A novel retinoic acid receptor-selective retinoid, ALRT1550, has potent antitumor activity against human oral squamous carcinoma xenografts in nude mice

We have identified a novel retinoid, ALRT1550, that potently and selectively activates retinoic acid receptors (RARs). ALRT1550 binds RARs with Kd values of approximately equal to 1-4 nM, and retinoid X receptors with low affinities (Kd approximately equal to 270-556 nM). We studied the effects of ALRT1550 on cellular proliferation in squamous carcinoma cells. ALRT1550 inhibited in vitro proliferation of UMSCC-22B cells in a concentration-dependent manner with an IC50 value of 0.22 +/- 0.1 (SE) nM. 9-cis-Retinoic acid (ALRT1057), a pan agonist retinoid that activates RARs and retinoid X receptors, inhibited proliferation with an IC50 value of 81 +/- 29 nM. In vivo, as tumor xenografts in nude mice, UMSCC-22B formed well-differentiated squamous carcinomas, and oral administration (daily, 5 days/week) of ALRT1550, begun 3 days after implanting tumor cells, inhibited tumor growth by up to 89% in a dose-dependent manner over the range of 3-75 micrograms/kg. ALRT1550 (30 micrograms/kg) also inhibited growth of established tumors by 72 +/- 3% when tumors were allowed to grow to approximately equal to 100 mm3 before dosing began. In comparison, 9-cis retinoic acid at 30 mg/kg inhibited growth of established tumors by 73 +/- 5%. Interestingly, retinoids did not appear to alter tumor morphologies in UMSCC-22B tumors. Notably, ALRT1550 produced a therapeutic index of approximately equal to 17 in this model, indicating a separation between doses that inhibited tumor growth and that induced symptoms of hypervitaminosis A. In summary, ALRT1550 potently inhibits cellular proliferation in vitro and in vivo in this squamous cell carcinoma tumor model. These data support additional study of ALRT1550 for its potential for improving anticancer therapy in human clinical trials.     

Densitometric assessment of regional left ventricular systolic function during graded ischemia in the dog by use of dual-energy digital subtraction ventriculography

Densitometric analysis of images obtained by digital subtraction angiography (DSA) allows for more reproducible and less operator-dependent quantitation of ventricular function. Conventional DSA uses temporal subtraction but is limited by misregistration artifacts. Dual-energy digital subtraction angiography (DE-DSA) is immune to such misregistration artifacts. The ability of DE-DSA to quantitate changes in regional ventricular volume resulting from ischemia was tested. Densitometric analysis of both phase-matched and ejection fraction DE-DSA images was used to quantitate regional left ventricular systolic function during four levels of ischemia ranging from mild to severe in open-chest dogs (n = 10). DE-DSA left ventriculograms were obtained by means of central venous injections of iodinated contrast medium. Ischemia was graded according to percentage of systolic wall thickening as measured by sonomicrometry. Phase-matched end-systolic images were obtained at each of four levels of ischemia by subtracting an end-systolic control image from each end-systolic ischemic image. Ejection fraction images were obtained at the control level and at each level of ischemia by subtracting an end-systolic image from an end-diastolic image of the same cardiac cycle. The resulting wall motion difference signals represent the changes in regional ventricular volumes and were quantitated by densitometry. Densitometry was able to detect the effect of all levels of ischemia on regional function, even the mildest. Densitometric analysis of both phase-matched and ejection fraction DE-DSA images provides a sensitive technique for detecting and quantitating the changes in regional left ventricular systolic volume that occur with ischemia.     

Evolution of the alpha-crystallin/small heat-shock protein family

The common characteristic of the alpha-crystallin/small heat-shock protein family is the presence of a conserved homologous sequence of 90-100 residues. Apart from the vertebrate lens proteins--alpha A- and alpha B-crystallin--and the ubiquitous group of 15-30-kDa heat-shock proteins, this family also includes two mycobacterial surface antigens and a major egg antigen of Schistosoma mansoni. Multiple small heat-shock proteins are especially present in higher plants, where they can be distinguished in at least two classes of cytoplasmic proteins and a chloroplast-located class. The alpha-crystallins have recently been found in many tissues outside the lens, and alpha B-crystallin, in particular, behaves in many respects like a small heat-shock protein. The homologous sequences constitute the C-terminal halves of the proteins and probably represent a structural domain with a more variable C-terminal extension. These domains must be responsible for the common structural and functional properties of this protein family. Analysis of the phylogenetic tree and comparison of the biological properties of the various proteins in this family suggest the following scenario for its evolution: The primordial role of the small heat-shock protein family must have been to cope with the destabilizing effects of stressful conditions on cellular integrity. The alpha-crystallin-like domain appears to be very stable, which makes it suitable both as a surface antigen in parasitic organisms and as a long-living lens protein in vertebrates. It has recently been demonstrated that, like the other heat-shock proteins, the alpha-crystallins and small heat-shock proteins function as molecular chaperones, preventing undesired protein-protein interactions and assisting in refolding of denatured proteins. Many of the small heat-shock proteins are differentially expressed during normal development, and there is good evidence that they are involved in cytomorphological reorganizations and in degenerative diseases. In conjunction with the stabilizing, thermoprotective role of alpha-crystallins and small heat-shock proteins, they may also be involved in signal transduction. The reversible phosphorylation of these proteins appears to be important in this respect.     

