Pharmacokinetics and pharmacodynamics of tetra(m-hydroxyphenyl)chlorin in the hamster cheek pouch tumor model: comparison with clinical measurements

The pharmacokinetics (PK) of the photosensitizer tetra(m-hydroxyphenyl)chlo rin (mTHPC) was measured by optical fiber-based light-induced fluorescence spectroscopy (LIFS) in the normal and tumoral cheek pouch mucosa of 29 Gold en Syrian hamsters with chemically induced squamous cell carcinoma. Similar measurements were carried out on the normal oral cavity mucosa of five pat ients up to 30 days after injection. The drug doses were between 0.15 and 0 .3 mg per kg of body weight (mg/kg), and the mTHPC fluorescence in the tiss ue was excited at 420 nm. The PK in both human and hamster exhibited simila r behavior although the PK in the hamster mucosa was slightly delayed in co mparison with that of its human counterpart. The mTHPC fluorescence signal of the hamster mucosa was smaller than that of the human mucosa by a factor of about 3 for the same injected drug dose. A linear correlation was found between the fluorescence signal and the mTHPC dose in the range from 0.075 to 0.5 mg/kg at times between 8 and 96h after injection. No significant se lectivity in mTHPC fluorescence between the tumoral and normal mucosa of th e hamsters was found at any of the applied conditions. The sensitivity of t he normal and tumoral hamster cheek pouch mucosa to mTHPC photodynamic ther apy as a function of the light dose was determined by light irradiation at 650 nm and 150 mW/cm(2), 4 days after the injection of a drug dose of 0.15 mg/kg. These results were compared with irradiations of the normal oral and normal and tumoral bronchial mucosa of 37 patients under the same conditio ns. The reaction to PDT of both types of human mucosae was considerably str onger than that of the hamster cheek pouch mucosa. The sensitivity to PDT b ecame comparable between hamster and human mucosa when the drug dose for th e hamster was increased to 0.5 mg/kg. A significant therapeutic selectivity between the normal and neoplastic hamster cheek pouch was observed. Less s electivity was found following irradiations of normal mucosa and early carc inomas in the human bronchi. The pharmacodynamic behavior of mTHPC was dete rmined by test irradiations of the normal mucosa of hamsters and patients b etween 6 h and 8 days after injection of 0.5 and 0.15 mg/kg in the hamsters and the patients, respectively. The normal hamster cheek pouch showed a ma ximum response to irradiation 6 h after injection and then decreased contin uously to no observable reaction at 8 days after injection. The reaction of the normal human oral mucosa, however, showed an increasing sensitivity to the applied light between 6 h and 4 days after mTHPC injection and then de creased again at 8 days. The hamster model with the chemically induced earl y squamous cell cancer in the cheek pouch thus showed some similarity to th e early squamous cell cancer of the human oral mucosa considering the PK. H owever, a quantitative difference in fluorescence signal for identical mTHP C doses as well as a significant difference in pharmacodynamic behavior wer e also observed. The suitability of this animal model for the optimization of PDT parameters in the clinic is therefore limited. Hence great care must be taken in screening new dyes for PDT of early squamous cell cancer of th e upper aerodigestive tract based upon observables in the hamster cheek pou ch model. (C) 2000 Elsevier Science S.A. All rights reserved.