Porphyrin sensitizers in tumour phototherapy. Novel sensitizers of the chlorin and bacteriochlorin class with amphiphilic properties.

The requirements for activity in a tumour-photosensitizing drug are outlined. A series of metallo tetrasulphonatophthalocyanines are shown to be inactive in an in vivo assay of tumour photosensitization; however, some less water-soluble compounds (hydroxylated derivatives of octaethylchlorin and octaethylbacteriochlorin) are shown to possess promising activity.

Porphyrins as photosensitizers.

The porphyrins have two important roles in photobiology: in photosynthesis, which has evolved and is highly organized morphologically; and in the photodynamic effect, which is adventitious. The damage to tissue that results from photodynamic action is regarded as arising from a number of pathways, but singlet oxygen generation is a major route. Even for the latter mechanism, a number of target molecules are possible. Compared with photosynthesis, it is a very disorganized process. Since the mid 1970s there have been increasing efforts to turn the photodynamic effect to good use as the basis of a phototherapy for cancer. The field has been dominated by the photosensitizer haematoporphyrin derivative. This is a complex mixture of molecules, and although we are learning more about it, it seems unlikely that it will be possible to separate out a useful single substance. A second generation of porphyrin sensitizers is emerging, which, unlike haematoporphyrin derivative, is designed for the job in hand. Some of these photosensitizers, especially the hydroporphyrins, look quite promising.

meso-Tetra(hydroxyphenyl)porphyrins, a new class of potent tumour photosensitisers with favourable selectivity.

We compared para-, meta- and ortho-isomers of meso-tetra(hydroxyphenyl)porphyrin (p-, m- and o-THPP) and the potassium salt of the para compound (K-p-THPP) with haematoporphyrin derivative (HpD) and Photofrin II in their ability to sensitise tumours, skin and brain to light. HpD and Photofrin II induced modest tumour photosensitisation at the cost of substantial skin and brain sensitisation. At doses low enough to keep sensitisation of these normal tissues within acceptable limits, tumour sensitisation was sufficient to give necrosis only approximately 2 mm deep after exposure to 10 J cm-2 light. In contrast, doses of p-THPP, K-p-THPP and m-THPP that produced skin and brain sensitivity within acceptable limits sensitised tumours enough to give 4-9 mm necrosis after 10 J cm-2 light. m-THPP was, on a molar basis, about 25-30 times as potent as HpD and Photofrin II in sensitising tumours. o-THPP was also a potent tumour photosensitiser, but induced a prohibitive degree of skin photosensitivity even at low doses. It is unlikely that these differences in relative selectivity are due to differences in such photophysical parameters as optimum activating wavelength (which would affect tissue penetration by light), or light absorption, and physicochemical factors that determine tissue localisation may be involved. The high tumour sensitising potency and favourable tissue selectivity of m-THPP, p-THPP and K-p-THPP make them promising candidates for clinical tumour phototherapy.