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The AKT/mamnialian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease., Introduction Prostate cancer is one of the most common neoplasms, particularly among aging males in the United States. Like many adenocarcinomas, prostate tumors arise from preinvasive lesions, mainly prostatic intraepithelial [...]

Intracellular calcium concentration ([[[Ca.sup.2+]].sub.i]) signals are central to the mechanisms underlying fluid and protein secretion in pancreatic and parotid acinar cells. Calcium release was studied in natively buffered cells following focal laser photolysis of caged molecules. Focal photolysis of caged-inositol 1,4,5 trisphosphate (Ins[P.sub.3]) in the apical region resulted in [Ca.sup.2+] release from the apical trigger zone and, after a latent period, the initiation of an apical-to-basal [Ca.sup.2+] wave. The latency was longer and the wave speed significantly slower in pancreatic compared with parotid cells. Focal photolysis in basal regions evoked only limited [Ca.sup.2+] release at the photolysis site and never resulted in a propagating wave. Instead, an apical-to-basal wave was initiated following a latent period. Again, the latent period was significantly longer under all conditions in pancreas than parotid. Although slower in pancreas than parotid, once initiated, the apical-to-basal wave speed was constant in a particular cell type. Photo release of caged-[Ca.sup.2+] failed to evoke a propagating [Ca.sup.2+] wave in either cell type. However, the kinetics of the [Ca.sup.2+] signal evoked following photolysis of caged-Ins[P.sub.3] were significantly dampened by ryanodine in parotid but not pancreas, indicating a more prominent functional role for ryanodine receptor (RyR) following Ins[P.sub.3] receptor (Ins[P.sub.3]R) activation. These data suggest that differing expression levels of Ins[P.sub.3]R, RyR, and possibly cellular buffering capacity may contribute to the fast kinetics of [Ca.sup.2+] signals in parotid compared with pancreas. These properties may represent a specialization of the cell type to effectively stimulate [Ca.sup.2+]-dependent effectors important for the differing primary physiological role of each gland. inositol 1,4,5 trisphosphate receptors; ryanodine receptors; imaging

We present two forward-adjoint models for recovering intrinsic fluorescence spectra and hemoglobin oxygen saturation of turbid samples. The first fits measured diffuse reflectance spectra to obtain the absorption and scattering spectra of the medium, and these are then used to correct distortions imposed on the fluorescence spectrum by absorption and scattering. The second fits only the measured fluorescence spectrum to determine simultaneously the amplitudes of absorption and fluorescence basis spectra and scattering parameters. Both methods are validated with Monte Carlo simulations and experimentally in scattering phantoms containing nicotinamide adenine dinucleotide and human erythrocytes. Preliminary measurements from murine tumors in vivo are presented. OCIS codes: 170.3890, 170.6280, 170.6510, 170.7050.

Deep tissue abscesses represent a significant source of morbidity and hospital stay, with standard of care drainage failing in many cases. We investigated photodynamic therapy (PDT) as an adjunct to standard of care, to reduce or eliminate bacterial burden. A Phase 1 clinical trial was performed to evaluate safety and feasibility of methylene blue (MB) PDT at the time of abscess drainage. Immediately following drainage, MB-PDT was performed. Diffuse reflectance spectroscopy was performed to evaluate abscess wall optical properties. No study-related adverse events were noted, and no side effects were observed. PDT was well tolerated by all subjects, and infused MB was recovered in all cases. Optical property measurements showed variability in hemoglobin concentration and oxygenation, as well as MB uptake, between subjects. MB-PDT at the time of percutaneous abscess drainage was safe and feasible, and optical property measurements showed wide variance between subjects. [ABSTRACT FROM AUTHOR]

We present a steady-state method for localizing a source of luminescence (i.e., fluorescence or phosphorescence) buried in a semi-infinite turbid medium with unknown optical properties. A diffusion theory expression describing the emittance of an isotropic point source is fit to spatially resolved surface measurements of the diffuse emittance from the luminescent source. The technique reports the location of the center of a 6.0-mm-diameter, fluorophore-containing spherical bulb embedded in a liquid phantom with an accuracy of 1.0 mm or better for source depths as great as 40.0 mm. Monte Carlo data are analyzed to investigate the range and the possible sources of error in the reconstructed source depth.

