Stabilization vs. destabilization of G-quadruplex superstructures: the role of the porphyrin derivative having spermine arms.

The interaction of the porphyrin derivative H2TCPPSpm4, having spermine pendants in the four meso positions, with the G-quadruplex (GQ) structure formed by the DNA aptamer TGGGAG has been investigated by means of UV, electronic circular dichroism and PAGE studies. The results reported here demonstrate that the porphyrin derivative is capable of stabilizing or destabilizing the higher-ordered structures of parallel GQs, depending on the method used to reach their relative stoichiometry (titration vs. single addition). Noteworthily, when two equivalents of H2TCPPSpm4 were mixed directly with one equivalent of the (TGGGAG)4 GQ to reach a 2 : 1 H2TCPPSpm4 : GQ ratio T1/2 higher than 80 °C was also observed confirming the presence of higher-ordered GQ structures.

Preclinical profile of bacopasides from Bacopa monnieri (BM) as an emerging class of therapeutics for management of chronic pains.

Chronic pains management costs billions of dollars in medical exchequer to the world population. Additionally, 77% of people with chronic pains also have a degree of medically treatable depression. Opioids have a narrower safety index due to their side effects associated with its tolerance, hyperalgesia and subsequent dependence. Likewise, non steroidal anti-inflammatory drugs and anticonvulsants, also have limited safety and tolerability profile in the management of chronic pains. Bacopa monnieri, a renowned ayurvedic medicine has a strong antidepressant effect and significant antinociceptive effect, which is comparable to the effect of morphine via adenosinergic, opioidergic, and adrenergic mechanisms. BM has been also reported to be effective in neuropathic pains. Additionally, it has a strong anti-inflammatory effect mediated via COX-2 inhibitory mechanism. Apart from its effect of augmenting morphine analgesia, BM also inhibits opioid-withdrawal induced hyperalgesia, and acquisition and expression of morphine tolerance. BM is reported to have a strong protective effect against toxic effects of opiates on major organs like brain, kidneys and heart. BM is well documented to be safe and well tolerated herbal therapy in multiple clinical trials including various age groups. This minireview evaluated the preclinical data that highlights potential of BM as a future candidate for clinical management of chronic pains.

Isolation and characterization of new lignans from the leaves of Cestrum parqui.

Three new compounds, a sesquilignans, an oxyneolignan and a norlignan, have been isolated from the aqueous fraction of Cestrum parqui. All of the compounds have been identified on the basis of their spectroscopic properties and tested on the species Lactuca sativa and Lycopersicon esculentum to evaluate their phytotoxic activity.

Potential allelochemicals from Sambucus nigra.

Twenty-four aromatic metabolites belonging to cyanogenins, lignans, flavonoids, and phenolic glycosides were obtained from Sambucus nigra. Structures were determined on the basis of their spectroscopic features. Two compounds have been isolated and identified as (2S)-2-O-beta-D-glucopyranosyl-2-hydroxyphenylacetic acid and benzyl 2-O-beta-D-glucopyranosyl-2,6-dihydroxybenzoate. All the compounds have been assayed on dicotyledons Lactuca sativa (lettuce) and Raphanus sativus (radish) and monocotyledon Allium cepa (onion) to test their stimulatory or inhibitory effects on seed germination and radicle elongation. Cyanogenins have a mainly inhibiting effect while lignans stimulate the growth. Some compounds show different effects on dicotyledons and monocotyledons.

Antialgal furano-diterpenes from Potamogeton natans L.

Six furano-ent-labdanes, 19-acetoxy-15,16-epoxy-8(17),13(16),14-ent-labdatrien-20-al, 15,16-epoxy-12-oxo-8(17),13(16),14-ent-labdatrien-20,19-olide, 12(S)-hydroxy-15,16-epoxy-8(17),13(16),14-ent-labdatrien-20,19-olide, 10alpha,19-dihydroxy-15,16-epoxy-8(17),13(16),14-nor-ent-labdatriene, 19,20-dihydroxy-15,16-epoxy-8(17),13(16),14-ent-labdatriene, 15,16-epoxy-12-oxo-8(17),13(16),14-ent-labdatrien-19,20-olide, were isolated, together with the known potamogetonin, from the aquatic plant Potamogeton natans. Their structures were determined on the basis of their chemical and spectral data. The compounds showed in vitro phytotoxicity against Raphidocelis subcapitata, a microalga used in aquatic tests.

