Multidrug resistance (MDR) poses a serious barrier to the efficacy of clinical treatment of human cancers with
chemotherapeutic drugs. This barrier might be reduced and eventually overcome by the simultaneous application of two
or more treatment modalities. This study reports on the synergetic effect of combined application of laser light and
cytostatic drugs to induce an improved tumour response in MDR cancer cells. The MDR breast cancer cell line
MaTu/ADR, resistant to the drug adriamycin (ADR), was treated with a combination of ADR (125-1000 ng/ml) and
laser light (488 nm with a total light dose between 6-18 J/cm2). This combined treatment leads to an additional reduction
of the cell vitality by a factor of 2-3 as compared to treatment with ADR alone, suggesting that combined application of
laser light and other treatment modalities might constitute a promising strategy for improvements in the tumour response.
Due to the experience in the exploitation of previous European telemedicine projects an open Euro-Mediterranean consortium proposes the Virtual Euro-Mediterranean Hospital (VEMH) initiative. The provision of the same advanced technologies to the European and Mediterranean Countries should contribute to their better dialogue for integration. VEMH aims to facilitate the interconnection of various services through real integration which must take into account the social, human and cultural dimensions. VEMH will provide a platform consisting of a satellite and terrestrial link for the application of medical e-learning, real-time telemedicine and medical assistance. The methodologies for the VEMH are medical-needs-driven instead of technology-driven. They supply new management tools for virtual medical communities and allow management of clinical outcomes for implementation of evidence-based medicine. Due to the distributed character of the VEMH Grid technology becomes inevitable for successful deployment of the services. Existing Grid Engines provide basic computing power needed by today's medical analysis tasks but lack other capabilities needed for communication and knowledge sharing services envisioned. When it comes to heterogeneous systems to be shared by different institutions especially the high level system management areas are still unsupported. Therefore a Metagrid Engine is needed that provides a superset of functionalities across different Grid Engines and manages strong privacy and Quality of Service constraints at this comprehensive level.
Multiphoton excitation of selected dye molecules for laser-induced fluorescence diagnosis (LIFD) and optical biopsy of biological tissue and microbiological samples has various advantages: greater tissue penetration, more spatial resolution and less photo-bleaching. New applicators and microscopical set-ups for the delivery of the fs-pulsed laser radiation as required for multiphoton LIFD and optical biopsy need to be developed. Beam delivery solutions and workplaces for microbiological and tissue diagnosis are presented.
Multiphoton excitation of photosensitizers for laser induced fluorescence diagnosis (LIFD) and photodynamic therapy (PDT) of tumors has the advantage of greater tissue penetration due to the longer wavelength of irradiation. However, multiphoton LIFD and PDT are presently not clinically applicable as there are no applicators available for the delivery of the pulsed laser radiation to the operating room. As an approach, in this contribution the beam delivery through photonic crystal fibers has been investigated. Pulses of a Ti:sapphire laser of 100 fs pulse duration and an average power of 150 mW have been transported through such a fiber of 25 m length and the resulting pulses show the absence of nonlinear contributions but still a broadening of the pulse to 2 ps due to the dispersion of the fiber. It is planned to compensate this broadening by a grating in front of the fiber. Alternatively, the transport of laser radiation of 150 fs and 100 mW through a mirror-joint-arm used for conventional CO2 lasers has been tested showing no broadening of the laser pulses. Two-photon photodynamic activity of mTHPC-CMPEG4 shall serve as a test of the laser light transport system.
Using off-the-shelf hardware components and a specially developed high-end software communication system (WinVicos) satellite networks for interactive telemedicine have been designed and developed. These networks allow for various telemedical applications, like intraoperative teleconsultation, second opinioning, teleteaching, telementoring, etc.. Based on the successful GALENOS network, several projects are currently being realized: MEDASHIP (Medical Assistance for Ships); DELTASS (Disaster Emergency Logistic Telemedicine Advanced Satellites Systems) and EMISPHER (Euro-Mediterranean Internet-Satellite Platform for Health, medical Education and Research).
