Biochemical Pharmacology, Vol. 28, pp. 2465-2470 @ Pergamon Press Ltd. 1979. Printed in Great Britain. 0006-295217910815-2465 $02.00/O zyxwvut ON THE MODE OF CYTOTOXIC ACTION OF PHOTO- ACTIVATED PORPHYRINS KENNETH KOHN and DAVID KESSEL* Departments of Pharmacology and Oncology. Wayne University School of Medicine. Detroit. MI 4820 1. U.S.A. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ (Received 28 November 1978: accepted 7 Februaty 1979) Abstrac-Upon photo~activation. certain ~rphyrjns can exert a substantial cytotoxic action on rn~mal~~ cells. A study of the interaction between a group of porphyrins and some tr~splantabie murine ascitic tumors has suggested several major determinants of porphyrin toxicity. Optimally effective porphyrins are water soluble; however, they can be extracted from aqueous solution by octanol. but not by decane. Upon photo- activation, porphyrins accumulated by tumor ceils catalyze cross-linking of membrane protein but not of glycoprotein. This cross-linking is associated with a decrease in ceil-surface hydrophobicity and with other alterations in vital membrane propeprties. A series of porphyrins has the interesting property of becoming localized in malignant tissue [ 1.21 where, upon exposure to light, they exert a substantial cyto- toxic actionleading to tumor regression [3,41. The mode of action involves a photo-activated process lead- ing to formation of singlet oxygen 15-71. This reaction * Reprints should be requested from Dr. Kesselat the Department of Oncology, Harper-Grace Hospitals. 4 160 John R. St.. Detroit. MI 48301. U.S.A. CH2 I CH2 I NH2 8 CH2C-NH I CH2 I CH2 I NH2 brings about oxidation of several compounds of biol- ogic importance, including lipids [ 8- 101, cholesterol [ 11, 121, and amino acids [S, 10, 13. 141. Ofthe latter. histidine appears to be the most likely candidate for porphyrin-induced oxidation [ 15 I. The consequences of these oxidative reactions are cross-linking of mem- brane protein IX, 13, 161, inhibiti~ of membrane- bound enzymes [ 17 1. disruption of membranes (e.g. of erythrocytes [ 10, 12, 16I), interference with membrane transport [ 181, and cell death [3, 181. -v-L&r -‘-Li-LE F n2 iliz Lot4 Fig. 1. Structure of porphyrins examined in this study. 2465