We present a steady-state radially resolved diffuse reflectance spectrometer capable of measuring the absorption and transport scattering spectra of tissue-simulating phantoms over an adjustable 170-nm wavelength interval in the visible and near infrared. Measurements in a variety of phantoms are demonstrated over the relevant range of tissue optical properties, and the accuracy of the instrument is found to be approximately 10% in both scattering and absorption. Monte Carlo simulations designed to test the accuracy of the instrument are presented that support the experimental findings. Key words: Diffuse reflectance, diffusion theory, Monte Carlo, tissue optics.

The archaeological applications of optimization theory that were applied to resource use are reviewed. A study that modeled agricultural productivity among the 18th-early 19th century Muscogee Creek Indians showed that the residents of Cussetuh were risk minimizers and were not maximizing long-term average rate of corn yield in their gardens.

Lymphangioleiomyomatosis (LAM) is a rare disease in women. Patients with LAM develop metastatic smooth-muscle cell adenomas within the lungs, resulting in reduced pulmonary function. LAM cells contain mutations in tuberous sclerosis genes (TSC1 or TSC2), leading to up-regulation of mTORC1 activity and elevated proliferation. The origin of LAM cells remains unknown; however, inactivation of Tsc2 gene in the mouse uterus resulted in myometrial tumors exhibiting LAM features, and approximately 50% of animals developed metastatic myometrial lung tumors. This suggests that LAM tumors might originate from the uterine myometrium, possibly explaining the overwhelming prevalence of LAM in female. Here, we demonstrate that mouse Tsc2-null myometrial tumors exhibit nearly all the features of LAM, including mTORC1/S6K activation, as well as expression of melanocytic markers and matrix metalloproteinases (MMPs). Estrogen ablation reduces S6K signaling and results in Tsc2-null myometrial tumor regression. Thus, even without TSC2, estradiol is required to maintain tumors and mTORC1/S6K signaling. Additionally, we find that MMP-2 and -9, as well as neutrophil elastase (NE), are overexpressed in Tsc2-null myometrial tumors in an estrogen-dependent fashion. In vivo fluorescent imaging using MMP- or NE-sensitive optical biomarkers confirms that protease activity is specific to myometrial tumors. Similar to LAM cells, uterine Tsc2-null myometrial cells also overexpress melanocytic markers in an estrogen-dependent fashion. Finally, we identify glycoprotein NMB (GPNMB) as a melanocytic marker up-regulated in Tsc2-null mouse uteri and human LAM samples. Our data highlight the potential importance of estradiol in LAM cells, suggesting that anti-estrogen therapy may be a treatment modality. Furthermore, proteases and GPNMB might be useful LAM biomarkers. [ABSTRACT FROM AUTHOR]

Purpose: For interstitial photodynamic therapy (iPDT) of bulky tumors, careful treatment planning is required in order to ensure that a therapeutic dose is delivered to the tumor, while minimizing damage to surrounding normal tissue. In clinical contexts, iPDT has typically been performed with either flat cleaved or cylindrical diffusing optical fibers as light sources. Here, the authors directly compare these two source geometries in terms of the number of fibers and duration of treatment required to deliver a prescribed light dose to a tumor volume. Methods: Treatment planning software for iPDT was developed based on graphics processing unit enhanced Monte Carlo simulations. This software was used to optimize the number of fibers, total energy delivered by each fiber, and the position of individual fibers in order to deliver a target light dose (D90) to 90% of the tumor volume. Treatment plans were developed using both flat cleaved and cylindrical diffusing fibers, based on tissue volumes derived from CT data from a head and neck cancer patient. Plans were created for four cases: fixed energy per fiber, fixed number of fibers, and in cases where both or neither of these factors were fixed. Results: When the number of source fibers was fixed at eight, treatment plans based on flat cleaved fibers required each to deliver 7180-8080 J in order to deposit 90 J/cm2 in 90% of the tumor volume. For diffusers, each fiber was required to deliver 2270-2350 J (333-1178 J/cm) in order to achieve this same result. For the case of fibers delivering a fixed 900 J, 13 diffusers or 19 flat cleaved fibers at a spacing of 1 cm were required to deliver the desired dose. With energy per fiber fixed at 2400 J and the number of fibers fixed at eight, diffuser fibers delivered the desired dose to 93% of the tumor volume, while flat cleaved fibers delivered this dose to 79%. With both energy and number of fibers allowed to vary, six diffusers delivering 3485-3600 J were required, compared to ten flat cleaved fibers delivering 2780-3600 J. Conclusions: For the same number of fibers, cylindrical diffusers allow for a shorter treatment duration compared to flat cleaved fibers. For the same energy delivered per fiber, diffusers allow for the insertion of fewer fibers in order to deliver the same light dose to a target volume. [ABSTRACT FROM AUTHOR]

