrazole induced DNA cleavage in vitro with isolated DNA topoisomerase II (isoform alpha) and DNA strand breaks in prostatic carcinoma cells. Although the molecular effects of losoxantrone and the 9-aza analogue on the enzyme target were comparable, the cytotoxic effects of BBR 3438 could be enhanced by long-term exposure as a consequence of favourable cellular accumulation and prominent DNA-binding affinity. In addition, a lower reduction potential of the 9-aza-anthrapyrazole in comparison with classical anthrapyrazoles suggests an increased ability of the drug to induce oxidative stress following free radical production, which may be a contributing factor in determining the long-term response (i.e. delayed cell death) to genotoxic damage. CONCLUSIONS: BBR 3438 exhibited a unique profile of preclinical activity with a superior efficacy against prostatic carcinoma models compared to reference compounds (doxorubicin and losoxantrone). The antitumour efficacy of BBR 3438 against prostatic carcinoma could be the result of a combination of favourable events, including enhanced intracellular accumulation and an increased DNA-binding affinity favouring the accumulation of multiple sublethal or lethal damage. In spite of its enhanced cytotoxic potency, the 9-aza compound was better tolerated in vivo than losoxantrone, thus improving the therapeutic index. The preclinical profile of efficacy against prostatic carcinoma, a tumour resistant to conventional antitumour drugs, makes the novel 9-aza-anthrapyrazole BBR 3438 a promising candidate for clinical evaluation.     

Nutritional characteristics of a rural Southern Italy population: the Ventimiglia di Sicilia Project

OBJECTIVE: Knowledge of alimentary habits among populations permits a better definition of appropriate public health interventions. We designed the epidemiological project "Ventimiglia di Sicilia" to characterize the risk profile in a rural village with low total cholesterol levels and low early cardiovascular mortality but with a large prevalence of overweight and obesity, which previously have been significantly associated with total mortality. METHODS: 488 individuals of age 20 to 69 years were included in the dietary survey conducted by a seven-day food record. RESULTS: Alimentary habits were characterized by high consumption of total and complex carbohydrates (respectively 52.5 +/- 7.6% and 46.6 +/- 8.2% of daily energy) and by a low cholesterol intake (92.5 +/- 35.0 mg/1000 kcal/day). Fat intake was 34.7 +/- 7.7% of daily energy due to a higher consumption of monounsaturated fats in respect to saturated fats (respectively 20.5 +/- 5.1% and 10.2 +/- 2.9% of daily energy). In particular, in this population there was a large consumption of bread, pasta, fresh vegetables, olive oil and fruits. We also observed an excess of total calories (about 2900 kcal/day in men and 2100 kcal/day in women) not balanced by a high degree of physical activity levels. Furthermore we found a significant higher total and saturated fat consumption in the youngest individuals and in people with higher educational levels. CONCLUSIONS: Dietary habits of Ventimiglia di Sicilia still follow the nutritional characteristics typical of the Mediterranean diet. The high total calorie intake indicates a quantitative more than qualitative problem, which may account the large prevalence of overweight and obesity and may represent a public health issue that needs to be corrected in such a rural population.     

Pancreatic Resection for Metastatic Melanoma. Case Report and Review of the Literature

Introduction

Pancreatic metastasis from several malignancies are increasingly encountered in clinical practice, and the usefulness of surgical resection has been suggested for certain neoplasms. Isolated pancreatic metastasis from malignant melanoma is a rare occurrence, and the role of surgery as an adjunct to systemic therapy for melanoma metastatic to a solitary or multiple sites is still debated.

Case Report

We report a patient with melanoma of unknown primary site metastatic simultaneously to the lung and pancreas 3 years after axillary lymph node dissection. Distal pancreatectomy with splenectomy and video thoracoscopic assisted resection of pulmonary metastasis were performed. The postoperative course was uneventful, but 6 months after surgery, the patient experienced single pulmonary recurrence. During chemotherapy with different drugs, pulmonary lesion remained stable for 1 year, and no abdominal recurrence occurred. After then, the size of the lesion progressively increased and a second metastasis occurred in the lung. Five months later, brain metastases occurred, and the patients died 24 months after surgery. Sixteen pancreatic resections for metastatic malignant melanoma, reported with adequate clinical details, were also retrieved from the literature.

Conclusion

In spite of the very limited experience, it appears that surgical resection is only a palliative procedure, because long-term survival is a rare event. However, considering the lack of effective systemic therapy, surgery may be considered as a part of an aggressive multidisciplinary approach in selected cases with malignant melanoma metastatic to single or multiple visceral sites.     