Two new polyhydroxylated sterols from Ruppia maritima.

Two new sterols have been isolated from the aquatic plant Ruppia maritima and their structures were established as (24R) ergosta-8,22-diene-3 beta,6 beta,7 alpha-triol (1) and (24R) ergosta-8(14),22-diene-3 beta,6 beta,7 alpha-triol (2) on the basis of spectroscopic analysis.

Toxicity evaluation of natural and synthetic phenanthrenes in aquatic systems.

Seven natural 9,10-dihydrophenanthrenes were isolated from the common reed Juncus effusus by means of chromatographic processes and identified by spectroscopic means. Furthermore, mimics of natural isolated compounds were synthesized to try to evaluate the influence of functional groups on the dihydrophenanthrene skeleton. Syntheses of compounds were based on the cross-coupling of 1-(2-iodo-5-methoxy)phenyl-ethanol with variously substituted iodobenzenes by zerovalent nickel. All the chemicals were tested to evaluate their effects on freshwater organisms from different trophic levels. Toxicity tests were performed on reducers (the bacterium Escherichia coli); producers (the alga Raphidocelis subcapitata, previously known as Selenastrum capricornutum); and consumers including a rotifer (Brachionus calyciflorus), a cladoceran (Daphnia pulex), and an anostracan (Thamnocephalus platyurus). Results suggested no one organism was uniquely sensitive to the chemicals tested. Toxicity depended on the kind and position of substituents on the aromatic skeleton.

Solid-state photodimerization of cholest-4-en-3-one.

Crystalline cholest-4-en-3-one undergoes solid-state dimerization by UV radiation to give two ring A - ring A connected dimers. No dimerization occurs in solution. The first dimer, characterized by a cyclobutane ring, is formed by connection of C-2 and C-3 of a moiety with C-5' and C-6' of another moiety, respectively. The latter dimer has a six-membered ketal ring formed by connection of C-2 with C-5' and of O, linked to C-3, with C-3'. The structures have been determined by spectroscopic means. X-ray analysis of title compound evidences the proximity of the axial H-2 of a molecule to the C-4' of a molecule in the upper layer. The transfer of the hydrogen and the connection between C-2 and C-5' might be the driving force of dimerization.

Lactone diterpenes from the aquatic plant Potamogeton natans.

Four lactone diterpenes and two related glucosides with a labdane skeleton have been isolated from the aquatic plant Potamogeton natans. The structures of three new compounds were determined as 19-acetoxy-20-oxo-8(17),13-ent-labdadien-15-->16 lactone, 8(17), 13-ent-labdadien-15-->16,19-->20 dilactone and 6'-acetyl-19-glucopyranosyloxy-8(17),13-ent-labdadien-15-->16 lactone, respectively, by means of spectral analysis. Antialgal assays showed inhibitory activity for some compounds.

Synthesis and antialgal activity of dihydrophenanthrenes and phenanthrenes II: mimics of naturally occurring compounds in Juncus effusus.

9,10-Dihydrophenanthrenes and phenanthrenes, mimics of natural compounds with strong antialgal activity, have been synthesized through cross-coupling by zerovalent Ni of 1-(2-iodo-5-methoxy)-phenylethanol or 2-iodo-5-methoxyacetophenone with iodoxylenes. The synthetic compounds had a hydroxyl or a methoxyl group at C-2 and two methyls in the C ring. Assays on the green alga Selenastrum capricornutum showed that all the compounds, except 2-methoxy-5,7-dimethylphenanthrene, caused strong inhibition of algal growth at 10(-4) M. 2-Hydroxy-7,8-dimethyl-9,10-dihydrophenanthrene and 2-methoxy-5,6-dimethylphenanthrene fully inhibited growth at 10(-5) M.

Antialgal ent-labdane diterpenes from Ruppia maritima.