We demonstrate the use of an enzyme-activatable fluorogenic probe, Neutrophil Elastase 680 FAST (NE680), for in vivo imaging of neutrophil elastase (NE) activity in tumors subjected to photodynamic therapy (PDT). NE protease activity was assayed in SCC VII and EMT6 tumors established in C3H and BALB/c mice, respectively. Four nanomoles of NE680 was injected intravenously immediately following PDT irradiation. 5 h following administration of NE680, whole-mouse fluorescence imaging was performed. At this time point, levels of NE680 fluorescence were at least threefold greater in irradiated versus unirradiated SCC VII and EMT6 tumors sensitized with Photofrin. To compare possible photosensitizer-specific differences in therapy-induced elastase activity, EMT6 tumors were also subjected to 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-PDT. NE levels measured in HPPH-PDT-treated tumors were twofold higher than in unirradiated controls. Ex vivo labeling of host cells using fluorophore-conjugated antibodies and confocal imaging were used to visualize Gr1+ cells in Photofrin-PDT-treated EMT6 tumors. These data were compared with recently reported analysis of Gr1+ cell accumulation in EMT6 tumors subjected to HPPH-PDT. The population density of infiltrating Gr1+ cells in treated versus unirradiated drug-only control tumors suggests that the differential in NE680 fold enhancement observed in Photofrin versus HPPH treatment may be attributed to the significantly increased inflammatory response induced by Photofrin-PDT. The in vivo imaging of NE680, which is a fluorescent reporter of NE extracellular release caused by neutrophil activation, demonstrates that PDT results in increased NE levels in treated tumors, and the accumulation of the cleaved probe tracks qualitatively with the intratumor Gr1+ cell population. [ABSTRACT FROM AUTHOR]

We examined effects of fluence rate on the photobleaching of the photosensitizer Pc 4 during photodynamic therapy (PDT) and the relationship between photobleaching and tumor response to PDT. BALB/c mice with intradermal EMT6 tumors were given 0.03 mg kg−1 Pc 4 by intratumor injection and irradiated at 667 nm with an irradiance of 50 or 150 mW cm−2 to a fluence of 100 J cm−2. While no cures were attained, significant tumor growth delay was demonstrated at both irradiances compared with drug-only controls. There was no significant difference in tumor responses to these two irradiances ( P = 0.857). Fluorescence spectroscopy was used to monitor the bleaching of Pc 4 during irradiation, with more rapid bleaching with respect to fluence shown at the higher irradiance. No significant correlation was found between fluorescence photobleaching and tumor regrowth for the data interpreted as a whole. Within each treatment group, weak associations between photobleaching and outcome were observed. In the 50 mW cm−2 group, enhanced photobleaching was associated with prolonged growth delay ( P = 0.188), while at 150 mW cm−2 this trend was reversed ( P = 0.308). Thus, it appears that Pc 4 photobleaching is not a strong predictor of individual tumor response to Pc 4-PDT under these treatment conditions. [ABSTRACT FROM AUTHOR]

