Modification by vasoactive drugs of tumour destruction by photodynamic therapy with haematoporphyrin derivative

Abstract

Since the vascular endothelium is a primary site of damage after photodynamic therapy (PDT), it seemed likely that drugs which affect the vasculature may modify the outcome of PDT. Noradrenaline, propranolol, hydralazine and phenoxybenzamine inhibited photodynamic damage to tumours if these drugs were administered concurrently with HPD, 2 h before irradiation. This inhibition was associated with reduced uptake of HPD into tumours. There was no inhibition if irradiation was delayed until 24 h after administration of vasoactive drug, presumably because HPD uptake continued after the drugs had ceased to affect the vasculature. Verapamil enhanced photodynamic destruction of tumours when administered concurrently with HPD and the enhancement was associated with increased uptake of HPD into tumours. Verapamil neither increased uptake of HPD nor enhanced photodynamic destruction of cells in vitro. When verapamil was administered after irradiation, regrowth of tumours was inhibited. A similar effect was previously demonstrated with glucocorticoids. Other calcium channel blocking agents diltiazem and nifedipine had no effect on uptake of HPD or inhibition of regrowth of tumours after PDT. Inhibition of capillary or stromal ingrowth into tumours seems a plausible explanation of this effect of verapamil. This commonly used drug may be useful to enhance the efficacy of PDT.

Effects of Light Exposure on the Uptake and Destruction of Hematoporphyrin Derivative in Ehrlich Carcinoma Cell Suspension

“…Therefore, many attempts have been made to enhance the absolute uptake of HpD or PII in tumours. Cowled & Forbes [3] demonstrated that the administration of verapamil, a calcium-channel-blocking agent, simultaneously with HpD, to mice bearing Lewis lung carcinoma increased the uptake of HpD in the tumour. Adriamycin and methotrexate, two chemotherapeutic drugs, were found to increase the accumulation of HpD in Lewis lung tumours in vivo [4].…”

Effect of aspirin on photodynamic therapy utilizing chloroaluminum sulfonated phthalocyanine (CASP)

“…The finding that elimination of the PDT vascular response was observed after pretreatment with the cyclo-oxygenase inhibitors indomajor effect on both tumor and nontumor vascu- methacin and acetyl salicylic acid tends to confirm this hypothesis. Cowled and Forbes [5] demonstrated that many vasoactive drugs could be used to modify the PDT response, and the addition of calcium channel blockers seemed to inhibit tumor regrowth after PDT. There is also evidence that the vascular changes that occur post-PDT are both light-dose and drug-dose related [61.…”

PRECLINICAL EXAMINATION OF FIRST and SECOND GENERATION PHOTOSENSITIZERS USED IN PHOTODYNAMIC THERAPY

“…Continued evidence that vascular injury is a primary in vivo site of PDT damage has led to an investigation of vasoactive drugs in combination with PDT by Cowled and Forbes (1989). Noradrenaline, propranonol, hydralazine and phenoxybenzamine inhibited tumoricidal effects of PDT by reducing porphyrin uptake in tumors.…”