Synthesis of a series ofcis-diamminedichloro-platinum (II) complexes linked to uracil and uridine as candidate antitumor agents

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II) (3a), [N-(2-aminoethyl)uracil-6-carboxamide]dichloroplatinum (II) (3b), [5-(2-aminoethyl)carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl) carbamoylu-carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxamide (2a) and N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-carboxy-2′,3′,5′-tri-0-acetyluridine (4a) and 6-carboxy-2′,3′,5′-tri-0-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).     

Hormone dependence of breast cancer cells and the effects of tamoxifen and estrogen:31P NMR studies

Many breast tumors appear to progress from estrogen-dependent growth to a more malignant phenotype characterized by estrogen-independent growth, antiestrogen resistance, and a high metastatic potential. Utilizing³¹P NMR spectroscopy on human breast cancer cells growingin vitro, we have investigated the effects of 17-estradiol and tamoxifen on the metabolic/bioenergetic spectra of a series of human breast cancer cells that vary in their estrogen and antiestrogen responsiveness. A comparison of baseline spectra associates higher levels of phosphodiesters and UDP-glucosides (e.g. UDP-glucose, UDP-N-acetylglucosamine), and lower phosphocholine/glycerylphosphocholine and phosphocholine/phosphoethanolamine ratios, with the acquisition of estrogen-independent growth in estrogen receptor expressing cells. No metabolic changes are clearly associated with the metastatic phenotype. Whilst estrogen treatment produces no consistently significant spectral changes in any of the cell lines, the estrogen-independent and estrogen-responsive MCF7/MIII cell line responds to tamoxifen treatment by significantly increasing all spectral resonances 30%-40% above baseline values. This may reflect a tamoxifen-induced change to a more differentiated or apoptotic phenotype, or an attempt by the cells to reverse the inhibitory effects of the drug. The ability to detect metabolic changes in response to tamoxifen by NMR spectroscopy may provide a novel means to identify those tumors that are responsive to antiestrogen therapy.Abbreviations CCS-IMEM steroid-deprived Improved Minimal Essential Medium - E2 17-estradiol - ER estrogen receptor - P_i inorganic phosphate - GPE glyceryl-phosphoethanolamine - GPC glyceryl-phosphocholine - PC phosphocholine - PE phosphoethanolamine - PDE phosphodiesters - PME phosphomonoesters - TAM tamoxifen (trans-1-(4--dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene) - UDPG uridine diphosphoglycoside     

MRI of the Stener lesion

Objective. To assess the utility of MR in detecting surgically induced Stener lesions (displaced thumb ulnar collateral ligaments) in cadaveric models. Design. Six cadaver thumbs had ulnar collateral ligament (UCL) tears created surgically. MR examinations (2D STIR and 3D GRASS) were performed identically on all specimens both before displacement (non-Stener) and after displacement (Stener lesion) of the UCL. The MR images were then randomly numbered. Each image was evaluated separately in blinded fashion by four musculoskeletal radiologists for the presence or absence of a Stener lesion. Each radiologist reinterpreted the images after an interval of several days. The interpretation was based on previously published criteria for Stener lesion diagnosis by MR. Results. The sensitivity of GRASS ranged from 0.17 to 0.67 with the most experienced reader scoring the lowest. The specificity of GRASS ranged from 0.33 to 1.0 (most experienced reader 0.67, 0.83). STIR had a sensitivity of 0.00–0.17 and a specificity of 0.53–0.83. The values for inter- and intraobserver agreement were measured. The intraobserver for GRASS was 0.27–0.75 (most experienced reader 0.75). Conclusions. 2D imaging is probably inadequate for the evaluation of Stener lesions. The most likely reason is that the STIR slice thickness of 3 mm limits resolution of small UCLs. The poor sensitivity and specificity of GRASS as well as poor interobserver agreement suggest that MR may not be sufficiently accurate for Stener lesion evaluation.     

Intracortical excitation of spiny neurons in layer 4 of cat striate cortex in vitro

Recordings were made from pairs of neurons in cat striate visual cortex in vitro to study the AMPA-channel-mediated components of intracortical excitatory synaptic connections between layer 4 spiny neurons and between layer 6 and layer 4 spiny neurons. Forty-six of the 72 cells recorded were identified morphologically. They consisted of spiny stellate and pyramidal cells in layer 4, and pyramidal cells in layer 6. Connections between layer 4 excitatory cells involve excitatory postsynaptic potentials (EPSPs) averaging 949 microV, with an average coefficient of variation of 0.21 (n = 30). The synapses operate at very high release probabilities (0.69-0.98). With repetitive stimulation these EPSPs show varying degrees of depression, largely mediated by presynaptic changes in release probability. Four pairs of layer 4 cells were reciprocally connected. The connections from layer 6 to layer 4 involve smaller, more variable EPSPs, with an average amplitude of 214 microV, and average coefficient of variation 0.72 (n = 7). These synapses operate at moderately high release probabilities (0.37-0.56). They show facilitation with repetitive stimulation, mediated largely by presynaptic changes in release probability. One excitatory connection from a layer 4 neuron to a layer 6 pyramidal cell was also detected. Thus, layer 4 spiny neurons receive effective excitation from two intracortical sources that have different synaptic dynamics and are likely to contribute significantly to the temporal properties of these cells in vivo.     