ABSTRACT Cutaneous and mucocutaneous Candida infections are considered to be important targets for antimicrobial photodynamic therapy (PDT). Clinical application of antimicrobial PDT will require strategies that enhance microbial killing while minimizing damage to host tissue. Increasing the sensitivity of infectious agents to PDT will help achieve this goal. Our previous studies demonstrated that raising the level of oxidative stress in Candida by interfering with fungal respiration increased the efficiency of PDT. Therefore, we sought to identify compounds in clinical use that would augment the oxidative stress caused by PDT by contributing to reactive oxygen species (ROS) formation themselves. Based on the ability of the antifungal miconazole to induce ROS in Candida, we tested several azole antifungals for their ability to augment PDT in vitro. Although miconazole and ketoconazole both stimulated ROS production in Candida albicans, only miconazole enhanced the killing of C. albicans and induced prolonged fungistasis in organisms that survived PDT using the porphyrin TMP-1363 and the phenothiazine methylene blue as photosensitizers. The data suggest that miconazole could be used to increase the efficacy of PDT against C. albicans, and its mechanism of action is likely to be multifactorial. [ABSTRACT FROM AUTHOR]

ABSTRACT Cutaneous and mucocutaneous Candida infections are considered to be important targets for antimicrobial photodynamic therapy (PDT). Clinical application of antimicrobial PDT will require strategies that enhance microbial killing while minimizing damage to host tissue. Increasing the sensitivity of infectious agents to PDT will help achieve this goal. Our previous studies demonstrated that raising the level of oxidative stress in Candida by interfering with fungal respiration increased the efficiency of PDT. Therefore, we sought to identify compounds in clinical use that would augment the oxidative stress caused by PDT by contributing to reactive oxygen species (ROS) formation themselves. Based on the ability of the antifungal miconazole to induce ROS in Candida, we tested several azole antifungals for their ability to augment PDT in vitro. Although miconazole and ketoconazole both stimulated ROS production in Candida albicans, only miconazole enhanced the killing of C. albicans and induced prolonged fungistasis in organisms that survived PDT using the porphyrin TMP-1363 and the phenothiazine methylene blue as photosensitizers. The data suggest that miconazole could be used to increase the efficacy of PDT against C. albicans, and its mechanism of action is likely to be multifactorial. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011. © 2011 American Cancer Society, Inc. [ABSTRACT FROM AUTHOR]

Mucosal infections caused by the pathogenic fungus Candida are a significant infectious disease problem and are often difficult to eradicate because of the high frequency of resistance to conventional antifungal agents. Photodynamic treatment (PDT) offers an attractive therapeutic alternative. Previous studies demonstrated that filamentous forms and biofilms of Candida albicans were sensitive to PDT using Photofrin as a photosensitizer. However, early stationary phase yeast forms of C. albicans and Candida glabrata were not adversely affected by treatment. We report that the cationic porphyrin photosensitizer meso-tetra ( N-methyl-4-pyridyl) porphine tetra tosylate (TMP-1363) is effective in PDT against yeast forms of C. albicans and C. glabrata. Respiratory-deficient (RD) strains of C. albicans and C. glabrata display a pleiotropic resistance pattern, including resistance to members of the azole family of antifungals, the salivary antimicrobial peptides histatins and other types of toxic stresses. In contrast to this pattern, RD mutants of both C. albicans and C. glabrata were significantly more sensitive to PDT compared to parental strains. These data suggest that intact mitochondrial function may provide a basal level of anti-oxidant defense against PDT-induced phototoxicity in Candida, and reveals pathways of resistance to oxidative stress that can potentially be targeted to increase the efficacy of PDT against this pathogenic fungus. [ABSTRACT FROM AUTHOR]

