We have generated a transgenic mouse line that overexpresses the rate-controlling enzyme of polyamine catabolism, spermidine/spermine N 1 -acetyltransferase. Tissues of these mice showed markedly distorted polyamine pools, which in most cases were characterized by the appearance of N 1 -acetylspermidine, not normally found in mouse tissues, a massive accumulation of putrescine, and decreases in spermidine and/or spermine pools. The most striking phenotypic change was permanent hair loss at the age of 3 to 4 weeks which was typified histologically by the appearance of extensive follicular cysts in the dermis. The effect seemed attributable to putrescine interference with hair development, possibly with differentiation/proliferation of epidermal cells located in hair follicles. Female members of the transgenic line were found to be infertile apparently due to ovarian hypofunction and hypoplastic uteri. The findings demonstrate the utility of spermidine/spermine N 1 -acetyltransferase overexpression as an effective means for genetically modulating total tissue polyamine pools in transgenic animals and examining the developmental and oncogenic consequences.The well recognized association of polyamines with cell growth (1-3) is best illustrated by findings related to the key polyamine biosynthetic enzyme, ornithine decarboxylase (ODC).1 Although ODC is sharply but transiently increased by growth stimuli, it is constitutively activated during cell transformation induced by carcinogens, viruses, or oncogenes. Overexpression of ODC has been correlated with increased proliferative potential (4), tissue invasiveness (5), and in certain cell types, with oncogene-like transforming capabilities (6 -8). Thus far, ODC appears to be the only growth-related gene activated by the transcription factors c-myc (9 -11) and n-myc (12), suggesting a critical role for the enzyme in growth control. However, as indicated below, findings obtained in cell culture may not be directly applicable to conditions prevailing in vivo.To define the role of polyamines in proliferative processes associated with the whole animal, we have generated a number of transgenic mouse and rat lines that overexpress ODC and/or other polyamine biosynthetic enzymes. Given the importance of polyamine biosynthetic activity to cell growth, the phenotypic changes were unexpectedly mild. In transgenic mice overexpressing ODC, the most marked effect was inhibition of meiotic DNA synthesis during spermatogenesis (13) ultimately leading to male infertility (14). It is also noteworthy that lifelong overexpression of ODC in mouse tissues did not seem to increase the incidence of spontaneous tumors (15). The absence of more profound phenotypic changes in these mice may be attributable to the relatively minor changes observed in higher polyamine pools. Despite severalfold increases in ODC activity, polyamine pool disturbances were mainly confined to putrescine accumulation, and the pools of those polyamines considered to be more significantly involved in cell growth, spermidi...

Summary Reasons for performing study: Correct placement of sutures (‘laryngeal tie‐forward’) in experimentally created dorsal displacement of the soft palate (DDSP) has been observed to replace the function of the thyrohyoideus muscles and prevent DDSP. Hypothesis: The ‘laryngeal tie‐forward’ procedure would prevent or delay the occurrence of DDSP during exercise in horses with naturally occurring DDSP and therefore improve performance. Methods: A clinical population (n = 116), mainly of racehorses was presented for treatment of naturally occurring exercise‐induced DDSP. All horses underwent the ‘laryngeal tie‐forward’ procedure. The relative position of the thyroid and cricoid cartilage in relation to the caudal aspect of the basihyoid bone was recorded; follow‐up was obtained by telephone communication with trainers, owners and/or referring veterinarians. In addition, a performance index and earnings were determined using race records. Results: Preoperatively, the median distance between the caudal aspect of the basihyoid bone and rostral aspect of the thyroid cartilage was 3.5 cm. Post operatively, the thyroid cartilage was moved a median distance of 4 cm rostrally and the larynx was shown to be in a position more rostral and dorsal than in preoperative radiographs. Of 98 horses for which follow‐up was available, the performance of 87% was classified as improved, 12% as unchanged and 2% as worse. In 20 horses in which the diagnosis had been confirmed by treadmill videoendoscopy, 80% had a significantly increased performance index and earnings (P = 0.007). For the entire population, there was a significant improvement in performance index and earnings after surgery (82%) (P = 0.0001). Conclusions: Placing the larynx in a more rostral and dorsal position may have improved the performance in 80–82% of the horses affected with naturally‐occurring DDSP. Potential relevance: ‘Laryngeal tie‐forward’ is a surgical technique that has a measurable effect on the position of the larynx and offers an alternative therapy for treating horses affected with DDSP. More experience may be needed with this technique prior to its widespread use in horses with a clinical diagnosis of DDSP.

Intra-articular administration of APS can be considered an effective treatment option for equine osteoarthritis, with the potential for disease-modifying effects.

IDN-5109 modulates Pgp activity, resulting in superior tumor growth inhibition against Pgp-expressing tumors as compared with paclitaxel. IDN-5109 may broaden the spectrum of taxane use to include colon tumors.

A clinically relevant photosensitizer, 3-devinyl-3-(1-hexyloxyethyl)pyropheophorbide-a (HPPH, a chlorophyll-a derivative), was conjugated with Gd(III)-aminobenzyl-diethylenetriaminepentaacetic acid (DTPA), an experimental magnetic resonance (MR) imaging agent. In vivo reflectance spectroscopy confirmed tumor uptake of HPPH-aminobenzyl-Gd(III)-DTPA conjugate was higher than free HPPH administered intraveneously (iv) to C3H mice with subcutaneously (sc) implanted radiation-induced fibrosarcoma (RIF) tumor cells. In other experiments, Sprague-Dawley (SD) rats with sc implanted Ward Colon Carcinoma cells yielded markedly increased MR signal intensities from tumor regions-of-interest (ROIs) 24 h post-iv injection of HPPH-aminobenzyl-Gd(III)-DTPA conjugate as compared to unconjugated HPPH. In both in vitro (RIF tumor cells) and in vivo (mice bearing RIF tumors and rats bearing Ward Colon tumors) the conjugate produced significant increases in tumor conspicuity at 1.5 T and retained therapeutic efficacy following PDT. Also synthesized were a series of novel bifunctional agents containing two Gd(III) atoms per HPPH molecule that remained tumor-avid and PDT-active and yielded improved MR tumor conspicuity compared to their corresponding mono-Gd(III) analogues. Administered iv at a MR imaging dose of 10 micromol/kg, these conjugates produced severe skin phototoxicity. However, by replacing the hexyl group of the pyropheophorbide-a with a tri(ethylene glycol) monomethyl ether (PEG-methyl ether), these conjugates produced remarkable MR tumor enhancement at 8 h post-iv injection, significant tumoricidal activity (80% of mice were tumor-free on day 90), and reduced skin phototoxicity compared to their corresponding hexyl ether analogues. The poor water-solubility characteristic of these conjugates was resolved by incorporation into a liposomal formulation. This paper presents the synthesis of tumor-avid contrast enhancing agents for MR imaging and thus represents an important milestone toward improving cancer diagnosis and tumor characterization. More importantly, this paper describes a new family of bifunctional agents that combine two modalities into a single cost-effective "see and treat" approach, namely, a single agent that can be used for contrast agent-enhanced MR imaging followed by targeted photodynamic therapy.