Comparison of dose contribution to normal pelvic tissues among conventional, conformal and intensity-modulated radiotherapy techniques in prostate cancer

High-energy external radiotherapy has become one of the most common treatment in localized prostate cancer. We compared the difference of dose distribution, mainly at the 5-30 Gy dose level, in the irradiated pelvic volume among three modalities of radiotherapy for patients with prostate cancer: conventional, conformal and intensity-modulated radiotherapy (IMRT). We selected six patients with prostate cancer treated by conformal radiotherapy at the doses of 46 Gy to PTVN (prostate and seminal vesicles), and 70 Gy to PTV-T (prostate). The conventional technique": an 8-field arrangement was used; the conformal technique 4 fields with a boost through 6 fields. For IMRT, a five-beam arrangement was used. Dose-volume histograms (DVH) were analyzed and compared among the three techniques. The IMRT technique significantly increased the pelvic volume covered by the isodose surfaces below 15 Gy as compared with the conventional and conformal techniques. The mean absolute increase for the pelvic volume included between 5-30 Gy for the IMRT technique, was about 2 900 ml as compared with the conventional technique. However, IMRT significantly reduced the irradiated volume of the rectum in the dose range of 5 to 40 Gy, also significantly reduced the irradiated volume of bladder and femoral heads, and obtained a similar or improved isodose distribution in the PTVs. In addition, the use of IMRT slightly increased the relative dose delivered to the body volume outside the pelvis, as estimated by the use of specific software. A long-term follow-up will be needed to evaluate potential late treatment complications related to the use of IMRT and the low or moderate irradiation dose level obtained in the pelvis and in the whole body.     

Bilateral (opercular and paracentral lobular) polymicrogyria and neurofibromatosis type 1

Anecdotal cases of polymicrogyria (PMG; a malformation of cortical development consisting of an excessive number of small gyri with abnormal lamination) in patients with neurofibromatosis type 1 (NF1) have been described; however, the cases were unilateral and had negative NF1 genetic testing. We describe an 11-year-old girl with NF1 manifesting as a complex epileptic syndrome, including partial seizures secondarily generalized and status epilepticus, who had in association, bilateral, asymmetrical (opercular and paracentral lobular) PMG. She had a 1-bp deletion (c.1862delC) in exon 12b of the NF1 gene. It is notable that, given the key role played by the NF1 gene product, neurofibromin, in normal brain development, and the relatively high frequency of other brain findings in NF1, there are not more NF1 cases with brain malformations manifesting as PMG.     

Tissue distribution, antitumour activity and in vivo apoptosis induction by MEN10755 in nude mice

MEN10755 is a disaccharide analogue of doxorubicin (DXR) endowed with a broader spectrum of activity compared with DXR in a panel of human tumour xenografts. In an attempt to investigate the pharmacological basis of the improvement of therapeutic efficacy of the analogue, a comparative pharmacokinetic (tissue and tumour distribution) and pharmacodynamic (antitumoral activity and ability to induce apoptosis) study of MEN10755 and DXR was performed in athymic nude mice bearing a human ovarian carcinoma xenograft (A2780). Drug level was quantified by high performance liquid chromatography (HPLC) with fluorimetric detection after a single intravenous (i.v.) injection of 7 mg/kg of MEN10755 or DXR. The results indicated a reduced accumulation of MEN10755 compared with DXR in all tissues investigated (tumour, heart, kidney and liver). The reduction was more marked in normal than tumour tissues. Moreover, in spite of the reduced drug uptake by tumour tissues, the new disaccharide anthracycline given in its optimal regimen showed an enhanced antitumour efficacy, compared with DXR. The drug effects on tumour growth paralleled a marked activation of apoptosis. In conclusion, the pattern of tissue distribution and the pharmacokinetic behaviour were consistent with a better tolerability of the novel analogue which allowed a higher cumulative dose to be delivered. The superior therapeutic efficacy of the analogue over DXR, in spite of a reduced tumour accumulation, supports an increased tumour selectivity.     

Effect of duration of breastfeeding on neuropsychological development at 10 to 12 years of age in a cohort of healthy children

Aim The aim of this article was to explore the effect of duration of breastfeeding on neurocognitive development. Method The long‐term effect of breastfeeding on neurodevelopment was examined through a battery of neuropsychological tests in 1403 children (693 females, 710 males; mean age 11y 9mo [SD 6mo], range: 10y 3mo–12y 8mo) who were originally recruited at 6 to 12 weeks of age for a clinical trial on acellular pertussis vaccines. An estimated IQ was obtained from scores of the vocabulary, similarities, block design, and coding tests. Breastfeeding data had been prospectively collected throughout the first year of life. Duration of exclusive breastfeeding was defined as the time during which children received breast milk without receiving any supplemental formula or food. Children were assessed at 10 to 12 years of age. We adjusted the analysis on test scores for multiple potential confounders. Results Multivariate analysis showed a significant association between exclusive breastfeeding duration and test scores in the vocabulary (odds ratio [OR] 0.05; confidence interval [CI] 0.00–0.10; p=0.04) and similarities (OR 0.06; CI 0.01–0.11; p=0.03) tests. These associations have a negligible effect size, however. Scores on one writing praxis test subcategory decreased with increasing duration of both exclusive breastfeeding (OR ?0.06; CI ?0.11 to ?0.01; p=0.03) and breastfeeding irrespective of consumption of other foods (OR ?0.06; CI ?0.11 to ?0.01; p=0.03). A negative association was also found between one subcategory of the California verbal learning test and breastfeeding duration longer than 6 months (OR ?0.21; CI ?0.42 to ?0.01; p=0.04). Interpretation Breastfed healthy children may perform better on neuropsychological tests in the language domain at 10 to 12 years of age. However, the effect of breast milk on neuropsychological performance in healthy children may have a limited clinical relevance and is confounded by parental education.