Meso-tetra-hydroxyphenyl-chlorin (mTHPC, Foscan®), a promising photosensitizer for photodynamic therapy (PDT), is approved in Europe for the palliative treatment of head and neck cancer. Based on work in mice that investigated optimal tumor accumulation, clinical protocols with Foscan® typically employ an interval of 96 h between systemic sensitizer administration and irradiation. However, recent studies in mouse tumor models have demonstrated significantly improved long-term tumor response when irradiation is performed at shorter drug-light intervals of 3 and 6 h. Using a previously published theoretical model of microscopic PDT dosimetry and informed by experimentally determined photophysical properties and intratumor sensitizer concentrations and distributions, we calculated photodynamic dose depositions following mTHPC-PDT for drug-light intervals of 3, 6, 24, and 96 h. Our results demonstrate that the singlet oxygen dose to the tumor volume does not track even qualitatively with tumor responses for these four drug-light intervals. Further, microscopic analysis of simulated singlet oxygen deposition shows that in no case do any subpopulations of tumor cells receive a threshold dose. Indeed, under the conditions of these simulations more than 90% of the tumor volume receives a dose that is approximately 20-fold lower than the threshold dose for mTHPC. Thus, in this evaluation of mTHPC-PDT at various drug-light intervals, any PDT dose metric that is proportional to singlet oxygen creation and/or deposition would fail to predict the tumor response. In situations like this one, other reporters of biological response to therapy would be necessary. [ABSTRACT FROM AUTHOR]

We present an in vivo fluorescence microscopic evaluation of intratumor distribution of the photosensitizer mono-L-aspartylchlorin-e6 (NPe6) in an intradermal mouse EMT6 tumor model. Although the identification of favorable photophysical and pharmacological properties has led to the development of new photosensitizers in photodynamic therapy, their intratumor distribution kinetics have remained relatively understudied. In this study, we used confocal fluorescence microscopy to follow the transport of NPe6 in vivo after systemic administration through the tail vein. Labeling of vasculature using fluorophore-conjugated anti-CD31 antibodies allows visualization of the uptake of NPe6 in tumor and normal vessels and its partitioning kinetics into the adjacent parenchyma for 3 hours after injection. During the initial 60 minutes after injection, the drug is predominantly confined to the vasculature. Subsequently, it significantly redistributes throughout the extravascular regions with no discernable difference in its extravasation rate between tumor and normal tissues. Further, we investigate the sensitizer's altered intratumor distribution in response to photodynamic therapy irradiation and observe that treatment-induced changes in vessel permeability caused enhanced accumulation of NPe6 in the extravascular space. Our findings are of immediate clinical relevance and demonstrate the importance of an in vivo imaging approach to examine the dynamic process of intratumor drug distribution. [ABSTRACT FROM AUTHOR]

lntracellular calcium concentration ([Ca2+]i) signals are central to the mechanisms underlying fluid and protein secretion in pancreatic and parotid acinar cells. Calcium release was studied in natively buffered cells following focal laser photolysis of caged molecules. Focal photolysis of caged-inositol 1,4,5 trisphosphate (InsP3) in the apical region resulted in Ca2+ release from the apical trigger zone and, after a latent period, the initiation of an apical-to-basal Ca2+ wave. The latency was longer and the wave speed significantly slower in pancreatic compared with parotid cells. Focal photolysis in basal regions evoked only limited Ca2+ release at the photolysis site and never resulted in a propagating wave. Instead, an apical-to-basal wave was initiated following a latent period. Again, the latent period was significantly longer under all conditions in pancreas than parotid. Although slower in pancreas than parotid, once initiated, the apical-to-basal wave speed was constant in a particular cell type. Photo release of caged-Ca2+ failed to evoke a propagating Ca2+ wave in either cell type. However, the kinetics of the Ca2+ signal evoked following photolysis of caged-InsP3 were significantly dampened by ryanodine in parotid but not pancreas, indicating a more prominent functional role for ryanodine receptor (RyR) following InsP3 receptor (InsP3R) activation. These data suggest that differing expression levels of InsP3R, RyR, and possibly cellular buffering capacity may contribute to the fast kinetics of Ca2+ signals in parotid compared with pancreas. These properties may represent a specialization of the cell type to effectively stimulate Ca2+-dependent effectors important for the differing primary physiological role of each gland. [ABSTRACT FROM AUTHOR]