Seven ent-labdane diterpenes have been isolated from Ruppia maritima. The structures 15,16-epoxy-ent-labda-8(17),13(16),14-trien-19-al; 15,16-epoxy-ent-labda-8(17),13(16),14-trien-19-ol acetate; methyl 15,16-epoxy-12-oxo-ent-labda-8(17),13(16),14-trien-19-oate; 15,16-epoxy-ent-labd-8(17),13E-dien-15-ol and 13-oxo-15,16-bis-nor-ent-labd-8(17)-ene have been assigned to the five new compounds by spectroscopic means and chemical correlations. The phytotoxicity of the diterpenes has been assessed using the alga Selenastrum capricornutum as organism test.

Homocysteine accumulation in human ovarian carcinoma ascitic/cystic fluids possibly caused by metabolic alteration of the methionine cycle in ovarian carcinoma cells.

The major role of the high-affinity folate-binding protein (FBP) is to regulate cellular folate homeostasis by increasing folate uptake in case of extracellular and intracellular folate deficiency. On this basis, we hypothesised that the overexpression of FBP in ovarian carcinoma might be physiologically associated with folate deficiency in the extracellular fluids, where ovarian carcinoma cells develop in vivo, or it might be the result of a reduced intracellular regeneration of the 5-methyltetrahydrofolate (5-CH3H4 folate). To test these hypotheses, we determined the bioavailability of folate in serum and in ascitic/cystic fluids of ovarian carcinoma patients (n = 36). The intracellular shortage of 5-CH3H4 folate was evaluated in the extracellular fluids by measuring the concentration of homocysteine (Hcy), which is a useful marker of intracellular folate deficiency. Patients with ascites from malignant and benign non-ovarian pathologies were used as controls (n = 30). We found no folate shortage in the serum and ascitic/cystic fluids of ovarian carcinoma patients. The folate concentration was within the normal range and superimposable on that observed in serum and ascites of control patients. However, the ascitic/cystic Hcy concentration was significantly higher (P < 0.005) than the corresponding serum concentration in a large fraction of ovarian carcinoma patients (72%, 26/36), whereas it was higher only in a small fraction of patients with non-ovarian malignant ascites (24%, 4/17), and in no patient with benign ascites. Hcy accumulation in ovarian carcinoma patients was not associated with a defect in the catabolic pathway of Hcy to cysteine, but was consistent with an impaired remethylation process of Hcy to methionine caused by an intracellular shortage of 5-CH3H4 folate. This suggests a possible association between FBP overexpression and a biochemical defect of the cellular folate metabolism involved in the methionine cycle.

Systematic pelvic and para-aortic lymphadenectomy in advanced ovarian cancer patients with no residual intraperitoneal disease.

A comparative non-randomized study was carried out to evaluate the role of systematic pelvic and para-aortic lymphadenectomy (SL) on patients with no residual intraperitoneal disease (NRID) of advanced ovarian cancer (stage IIIC-IV). A total of 142 optimally cytoreduced patients (macroscopic disease absent on peritoneal surface) were divided into two groups: Group A, consisting of 98 patients (53 previously untreated and 45 pretreated at other Institutions), who underwent SL; Group B, consisting of 44 patients (21 previously untreated and 23 pretreated at other Institutions), who did not undergo SL. Each group had statistically equivalent histology, grading, performance status and variety of cytoreductive operations performed. Group A pretreated patients had a greater number of stage III than Group B (P = 0.03). Systematic pelvic and para-aortic lymphadenectomy could be carried out with an acceptable morbidity and no mortality. All 142 patients received post-operative chemotherapy including carboplatin. The number of chemotherapy sessions did not differ between the two groups. Comparison of survival revealed that SL significantly improved the survival of previously untreated patients (P = 0.02). The survival was significantly different with nodal status (P = 0.006). Cox's proportional hazard analysis showed that only systematic lymphadenectomy was a significant covariate. The survival was not significantly different in Group A vs Group B pretreated patients; however, it was significantly different with respect to nodal status (P<0.001). Cox's proportional hazard analysis showed that only the initial stage of disease was a significant covariate. The results of the present study shows that aggressive surgical cytoreduction with SL could be therapeutic in previously untreated patients with NRID. Currently, an international prospective randomized study is ongoing to clarify definitively the clinical role of SL.