Carcinoma of the parotid gland. Analysis of treatment results and patterns of failure after combined surgery and radiation therapy

BACKGROUND: The authors retrospectively studied 62 patients with malignant parotid tumors, treated by combined surgery and radiation therapy between 1975 and 1989. No patients were lost to follow-up, and all living patients were interviewed. The median follow-up time was 66 months. RESULTS: Among the 62 patients, there were five isolated local failures. Distant failure was observed in 11 patients. Neck failure was uncommon except in patients with advanced neck disease on presentation. The actuarial 5-year and 10-year local control rates were 95% and 84%, respectively. The corresponding actuarial disease-free survival (DFS) rates were 77% and 65%, respectively. Patients with larger tumors, recurrent disease, or involvement of the facial nerve tended to have lower DFS rates. No statistically significant differences were observed for patients treated with once-daily versus twice-daily radiation therapy fractionation schemes. CONCLUSIONS: Treatment was well tolerated, and severe treatment sequelae were uncommon. In summary, surgery in combination with radiation therapy is highly efficacious in controlling malignant tumors of the parotid gland.     

Balancing social acceptability with treatment effectiveness of an intrusive procedure: a case report

The debate over social acceptability of intrusive procedures has led some school districts to adopt policies allowing punishment for only the most extreme forms of destructive behavior. We investigated the effectiveness of selectively implementing punishment for only the most severe topographies of aggression and property destruction, while less extreme behaviors were ignored. Results indicated that severe behaviors were reduced to near-zero levels only when both severe and less severe behaviors were similarly punished.     

The role of leukotrienes in asthma and allergic rhinitis

The recent elucidation of the inflammatory responses underlying asthma and allergic rhinitis has stimulated the development of new anti-asthma treatments, including numerous antileukotriene agents. These agents, which represent a new direction in targeted therapy, either antagonize the leukotriene receptor (e.g. zafirlukast) or block the synthesis of leukotrienes (e.g. zileuton). They have been used in preclinical and clinical studies involving normal subjects and patients with asthma or allergic rhinitis. These studies have generally supported the putative role of leukotrienes in the mechanisms of asthma and allergic rhinitis. With respect to asthma, the leukotrienes also appear to function as potent mediators of bronchoconstriction. The above cited results indicate that antileukotriene agents offer incremental improvements in airway caliber and may also attenuate the inflammatory response. Because they are orally administered, they should have the additional benefit of increasing patient compliance relative to other currently available treatments. In their current form, however, they may not be expected to replace the mainstays of current therapy but to act rather, as adjuvant therapy. Patients with relatively mild asthma may be able to achieve efficacy with an antileukotriene agent plus as needed beta-adrenergic agonists; patients with more significant disease might use antileukotriene agents as a supplement to another anti-inflammatory agent, such as cromolyn, nedocromil, or corticosteroids. Studies of asthma patients have confirmed the ability of antileukotriene agents to attenuate asthma-associated bronchoconstriction. Antileukotriene agents appear to significantly attenuate aspirin-, allergen-, and exercise-induced asthma, as well as the signs and symptoms of nocturnal and chronic asthma; they may have efficacy in other inflammation-associated disorders such as allergic rhinitis as well.     

Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa

Ribozymes, catalytic RNA molecules that cleave a complementary mRNA sequence, have potential as therapeutics for dominantly inherited disease. Twelve percent of American patients with the blinding disease autosomal dominant retinitis pigmentosa (ADRP) carry a substitution of histidine for proline at codon 23 (P23H) in their rhodopsin gene, resulting in photoreceptor cell death from the synthesis of the abnormal gene product. Ribozymes can discriminate and catalyze the in vitro destruction of P23H mutant mRNAs from a transgenic rat model of ADRP. Here, we demonstrate that in vivo expression of either a hammerhead or hairpin ribozyme in this rat model considerably slows the rate of photoreceptor degeneration for at least three months. Catalytically inactive control ribozymes had less effect on the retinal degeneration. Intracellular production of ribozymes in photoreceptors was achieved by transduction with a recombinant adeno-associated virus (rAAV) incorporating a rod opsin promoter. Ribozyme-directed cleavage of mutant mRNAs, therefore, may be an effective therapy for ADRP and also may be applicable to other inherited diseases.     

Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses. RESULTS: The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1.94 to 5.83) and 3.62 mg/mL.min for the sequence P-->C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses < 175 mg/m2 v 7.9 months for doses > or = 175 mg/m2, P = .07; P-T > or = 0.1 mumol/L, 4.8 months for < 15 hours v 8.2 months for > or = 15 hours, P = .06). CONCLUSION: There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter P-T > or = 0.1 mumol/L was related to improved survival in this study.     

Gastric ulcers in finishing pigs: their prevalence and failure to influence growth rate

In an abattoir survey the stomachs of 1242 pigs from 15 farms were examined. Ulceration of the pars oesophagea was present in 22.95 per cent with a range from 4.7 to 57.4 per cent. The ulcers were graded mild in 9.5 per cent and severe in 13.4 per cent of the stomachs. Bile staining and hyperkeratinisation of the pars were significantly more common in stomachs with ulcers than in those without (P < 0.001), although the difference between the hyperkeratinisation in cases with severe ulcers and cases without ulcers was not significant. The daily liveweight gains of 208 males and 150 females from two units with a high prevalence of ulcers were calculated from their weaning weights at about five weeks of age and their slaughter weights at around 90 kg. At the abattoir their stomachs were examined for the presence of ulcers of the pars. The daily liveweight gain of the males was significantly greater than that of the females (P < 0.001), but the presence of mild or severe ulcers had no influence on the rate of gain of the pigs from either unit. The prevalence of ulcers in the males and females was 57.2 and 49.3 per cent, respectively, but the difference was not significant.