The Theory Of Photodynamic Therapy Dosimetry: Consequences Of Photodestruction Of Sensitizer

The theory of photodynamic therapy dosimetry: consequences of photodestruction of sensitizerWilliam R. PotterDiv. of Radiation Biology, Department of Radiation Medicine, Roswell Park Memorial Institute666 Elm Street, Buffalo, New York 14263 U. S. A.AbstractPhotodynamic dose is defined as the area under the curve of sensitizer level plotted as afunction of light dose. The photodestruction of sensitizer during photodynamic therapy isshown to result in an upper limit on the photodynamic dose which can be delivered by anunlimited light dose. This limit results in the opportunity to make total photodynamic doseuniform to considerable depths (one to two centimeters). The existence of thresholds forpermanent tissue damage allows protection of normal tissue from the large light dosesrequired to achieve this limiting dose deep in the tissue. Higher sensitizer levels in thetumor permit tumor destruction while the normal tissues are protected. A clinical trial todetermine the proper level of injected dose necessary for these results is required.This theory of photodynamic therapy (PDT) dosimetry is tested in the DBA -SMT experimentalmouse tumor system. Combinations of drug and light which are not reciprocal but are nearlyequal by this theory are shown to give equivalent tumor control at seven days posttreatment. Reciprocal combinations of drug and light fail to give equivalent results whenthey are selected using the theory to choose a combination where reciprocity should fail.IntroductionPhotodynamic therapy (PDT) is an experimental treatment for cancer involving theinjection of a photosensitizer with tumor localizing ability.1 The sensitizer clears mostnormal tissues rapidly but is retained by essentially all tumors. To be clinically usefulthe sensitizer must also be activated by light which has good tissue penetration. In thevisible spectrum red light has the best tissue penetration.2 Photofrin® II, ordihematoporphyrin ether (DHE), the drug currently used in clinical trials, is activated by630 nm (red) light.1Photodynamic therapy has been applied to a wide variety of malignant tumors generallyafter failure of other therapies. To date more than 2000 patients have been treatedincluding those with lung, bladder, esophagus, gynecological, eye and skin cancer.DHE is highly lipophyllic and is found in cell membranes. Both the plasma membrane andthe mitochondria are possible targets of PDT.3 In water DHE is highly aggregated and thusinefficient in production of singlet oxygen. In a lipid environment DHE disaggregates andis capable of efficient generation of singlet oxygen.4Theory of doseCowled and Forbes5 have noted the injected sensitizer (DHE) and light dose can be variedreciprocally with equivalent biological effect. This reciprocity of drug (in mg /kg) andlight (in Joules /square cm) holds over a limited range. Over this range the product of drugand light is a useful definition of dose.Geometrically this product is the area under the curve of tissue drug level plotted as afunction of delivered light dose. In the case where drug level is independent of light dosethe products of reciprocal variations are equivalent.A more general way in which the geometric definition of photodynamic dose, E, can beexpressed is: