Photosensitization of pancreatic tumour cells by delta-aminolaevulinic acid esters.

A series of straight chain, branched and cyclo-delta-aminolaevulinic acid (ALA) esters have been synthesized and their photosensitizing properties analysed using an in vitro system of rat pancreatoma cells. Structurally favourable ALA esters not only induced the formation of more of the endogenous photosensitizer, protoporphyrin IX (PpIX), but they did so at a faster rate than ALA itself. This action was reflected in a substantial increase in photocytotoxicity of some 270 times, using the more potent ALA esters. An important structural feature was identified in two of the ALA esters which greatly limited PpIX production, i.e. a branch point located next to the site of ester cleavage. Experiments on the transport of ALA and of ALA esters across the cell membrane showed that ALA, but not ALA esters, gain access to the cell via the di- and tripeptide transporter, PEPTI. Finally, these results show that the esterification of ALA can greatly increase its cellular uptake, so generating more intracellular PpIX, improved tumour cell photosensitization and enhanced photocytotoxicity.

Photon pharmacology of an iron-sulphur cluster nitrosyl compound acting on smooth muscle.

1. The mechanisms of action on smooth muscle of the iron-sulphur cluster nitrosyl compound, heptanitrosyl-tri-mu 3-thioxotetraferrate (1-), (RBS), a photosensitive nitric oxide donor, have been investigated in the guinea-pig taenia caeci (coli) in vitro. 2. After exposure to RBS (50 microM) for 30 min, and subsequent washout, a sustained contraction was recorded in the absence of light to either the agonist carbachol (50 microM) or a depolarizing concentration of KCl (23.5 mM). Photon irradiation (> 400 nm) caused a prompt relaxation of precontracted RBS-treated muscle, the magnitude of which depended upon the intensity (1.1 x 10(3) to 1.1 x 10(5) lux), duration (30 s to 20 min) and wavelength (400 to 800 nm), of the incident illumination. 3. Repeated periods of illumination at 1.1 x 10(4) lux produced a reversible relaxation of both carbachol and KCl-evoked tone in muscle pretreated with RBS (50 microM). These photorelaxations were reproducible at 10 min intervals for several hours with a maximal relaxation amounting to 80 to 90% that of the tone produced by carbachol (50 microM). 4. The nitric oxide synthase inhibitor, NG-nitro-L-arginine (60 microM), caused no inhibition of the photon-induced relaxation of RBS-treated muscle. In contrast, N-methylhydroxylamine (2 mM), L-cysteine (10 mM), DL-dithiothreitol (2 mM), methylene blue (30 microM), and haemoglobin (20 microM), all reversibly but significantly inhibited (P < 0.001) the photorelaxation response. However, neither the aminothiol N-acetyl-L-cysteine (10 mM) nor the tripeptide glutathione (10 mM) blocked the RBS-induced photorelaxation. 5 The photolytic cleavage of RBS depended on the intensity and duration of illumination; it was accompanied by a corresponding decrease in absorbance and by the liberation of NO as measured by the Griess diazo reaction with sulphanilic acid. L-Cysteine (10 mM) prevented the decrease in absorbance and the photolytic liberation of NO.6 It is concluded that (i) sequestered or bound RBS, when photon-activated, liberates NO by a process which can be controlled by the wavelength, intensity and duration of the incident light, (ii) the photon-released NO rapidly relaxes the smooth muscle cells of the taenia coli primarily via cyclic GMP-dependent pathways which can be blocked by use of appropriate inhibitors, and (iii) the RBS-induced photorelaxation effect does not involve the activation of NO synthase. RBS is therefore a valuable photosensitive NO donor for establishing the functional and pharmacological significance of NO.

Supracostal approach for percutaneous ultrasonic lithotripsy.

The supracostal approach to renal access for ultrasonic lithotripsy continues to be used with good results at The Oregon Health Sciences University when indicated, because it provides better access to much of the kidney collecting system and proximal ureter. The complication rate is acceptably low if the precautions outlined above are followed. Access above the 11th rib is discouraged unless there is no other choice.

The supracostal approach for percutaneous nephrostolithotomy.

Sixty-nine patients underwent percutaneous nephrostolithotomy or ultrasonic lithotripsy through a nephrostomy tract placed over the 12th rib. All procedures were accomplished as a single stage in a standard operating room with patients under general anesthesia. With the exception of a single failed access the targeted calculus was removed in all instances. There were no episodes of postoperative pneumothorax or hydrothorax. One patient suffered delayed postoperative pneumonia and another patient had a delayed pleural effusion. The supracostal approach for percutaneous nephrostolithotomy is an important and safe modification of the traditional percutaneous approach to the kidney for an endourological procedure.