Phthalocyanine 4 (Pc 4) is a promising photosensitizer currently in clinical trials. Photobiological responses to Pc 4 photodynamic therapy (Pc 4-PDT) have been characterized extensively, but relatively little has been done to evaluate dose metrics for this sensitizer. We describe an irradiation-induced increase in fluorescence in tumor cell monolayers. This increase is due solely to enhanced fluorescence from Pc 4, as confirmed by confocal spectroscopy. In EMT6 cells incubated with 250 n M Pc 4 for 24 h, the maximum increase in fluorescence is approximately 3.7-fold above baseline levels. This increase occurs over a range of fluences, 0.05 – 0.6 J cm−2, where clonogenic survival decreases by 3 orders of magnitude. Light scattering measurements performed on similarly treated EMT6 cells in suspension suggested a Pc 4-PDT-mediated mitochondrial swelling of approximately 13% at 0.6 J cm−2, where fluorescence enhancement saturates under these treatment conditions. Fluorescence imaging and light scattering experiments performed at a five-fold lower Pc 4 incubation concentration revealed a reduced fluorescence enhancement at a five-fold higher fluence, which produced comparable mitochondrial swelling. Taken together, these data suggest that Pc 4 is initially aggregated at high local concentration in mitochondria and that irradiation relaxes the quenching of Pc 4 fluorescence through a mechanism that may involve mitochondrial swelling. [ABSTRACT FROM AUTHOR]

We have developed a comprehensive theoretical model for rigorously describing the spatial and temporal dynamics of oxygen (3O2) consumption and transport and microscopic photodynamic dose deposition during photodynamic therapy (PDT) in vivo. Previously published models have been improved by considering perfused vessels as a time-dependent 3O2 source and linking the 3O2 concentration in the vessel to that within the tissue through the Hill equation. The time-dependent photochemical 3O2 consumption rate incorporates sensitizer photobleaching effects and an experimentally determined initially nonuniform photosensitizer distribution. The axial transport of 3O2 is provided for in the capillaries and in the surrounding tissue. A self-sensitized singlet oxygen (1O2)-mediated bleaching mechanism and the measured, initially nonuniform distribution of meso-tetrahydroxyphenyl chlorin at 3 h after intravascular administration were used to demonstrate the capabilities of the model. Time-evolved distributions of 3O2 concentration were obtained by numerically solving two-dimensional diffusion-with-reaction equations both in the capillary and the adjacent tissue. Using experimentally established physiological and photophysical parameters, the mathematical model allows computation of the dynamic variation of hemoglobin-3O2 saturation (SO2) within the vessels, irreversible sensitizer degradation due to photobleaching, and the microscopic distributions of 3O2, sensitizer concentration, and 1O2 dose deposition under various irradiation conditions. The simulations reveal severe axial gradients in 3O2 and in photodynamic dose deposition in response to a wide range of clinically relevant treatment parameters. Thus, unlike former Krogh cylinder-based models, which assume a constant 3O2 concentration at the vessel, this new model identifies conditions in which 3O2 depletion and minimal deposition of reacting 1O2 exist near the end of axial segments of vessels and shows that treatment-limiting 3O2 depletion is induced at fluence rates as low as 10 mW cm-2. These calculations also demonstrate that intercapillary heterogeneity of photosensitizer contributes significantly to the distribution of photodynamic dose. This more rigorous mathematical model enables comparison with experimentally observable, volume-averaged quantities such as SO2 and the loss of sensitizer fluorescence through bleaching that have not been included in previous analyses. Further, it establishes some of the intrinsic limitations of such measurements. Specifically, our simulations demonstrate that tissue measurements of SO2 and of photobleaching are necessarily insensitive to microscopic heterogeneity of photodynamic dose deposition and are sensitive to intercapillary spacing. Because prior knowledge of intercapillary distances in tumors is generally unavailable, these measurements must be interpreted with caution. We anticipate that this model will make useful dosimetry predictions that should inform optimal treatment conditions and improve current clinical protocols. [ABSTRACT FROM AUTHOR]