Developmental pharmacology: overview.

Zinc phthalocyanine substituted with four hydroxyl groups attached to the macrocycle, either directly or via spacer chains of three or six carbon atoms, were tested for their photodynamic ability to inactivate Chinese hamster lung fibroblasts (line V-79) in vitro, and to induce regression of EMT-6 tumours grown subcutaneously in Balb/c mice. Their potential to inflict direct cell killing during photodynamic therapy was investigated by examining vascular stasis immediately following photoirradiation using fluorescein as a marker, and also by an in vivo/in vitro EMT-6 cell survival assay. Both of the tetraalkylhydroxy substituted zinc phthalocyanines are effective photodynamic sensitisers in vivo with the tetrapropylhydroxy compound exhibiting about twice the activity of the tetrahexylhydroxy analogue. The differences in activities were accentuated in vitro, the tetrapropylhydroxy compound was two orders of magnitude more potent than the tetrahexylhydroxy analogue in photoinactivating V-79 cells. The tetrahydroxy compound lacking spacer chains failed to exhibit photodynamic activity in either system. Tumour response with the active compounds was preceded by vascular stasis immediate following irradiation which suggests, together with the absence of activity in the in vivo/in vitro assay, that tumour regression involves an indirect response to the photodynamic action rather than direct cell killing. These data demonstrate the importance of the spatial orientation of functional groups around the macrocycle of photosensitisers for their efficacy in the photodynamic therapy of cancer. of solid tumours is in phase III clinical trials and is soon likely to be an established treatment complementing radio-and chemotherapy. The photosensitiser currently used, Photofrin II.m (P-II), is a complex mixture of porphyrin dimers and oligomers, the active component of which, as yet, remains unidentified. It is, therefore, of increasing importance that 'second generation' photosensitisers of known composition and increased photo-dynamic activity are developed to provide an alternative to P-II. Phthalocyanines (Pc's) have been proposed as promising potential PDT agents (for recent reviews see van Lier, 1990; Rosenthal, 1991) primarily because of the high molar absorp-tivity of these compounds in the red region of the visible spectrum (et105 M' cm' at 670-680 nm when fully monomerised compared to a103M-'cm'1 at 630nm for P-II) where tissue transmission by visible light is more efficent. Their photodynamic activities in vivo largely depend on pharmacokinetics and intratissular distribution pattern and only limited structure-activity relationships have been put forth (Paquette & van Lier, 1992). Degree of sulfonation of Pc's is the most studied structural variable, however, many alternative substituents are possible and …