Palliative treatment of upper intestinal obstruction by gynecological malignancy: the usefulness of percutaneous endoscopic gastrostomy.

The usefulness of percutaneous endoscopic gastrostomy (PEG) for decompression in patients with unresolving intestinal obstruction by gynecological malignancy is examined. Between April 1993 and August 1995, 34 consecutive patients with small-bowel obstruction by gynecological cancer, heavily pretreated with surgery and chemotherapy, were admitted to our prospective study. PEG was performed in 32/34 patients (94.1%). Failure in the placing of the tube occurred in 2 patients (5.9%). Twenty-seven patients (84.4%) experienced symptomatic relief after a few days from PEG and tolerated soft and liquid foods. All of these patients were discharged from the hospital and underwent parenteral nutrition at home. The median postoperative hospital stay was 7 days (range 3-45). No major complications due to PEG placement itself occurred in our patients. Only 4 patients (12.5%) had postprocedure nausea and vomiting that was unresponsive to the conventional therapy. The use of Octreotide (0.6 mg/24 hr) obtained relief from symptoms until death. The gastrostomy remained in place for a median of 74 days (range 5-210). Relief from symptoms after PEG placement and total parenteral nutrition permitted continuation of palliative chemotherapy in 8 patients (25%). We suggest percutaneous endoscopic drainage gastrostomy technique as the procedure of choice for long-term drainage of unresolving small bowel obstruction in patient with metastatic abdominal gynecologic malignancy.

Multimodal treatment with neoadjuvant intraarterial chemotherapy and radical surgery in patients with stage IIIB-IVA cervical cancer. A preliminary study.

BACKGROUND: The purpose of this study was to determine the role of neoadjuvant intraarterial chemotherapy (NIC) in patients with advanced cervical cancer. METHODS: From June 1989 to December 1993, 36 consecutive patients with International Federation of Gynecology and Obstetrics Stage IIIB-IVA cervical cancer were admitted to the study. Treatment consisted of a bilateral infusion in the internal iliac artery of bleomycin (2.5 mg), doxorubicin (10 mg), and cisplatin (20 mg) for five courses after a 4-day rest period. RESULTS: Twenty-nine (80.5%) patients received 100% of the programmed chemotherapeutic dose. The major toxic effects, according to World Health Organization criteria, were hematologic (19.4%, Grade 3 or 4), renal (2.8%, Grade 2), and gastrointestinal (61.1%, Grade 1 or 2). Only four patients (11.1%) had scanty bleeding around the site of catheter insertion. Neoadjuvant intraarterial chemotherapy induced responses in 33 of the 36 patients (5 complete, 28 partial; overall response rate, 91.7%), thus permitting radical surgery in all of these cases. Pretreatment characteristics were analyzed for response to NIC. None of the clinical parameters studied were related to chemoresponsiveness. A lower than expected incidence of lymph node metastases was detected (33.3%). Ten (30.3%) of the 33 patients who underwent surgery had disease recurrence. Lymph node status and pathologic parametrial involvement were significant prognostic factors for recurrence. The 5-year estimated survival for patients with a complete response, partial response, and stable disease was 100%, 36.2%, and 0%, respectively (P < 0.001). Clinical stage (P = 0.003) and response to NIC (P < 0.001) were significant prognostic factors in the overall estimated survival. The 5-year actuarial survival for patients with Stage IIIB and IVA disease was 66.7% and 0%, respectively. CONCLUSION: These results suggest that NIC should be considered as a means of achieving prompt local control before surgery and/or radiotherapy.

Systematic pelvic and para-aortic lymphadenectomy during cytoreductive surgery in advanced ovarian cancer: potential benefit on survival.