In GALENOS (Generic Advanced Low-cost trans-European Network Over Satellite) a trans-European competence network via satellite, dedicated to telemedical applications, has been realized. Using off-the-shelf hardware components and a specially developed high-end software communication system (WinVicos) various telemedical applications, like teleteaching, intraoperative teleconsultation, have been realized.
In laser-induced fluorescence diagnosis and photodynamic therapy of cancer the applied photosensitizers (PS) are often covalently derivatized with macromolecules to improve their selective accumulation in the cancerous tissue, while maintaining its single-photon excited photophysical properties. In this contribution methoxy-polyethylene glycol (MPEG, MW ~5 kDa) and human serum albumin (HSA, MW ~60 kDa) are used as PS carriers. Multiphoton (MP) excitation of the PS is favorable as compared to single-photon excitation because the penetration depth of the laser light is improved (>5 mm) due to the longer wavelength of the ~200 fs laser pulses used in this case (700-1050 nm). In this study cotton fibers and silica gel beads (<20 mm) were stained with various PS and multiphoton-induced fluorescence was detected with a MP laser scanning microscope. The slopes of the log-log plots of the detected fluorescence intensity versus the laser excitation intensity vary between 1.8-2.6 for the various PS investigated. The excitation wavelength dependence of the MP-induced fluoresence indicates that the excitation cross section maxima can be shifted substantially relative to twice the wavelength of the one-photon absorption maxima. Some PS (photofrin II, purpurin, mTHPC-[MPEG]2 and diaminoanthra-quinone) do not exhibit multiphoton-induced fluorescence. Some derivatized PS (sulforhodamine B, erythrosin B, purpurin) exhibit MP-induced fluorescence, although no single-photon absorption band exists in the spectral region around half the excitation wavelength
Photodynamic treatment of cancer cells is known to eventually cause cell death in most cases. The precise pathways and the time course seem to vary among different cell types and modes of photodynamic treatment. In this contribution, the focus was put on the responses of human colon carcinoma cells HCT-116 within the first 15 minutes after laser irradiation in the presence of Photofrin® II (PII). To monitor the cell response in this early time period laser phase microscopic imaging was used, a method sensitive to changes in overall cell shape and intracellular structures, mediated by changes in the local refractive index. Laser irradiation of cells loaded with PII induced a significant reduction of the phase shifts, which probably reflects the induced damage to the different cellular membrane structures. The data suggest that even within the first 30 s after the onset of laser illumination, a significant reduction of the phase shifts can be detected. These results underline that laser phase microscopy is a suitable diagnostic tool for cellular research, also in the early time domain.
Multiphoton excitation of photosensitizers in photodynamic therapy constitutes a promising approach, because of the increasing tissue penetration for longer wavelength of illumination. In this contribution the photodynamic activity of polyethylene glycol macromolecular derivatized mTHPC upon two-photon excitation is established. To test the photo- activity of the photosensitizer, human colon carcinoma cells, HCT-116, were incubated with 2 (mu) g/ml of mTHPC- CMPEG4 in the nutrition medium. Subsequent pulsed laser irradiation at 784 nm focused down on growing cell monolayers restricts cell vitality clearly within 24 hours after irradiation. To investigate whether an anoxic or euoxic energy transfer mechanism is involved, a uric acid assay was performed to test for the generation of singlet oxygen. Upon single-photon excitation mTHPC-CMPEG4 in TriPEG decomposed uric acid via the generation of singlet oxygen. Using femtosecond pulsed laser irradiation no decomposition of the uric acid was found, implying an anoxic energy transfer mechanism after tow-photon excitation. However, at present, we cannot exclude local hyperthermic effects in the cells containing the photosensitizer to contribute to the photodynamic activity upon two-photon excitation.
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