THE EFFECTS OF THROMBOXANE INHIBITORS ON THE MICROVASCULAR AND TUMOR RESPONSE TO PHOTODYNAMIC THERAPY

Abstract— Vascular stasis and tissue ischemia are known to cause tumor cell death in several experimental models after photodynamic therapy (PDT); however, the mechanisms leading to this damage remain unclear. Because previous studies indicated that thromboxane release is implicated in vessel damage, we further examined the role of throm-boxane in PDT. Rats bearing chondrosarcoma were injected with 25 mg/kg Photofrin® (intravenously) 24 h before treatment. Light (135 J/cm ² , 630 nm) was delivered to thc tumor area after injection of one of the following inhibitors: (1) R68070: a thromboxane synthetase inhibitor; (2) SQ-29548: a thromboxane receptor antagonist; and (3) Flunarizine: an inhibitor of platelet shape change. Systemic thromboxane levels were determined. Vessel constriction and leakage were evaluated by intravital microscopy. Tumor response was assessed after treatment. Thromboxane levels were decreased more than 50% with SQ-29548 as compared to controls. Thromboxane levels in animals given R68070 and Flunarizine remained at baseline levels. SQ-29548 and R68070 reduced vessel constriction compared to controls, while Flunarizine totally prevented vessel constriction. R68070 and SQ-29548 inhibited vessel permeability compared to PDT controls; Flunarizine did not. Animals given these inhibitors showed markedly reduced tumor cure. These results indicate that the release of thromboxane is linked to the vascular response in PDT.     

PHOTODYNAMIC THERAPY INDUCED ULTRASTRUCTURAL ALTERATIONS IN MICROVASCULATURE OF THE RAT CREMASTER MUSCLE

Abstract— Photodynamic therapy disrupts blood flow to tumors and produces tumor necrosis. These effects may be due to a localized generation of singlet oxygen. The current studies used direct observations of the rat cremaster microvasculature to examine the vascular effects of PDT. The objective of the morphological examination was to delineate the structural basis for the altered blood flow in photodynamic therapy. Dihematoporphyrin ether given 30 min or 48 h prior to the experiment was activated with green light (wavelength530–560 nm, 120 J/cm²). After the in vivo activation the tissues were prepared for electron microscopy. Light alone induced little or no change in the luminal content or vessel wall. On exposure to activating light both acute (30 min) and long term (48 h) dihematoporphyrin ether pretreated samples displayed formation of luminal aggregates, granulocyte margination and migration, and endothelial cell and smooth muscle cell damage. The latter was more pronounced in the arterioles than the venules. Perivascular changes included interstitial edema and damage to striated myocytes. Some of the alterations such as interstitial edema may be transient; however, smooth and skeletal muscle cell injury are important in normal and tumor tissue necrosis after photodynamic therapy.     

THE MICROVASCULAR EFFECTS OF PHOTODYNAMIC THERAPY: EVIDENCE FOR A POSSIBLE ROLE OF CYCLOOXYGENASE PRODUCTS

Photodynamic therapy (PDT) of malignant tumours may involve the interruption of tumor and peritumor microcirculation. We have studied the effect of light activation of the photosensitizing drug dihematoporphyrin ether (DHE) on rat subcutaneous arterioles and the modulation of these effects by cyclooxygenase inhibitors indomethacin and acetyl salicylic acid (ASA). Animals received DHE 48 h prior to light activation and additionally either indomethacin, ASA or saline 3 h prior to treatment. Light activation (630 nm, 60 J/cm2) resulted in a significant reduction to 62 +/- 2% SEM of initial blood flow. This effect was inhibited by ASA (98 +/- 8% SEM) and indomethacin (87 +/- 8% SEM). Results from the administration of various doses of both compounds indicate that this inhibition is dose related. The data presented here show that PDT causes a significant reduction in blood flow in normal arterioles and that this effect was inhibited by ASA and indomethacin indicating that prostaglandins or thromboxane A2 may play an important role in the microvascular response to PDT.     

Nuclear disintegration in relativistic heavy ion collisions

The breakdown of the participant spectator model for central relativistic nuclear collisions is discussed and a different picture of a hot spot followed by a target explosion is suggested to be more consistent with the data.     

The creation of Bose-Einstein condensation in a cold vapor

This paper discusses the achievement of Bose-Einstein condensation in a gas and the work in laser cooling and trapping, spin polarized hydrogen, and low temperature atomic collisions that led to it.     

Observation of heteronuclear Feshbach molecules from a 85Rb-87Rb gas

We report on the observation of ultracold heteronuclear Feshbach molecules. Starting with a 87Rb Bose-Einstein condensate and a cold atomic gas of 85Rb, we utilize previously unobserved interspecies Feshbach resonances to create up to 25,000 molecules. Even though the 85Rb gas is nondegenerate, we observe a large molecular conversion efficiency due to the presence of a quantum degenerate 87Rb gas; this represents a key feature of our system. We compare the molecule creation at two different Feshbach resonances with different magnetic-field widths. The two Feshbach resonances are located at 265.44+/-0.15 G and 372.4+/-1.3 G. We also directly measure the small binding energy of the molecules through resonant magnetic-field association.     

Collisional stability of fermionic Feshbach molecules

Using a Feshbach resonance, we create ultracold fermionic molecules starting from a Bose-Fermi atom gas mixture. The resulting mixture of atoms and weakly bound molecules provides a rich system for studying few-body collisions because of the variety of atomic collision partners for molecules; either bosonic, fermionic, or distinguishable atoms. Inelastic loss of the molecules near the Feshbach resonance is dramatically affected by the quantum statistics of the colliding particles and the scattering length. In particular, we observe a molecule lifetime as long as 100 ms near the Feshbach resonance.