A case-control study was carried out to evaluate the potential benefit on survival of systematic pelvic and para-aortic lymphadenectomy (SL) during primary or secondary cytoreductive surgery on patients with Stage IIIC-IV of epithelial ovarian cancer. A total of 105 optimally cytoreduced (macroscopic disease < 2 cm on peritoneal surfaces) patients were divided into two groups: Group A, consisting of 60 patients (30 previously untreated and 30 pretreated at other institutions), underwent SL; Group B, consisting of 45 patients (23 previously untreated and 22 pretreated at other institutions), did not undergo SL. Consideration was given toward the inclusion of previously untreated and pretreated patients in two different groups for survival analysis. Each group had statistically equivalent stage, histology, grading, age, performance status, largest diameter metastasis (> 10 cm), type of surgery, and variety of cytoreductive operations performed. Group A patients had a longer median operation time than Group B patients (P = 0.01). SL could be carried out with an acceptable morbidity and no mortality. All 105 patients received postoperative chemotherapy including Carboplatin. Comparison on survival revealed that SL significantly improved the survival of previously untreated patients (P < 0.001). Cox's proportional analysis shows that SL was the most significant covariate, followed by stage of disease. The survival was not significantly different in Group A and Group B pretreated patients. Only stage of disease (III vs IV) significantly influenced the survival (P < 0.01). The results of the present study show that aggressive surgical cytoreduction with SL may be advisable only in previously untreated patients optimally cytoreduced. We also suggest the need for a randomized, prospective study to clarify the clinical role of SL.

[Second surgery in the management of ovarian cancer]. / La seconda chirurgia nel trattamento del cancro ovarico.

The aim of this study was to evaluate the value of second surgery in the combined and multidisciplinary treatment of mullerian ovarian cancer. A retrospective study was carried out in 86 consecutive patients with advances stages of mullerian ovarian cancer (stage 3-4) referred to the Division of Gynecological Surgical Oncology of the Oncological Reference Centre at Aviano for continuation of treatment following initial surgery and chemotherapy performed in various peripheral institutions. Second surgery only revealed 11.6% of complete endocelomatic pathological responses (10 patients) to earlier treatments; among the 76 patients with persistent disease it was possible to achieve optimal redebulking in 50 (65.8%) (31 R0 and 19 R1 after second surgery), whereas it was not possible to perform adequate second surgery in 26 (34.2%). The impact of second surgery on the probability of survival (mean survival rate) was highly significant in the 50 patients in whom it was possible to perform adequate second surgery compared to the non-operated group (14.34 months versus 6.10, chi square = 12.671, p = 0.0004). The authors underline both the prognostic value of lymph node status with increased mortality among patients with positive retro-peritoneal lymph nodes (LN+), and the value of retroperitoneal re-evaluation in predicting endo-peritoneal recidivation in patients with free abdomen who subsequently relapsed.

[Splenectomy in cytoreductive surgery in ovarian cancer]. / La splenectomia nella chirurgia citoriduttiva del carcinoma ovarico.

During the course of surgery for the treatment of ovarian cancer, splenectomy is rarely performed since this tumour rarely infiltrates the parenchyma although it spreads around the spleen. Surgery is significant if surgical efforts successfully reduce tumour volume to less than one centimetre in diameter. Perisplenic involvement is frequent, even if not always massive and infiltrating, in relation both to biological aggressiveness and clinical and instrumental diagnostic delay. Between January '81 and December '91 a total of 16 splenectomies were performed during the course of surgery relating to 311 (5.1%) patients suffering from mullerian ovarian carcinoma at the 3rd and 4th stage. Of these, 7 were performed during the first operation and 9 during the course of a second-look. The mean age of patients was 56 with a range of 33-71 years. Massive hilar infiltration was found in 14 cases, in 7 together with contemporary capsular infiltration. Parenchymal infiltration was present in 3 cases; one splenectomy was performed following an iatrogenic complication during the mobilization of the left colic flexure, necessary for the creation of the colon-rectal anastomosis. Splenectomy was always well tolerated in an overall assessment of surgery and was without severe local complications. The most frequent complications were pleural (7/16) with reactive effusion and bronchopulmonary with basal dystelectasia (3 cases) and bronchopneumonic foci (4 cases). A silent hematoma in a splenic site was revealed using ultrasonography in 3 cases but resolved spontaneously without requiring drainage.(ABSTRACT TRUNCATED AT 250 WORDS)