HIV vaccine research continues despite setbacks

New agents for treating asthma and allergic disease are now under development. From Arris Pharmaceutical comes recombinant neutral endopeptidase (rNEP), ^* an agent that may prove effective as prophylaxis against symptomatic episodes in patients with moderate-to-severe asthma. A group of compounds known as tryptase inhibitors may also be of use in inflammatory diseases such as asthma, as preclinical studies have shown that they can prevent airway inflammation in sheep. In addition, Tanox Biosystems is developing therapies that target immunoglobulin E (IgE), which is a key mediator of atopic allergic disease. News of recent progress with these agents was presented at an IBC USA conference on Asthma [ Philadelphia, US; October 1995 ].     

Indicators of free radical activity in patients developing radiation pneumonitis

PURPOSE: Radiation pneumonitis is thought to occur as the result of excess free radical generation following radiotherapy. Various in vitro studies have shown that large doses of irradiation can cause membrane lipid peroxidation and the oxidation of protein sulphuryl groups. We, therefore, studied two circulating markers of lipid peroxidation and an indicator of "catalytic iron" (potentially available iron to catalyze the generation of free radicals) in patients undergoing radiotherapy. METHODS AND MATERIALS: The 9,11 diene conjugate of 9,12 linoleic acid, expressed as their molar ratio (percentage molar ratio (MR)) and thiobarbituric acid reactive acid-substances (TBARS), as well as levels of circulating desferrioxamine-chelatable iron assay, were assayed. Serial blood samples were taken over a 3-month period in 25 patients with inoperable nonsmall cell lung cancer. RESULTS: Ten patients developed radiation pneumonitis. The patients who developed pneumonitis showed a tendency for the serum percentage molar ratio to increase after a week. The change in the percentage molar ratio between Time 0 and 1 week of radiotherapy was significantly higher in the group that subsequently developed pneumonitis compared to the group that did not (p = 0.002). The initial serum TBARS levels in patients were not significantly elevated compared to controls and there was no difference in the serum TBARS levels in the pneumonitis and nonpneumonitis groups throughout the study period. After 1 week of radiotherapy the group that subsequently developed pneumonitis had a significantly higher level of desferrioxamine-chelatable iron (DFx-iron) compared with the nonpneumonitis group (p = 0.05). CONCLUSION: These data suggest that both the percentage MR and DFx-iron appear to reflect an increased susceptibility to develop radiation pneumonitis and after 1 week of radiotherapy they indicate patients who are likely to subsequently develop pneumonitis. Hence, these indicators could indicate the group of patients that could benefit from intervention therapies with antioxidants.     

nm23-H1 expression in squamous cell carcinoma of the head and neck

Archival material from 47 patients with primary squamous cell carcinoma of the head and neck (SCCHN) was studied immunohistochemically for the presence of nm23-H1 protein. Our data indicate that nm23-H1 protein expression is a common event in SCCHN and that there is a trend toward correlation of increased expression of nm23-H1 with increasing tumor size (p = 0.072). The results also show that when adjusting for age and cause of death, there tended to be an inverse relationship between overall survival and the expression of nm23-H1 gene in the primary tumor (p = 0.088).     

Technique of Harvesting Buccal Mucosa for Urethral Reconstruction

Purpose

Buccal mucosa has been used increasingly by urologists for urethral substitution in complex hypospadias repair. We have found buccal mucosa to be useful in reconstruction of bulbar urethral strictures, and describe a simple and reliable technique for harvest.

Materials and Methods

In 11 patients with refractory bulbar urethral strictures a nontubularized onlay patch of buccal mucosa was used for urethral reconstruction. All procedures were done with a 2-team approach in which 1 team (usually an oral surgeon and urologist) harvested the graft from the mouth, while the perineal team simultaneously exposed and calibrated the stricture.

Results

The length of buccal mucosa used ranged from 3.5 to 17 cm. (average 6.4). All patients achieved excellent results. No oral complications were noted, even in patients in whom multiple buccal mucosal grafts were obtained.

Conclusions

With the technique reported, buccal mucosa is a reliable, easily obtained tissue for patch graft urethroplasty. Our 2-team approach decreased operative time considerably.     

Complications of Penile Lengthening and Augmentation Seen at 1 Referral Center

Purpose

Complications of the recent cosmetic technique of penile lengthening and girth enhancement are reviewed.

Materials and Methods

During a 16-month period 12 men presented with complications of penile augmentation performed elsewhere. All 12 patients had undergone release of the suspensory ligament and 10 had received autologous fat injection.

Results

the chief complaint was poor cosmetic appearance (irregular residual fat nodules in 7 men, skin deformity and scarring in 4 and scrotalization in 4). Reoperation was necessary in 6 patients, wound complications occurred in 6 and sexual dysfunction was reported by 4. Only 1 patient reported a subjective increase in penile length.

Conclusions

Although a verifiable complication rate may never by available, the morbidity of elective penile lengthening and girth enhancement is noteworthy. These cosmetic techniques should be regarded as experimental.     

Experimental analysis of the ‘happy hour’: Effects of purchase price on alcohol consumption

An experimental analogue of a discount drink policy known as the happy hour was used to study the effects of purchase price on drinking behavior. Male volunteers with a prior history of either casual (N=20) or heavy (N=14) drinking were given free access to beverage alcohol during a 20-day period. Approximately half the subjects could purchase alcohol under a single-price condition (50 ¢/drink), while a matched group was given a price reduction daily (25 ¢/drink) during a three-hour period in the afternoon. The results demonstrated that the afternoon price reduction significantly increased alcohol consumption in both casual and heavy drinkers. Reinstatement of the standard purchase price effectively suppressed drinking in both groups. The findings are discussed in terms of the theoretical and research implications of environmental influences on drinking.