Comparative Sensitivity of Microvascular Endothelial Cells, Fibroblasts and Tumor Cells after In Vitro Photodynamic Therapy with meso-Tetra-Hydroxyphenyl-Chlorin¶ (original) (raw)
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Outcome of mTHPC Mediated Photodynamic Therapy is Primarily Determined by the Vascular Response
Photochemistry and Photobiology, 2005
We have previously shown that the efficacy of photodynamic therapy (PDT) using the photosensitizer meso-tetra-hydroxyphenyl-chlorin (mTHPC) correlated with plasma drug levels at the time of illumination rather than drug levels in human tumor xenografts or mouse skin. These results suggested that vascular-mediated effects could be important determinants of PDT response in viva In the present study we further investigated the relationship between PDT response, mTHPC pharmacokinetics and the localization and extent of vascular damage induced in human squamous cell carcinoma xenografts (HNXOE). Plasma levels of mTHPC decreased exponentially with time after injection, whereas tumor drug levels remained maximal for at least 48 h. At 3 h after administration mTHPC was localized in the blood vessels, whereas at later times it was distributed throughout the whole tumor. Illumination at 3 h after mTHPC, which resulted in 100% long-term tumor cure, led to a marked reduction of vascular perfusion and increased tumor hypoxia at 1 h after treatment. Illumination at 48 h resulted in rapid regrowth of most tumors and only 10% cure. This protocol did not affect a significant decrease in vascular perfusion or increase in tumor hypoxia. These data show that optimal responses to mTHPC-mediated PDT were primarily dependent on the early vascular response, and that plasma drug levels at the time of illumination could predict this relationship.
Photodiagnosis and Photodynamic Therapy, 2007
Background: Photodynamic therapy (PDT) is being widely used for treatment of cancer and non-malignant diseases. The mechanisms of phototoxicity to solid tumor are not yet completely understood. Knowledge of the inherent sensitivity of endothelial cells in comparison to tumor cells would be helpful to predict tumor response to PDT, and thereby optimize treatment protocols. Methods and results: The intrinsic sensitivity of rodent endothelial and tumor cells to PDT was studied using an in vitro clonogenicity assay that strictly controlled for light and photosensitizer exposure, as well as cellular photosensitizer and oxygen concentration. Taking into consideration cell size, ploidy and glutathione content, no significant difference in sensitivity to phototoxicity was observed between tumor and endothelial cells. Electron microscopy studies were also conducted to examine endothelial and tumor cells for differential cellular damage following interstitial PDT of rat prostate tumor. No evidence for selective damage to endothelial cells was demonstrated. Conclusions: Rodent tumor cells and endothelial cells are equally susceptible to Photofrinmediated PDT damage. Sufficient photosensitizer accumulated in solid tumor seems to be one of the key factors for PDT effectiveness. Crown
Photodiagnosis and Photodynamic Therapy, 2005
Photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as cancer therapy, some of its most successful applications are for non-malignant disease. The majority of mechanistic research into PDT, however, is still directed towards anti-cancer applications. In the final part of series of three reviews, we will cover the possible reasons for the well-known tumor localizing properties of photosensitizers (PS). When PS are injected into the bloodstream they bind to various serum proteins and this can affect their phamacokinetics and biodistribution. Different PS can have very different pharmacokinetics and this can directly affect the illumination parameters. Intravenously injected PS undergo a transition from being bound to serum proteins, then bound to endothelial cells, then bound to the adventitia of the vessels, then bound either to the extracellular matrix or to the cells within the tumor, and finally to being cleared from the tumor by lymphatics or blood vessels, and excreted either by the kidneys or the liver. The effect of PDT on the tumor largely depends at which stage of this continuous process light is delivered.
Time-Dependent Photodynamic Damage to Blood Vessels: Correlation with Serum Photosensitizer Levels
Photochemistry and Photobiology, 1995
We have used the technique of dynamic capillaroscopy to study the time-course of photodynamic vascular occlusion in mice injected intrapentoneally with either of two photosensitizers; hematoporphyrin esters (HPE) or meso-tetrahydroxyphenyl chlorin (mTHPC). The peak of vascular occlusion induced by HPE coincided in time with peak serum levels of this photosensitizer (about 3 h after injection). However, there was also a second peak of occlusive activity at about 12 h after injection, at which time serum HPE was falling monotonically. In the case of mTHPC, no peak of occlusive activity was seen at 3 h after injection, even though the serum levels of this photosensitizer, like those of HPE, were highest around this time. Instead, a steady rise in photosensitizing activity was observed, peaking at 1 1 h. This decoupling between serum drug levels and vascular photosensitization-partial for HPE and complete for mTHPC-suggests that direct photosensitization of endothelial cells is unlikely wholly to explain the vascular collapse. Instead, there must be either another compartment that accumulates photosensitizer more slowly and in which photodynamic activity has an indirect effect on the blood capillaries or a slow metabolic transformation of mTHPC into a more active sensitizer.
Molecular, cellular, and tissue responses following photodynamic therapy
Lasers in Surgery and Medicine, 1988
Photodynamic therapy (PDT) is being utilized in the treatment of a wide variety of malignant tumors. Results using PDT have been encouraging, and controlled clinical trials are currently being performed. The procedure exploits both the tumor-localizing and -photosensitizing properties of hematoporphyrin derivative or its purified component, Photofrin 11. When this porphyrin mixture is administered systemically, it is retained preferentially in tumor tissue as compared to surrounding normal tissue. Localized tumor destruction induced by PDT results from the photochemical generation of cytotoxic oxygen species within the tumor. This review will provide a summary of historical and current research pertaining to molecular, cellular, and tissue responses induced by PDT. Emphasis is placed on information related to the chemistry of current photosensitizers, subcellular targets, preclinical treatment parameters, and clinical responses following PDT.
Tumor Vascular Microenvironment Determines Responsiveness to Photodynamic Therapy
Cancer Research, 2012
The efficacy of photodynamic therapy (PDT) depends upon the delivery of both photosensitizing drug and oxygen. In this study, we hypothesized that local vascular microenvironment is a determinant of tumor response to PDT. Tumor vascularization and its basement membrane (collagen) were studied as a function of supplementation with basement membrane matrix (Matrigel) at the time of tumor cell inoculation. Effects on vascular composition with consequences to tumor hypoxia, photosensitizer uptake, and PDT response were measured. Matrigel-supplemented tumors developed more normalized vasculature, composed of smaller and more uniformly spaced blood vessels than their unsupplemented counterparts, but these changes did not affect tumor oxygenation or PDT-mediated direct cytotoxicity. However, PDT-induced vascular damage increased in Matrigel-supplemented tumors, following an affinity of the photosensitizer Photofrin for collagen-containing vascular basement membrane coupled with increased c...