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Tumor-secreted Vascular Permeability Factor/Vascular Endothelial Growth Factor Influences Photosensitizer Uptake¹

Wellman Laboratories of Photomedicine, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

The role of vascular permeability in the preferential accumulation of photosensitizers in tumor tissue was investigated. Two murine tumors [experimental mammary tumor carcinoma (EMT-6) and methylcholan-threne-induced rhabdomyosarcoma (M1S)] and a human bladder carcinoma (EJ) were grown s.c. on the flank in athymic nude mice and analyzed for in vivo vessel permeability, vascular permeability factor (VPF) secretion, and accumulation of the photosensitizer, chloroaluminum sulfonated phthalocyanine. In vivo tumor vessel permeability and vascular volume were quantitated by measuring Evans blue extravasation and accumulation of a high molecular weight fluoresceinated dextran, respectively. VPF was isolated from serum-free tumor cell conditioned medium using heparin-Sepharose affinity chromatography. Dot and Western blots stained with anti-VPF antiserum positively identified VPF in samples from each tumor. Chloroaluminum sulfonated phthalocyanine pharmacokinetics in tumor-bearing mice were measured using a fiber-based spectrofluorometer.

In vivo vessel permeability was found to be greatest in M1S tumors, next in EMT-6 tumors and finally in EJ tumors. Consistent with in vivo data, M1S and EMT-6 tumor cells in culture secrete significantly more VPF than EJ tumor cells. Chloroaluminum sulfonated phthalocyanine accumulation was approximately 2 times greater in M1S and EMT-6 tumors compared to EJ tumors. Our data present evidence that photosensitizer accumulation can be correlated to in vivo tumor vessel permeability and VPF secretion of that tumor. Taken together, the data support the hypothesis that vascular permeability differences among tumors play a significant role in the uptake and retention of photodynamic agents.

¹ This work was supported in part by ONR Contracts N00014-86-K0117 and R29 AR38918. W. G. R. received support from the Ford Foundation Postdoctoral Fellowship and NIH Postdoctoral Fellowship (GM13763).

² Present address: Center for Cellular and Molecular Medicine-0669, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0669.

³ To whom requests for reprints should be addressed.

Received 11/ 2/91. Accepted 10/20/92.

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