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COMPETITIVE FREE RADICAL MECHANISM RESULTING IN PHOTODYNAMIC EFFECTS : TYPE III MECHANISM COMMENTS AND QUESTIONS TO THE PUBLICATION OF M. AVELINE AND R.W REDMOND (IN 13) Dezso Gál Central Research Institute for Chemistry, Hungarian Academy of Sciences, Pusztaszeri u. 59-67, Budapest, Hungary. It was a pleasure, indeed, to read the „paper" of Aveline and Redmond on the first internet conference advocating the important role of free radicals in photosensitization. I would like to supplement this material by certain comments based mainly on our earlier experimental results and kinetic considerations. In the early nineties we have suggested [1], that parallel to the Type I. and Type II. mechanisms, there might proceed a direct interaction between the relatively long-lived triplet sensitizer and free radicals present in the system, a so called triplet - doublet process studied by others in detail in purely chemical systems already in the seventies. At that time we have called it the modified type one (MTO) mechanism. Experimental results and further kinetic approach since then made it clear that this MTO mechanism differs basically from the Type I. and thus we intend to call it the Type III. mechanism. Briefly, these resulta are as follows. Laser flash photolysis and ESR measurements studying both the quenching of the triplets of photosensitizers (e.g. Photofrin II) by (fifteen various) stable free radicals as well as the disappearance of the spin of stable free radicals in the presence of triplet sensitizer, indicated that interactions suggested actually can take place with sensitizers used in vivo[2-3]. The direct determination of the steady state concentration of free radicals (by ESR method) in tumor tissues of mice has shown that during the fast proliferation period of cancer cells, the steady state concentration of (native) free radicals increases to a given maximum (to about 10-5 - 10-6 spin M) and excited sensitizer molecules diminish these concentrations considerably [4-5]. Similarly, the luminol dependent chemiluminescence observed in the course of respiratory burst of macrophages decreases sharply in the presence of either radical inhibitor or excited sensitizer molecules [6]. These results indicate that the interaction between triplet sensitizer and native free radicals generated in the tissue might successfully compete with the Type I. and Type II. mechanisms if taking into account that the rate constants of processes between triplets and oxygen resulting in singlet oxygen and of the triplet - doublet interactions are (2-3)x109 and (6-8)x109 M-1s-1, respectively. Under special conditions we might have also an „exclusive free radical mechanism" as observed in your system. Furthermore, above facts support our kinetic calculations according to which while during sensitization in homogeneous solutions singlet oxygen can be easily detected, the same was mainly unsuccessful under in vivo conditions [7] In summary, the role of free radicals in photosensitization seems to be more important than it was assumed, so far. In addition, I would like to ask some questions concerning your paper: 1. Since your mechanism differs from the „classic" Type I. mechanism which according e.g. to Foote cited in the paper assumes a H or electron transfer between the triplet and biomolecules or the solvent resulting in sensitizer radicals or radical ions (being a sort of propagation) radicals in your system stem from the direct photochemical decomposition into a pair of radicals (a sort of initiation or branching), it would be interesting to know the rates for the decomposition in order to compare the efficiency to the other mechanisms. 2. Concerning the hydrogen abstraction by primary radicals, although e.g. the activity of dipehylmethyl radical was followed under deaerated conditions, would it not be justified to say that under normal photosensitization practically the corresponding peroxy radicals react with molecules (the oxygen additions proceeds by a rate constant between 107 - 109 M-1 s-1) 3. In organic solvents and aqueous media of pH < 4.7 where the parallel formation of triplets and free radicals is envisaged, an increasing quenching of the triplet by the radicals with increasing laser energy was not observed ? We are looking with great interest to your next publications concerning the bioreactivitties of various free radicals. Some of our recent publications dealing with the role of free radicals and cited presently are as follows : [1] D.Gál : Effect of Photosensitizers in Chemical and Biological Processes: the MTO Mechanism in Photodynamic Therapy. Biochem. Biophys. Res. Commun. 186; 1032-1036; 1992 [2] T. Vidóczy, S. Elzemzam, D. Gál : Physico Chemical Modeling of the Role of Free Radicals in Photodynamic Therapy. I. Utilization of Quantum Yield Data of Singlet Oxygen Formation for the Study of the Interaction between Excited Photosensitizer and Stable Free Radicals. Biochem. Biophys. Res. Commun. 189; 1548-1552; 1992 [3] T. Kriska, L. Korecz, I. Nemes, D. Gál: Physico Chemical Modeling of the Role of Free Radicals in Photodynamic Therapy. III. Interaction of Stable Free Radicals and Triplet excites Photosensitizer Studied by Kinetic ESR Spectroscopy. Biochem. Biophys. Res. Commun. 215; 192-198; 1995 [4] T. Shulyakovskaya, L. Sümegi and D.Gál : In Vivo Experimental Studies on the Role of Free Radicals in Photodynamic Therapy. I. Measurement of the Steady State Concentration of Free Radicals in Tumor Tissues of Mice. Biochem. Biophys. Res. Commun.195; 581-587; 1993 [5] T.Kriska, Elena Maltseva and D.Gál : In Vivo Experimental Studies on the Role of Free Radicals in Photodynamic Therapy. II. Photodynamic Effect on Free Radical Concentration in Mice Tumors Measured by ESR Spectroscopy. Biochem. Biophys. Res. Commun., 223, 136-140, 1996 [6] Dezsô Gál, Tamás Kriska, Elena Maltseva : In Vivo Experimental Studies on the Role of Free Radicals in Photodynamic Therapy. III. Photodynamic Effect on Free Radicals Generated in Cell Cultures. Biochem. Biophys. Res. Commun., 233, 173-176, 1997 [7] D. Gál: Hunt for Singlet Oxygen under in Vivo Conditions. Biochem. Biophys. Res. Commun. 202; 10-16; 1994.