Improving the efficacy and selectivity of photodynamic therapy (PDT): Preclinical evaluation of a novel combination strategy for cancer
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Clinical application of photodynamic therapy (PDT) is limited by treatment failures that lead to tumor recurrences in patients. Based on previous observations that administration of tumor necrosis factor-alpha (TNF-α) significantly improved the antitumor activity of PDT, it was hypothesized that DMXAA, a potent vascular targeting agent, known to result in the selective induction of TNF-α in situ , would also augment the antitumor activity of PDT. Preliminary studies showed that DMXAA augmented the antitumor activity of PDT using the Food and Drug Administration (FDA)-approved sensitizer Photofrin. However, Photofrin is associated with prolonged cutaneous phototoxicity in patients. Therefore, further evaluation of the combination was carried out using the second-generation sensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) that exhibits remarkable antitumor activity similar to Photofrin but with weak, rapidly diminishing photosensitivity in patients. Utilizing four different fluence and fluence-rate combinations, it was found that the administration of a low, minimally effective dose of DMXAA (25 mg/kg, 5% 90-day cures) significantly augmented the antitumor activity of HPPH-PDT against murine colon carcinomas (Colon 26) in a PDT regimen-dependent manner. Maximal enhancement of antitumor activity (65--70% 90-day tumor cures) was seen with the combination of low dose DMXAA and an ineffective PDT regimen (48 J/cm 2 at 112 mW/cm 2 , 0% 90-day cures, treatment duration = 7 min). Only a marginal improvement in cure rates was observed with a highly effective PDT regimen (128 J/cm 2 at 14 mW/cm 2 , ∼60% 90-day cures, treatment duration = 2.5 hours) Intratumoral TNF-α levels measured 4h after treatment correlated with the degree of enhancement seen following combination therapy. Administration of anti-TNF antibodies completely abolished the cures obtained with 48 J/cm 2 at 112 mW/cm 2 in combination with DMXAA but had no effect on the cures obtained with 128 J/cm 2 at 14 mW/cm 2 and low-dose DMXAA. Whole body MR angiography showed that the vascular response following PDT was also regimen-dependent with the low fluence, fluence rate PDT resulting in greatest increase in vascular permeability. MR imaging also revealed a highly tumor-selective vascular response following PDT-DMXAA combination therapy compared to PDT monotherapy. In conclusion, DMXAA can significantly improve the efficacy and selectivity of PDT. The short treatment time associated with this regimen, in combination with DMXAA offers a clinically feasible alternative to low-fluence rate oxygen conserving regimens that may be equally effective but take hours to deliver. Clinical evaluation of this combination strategy is warranted.