Tumor Vascular Response to Photodynamic Therapy and the Antivascular Agent 5,6-Dimethylxanthenone-4-Acetic Acid: Implications for Combination Therapy

Abstract

Purpose: Photodynamic therapy (PDT) is a clinically approved treatment for a variety of solid malignancies. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a potent vascular targeting agent that has been shown to be effective against a variety of experimental rodent tumors and xenografts and is currently undergoing clinical evaluation. We have previously reported that the activity of PDT against transplanted mouse tumors is selectively enhanced by DMXAA. In the present study, we investigated the in vivo tumor vascular responses to the two treatments given alone and in combination. ) and low-dose DMXAA were studied in BALB/c mice bearing Colon-26 tumors. Results: PDT-induced changes in vascular permeability, determined using noninvasive magnetic resonance imaging with a macromolecular contrast agent, were regimen dependent and did not predict tumor curability. However, a pattern of increasing (4 hours after treatment) and then decreasing (24 hours after) contrast agent concentrations in tumors, seen after high-dose DMXAA or the combination of PDT and low-dose DMXAA, was associated with long-term cure rates of >70%. This patternwas attributed to aninitialincreaseinvesselpermeability followedbysubstantial endothelial cell damage (CD31immunohistochemistry) and loss of blood flow (fluorescein exclusion assay). Low dose^rate PDT, regardless of the delivered dose, increased the level of magnetic resonance contrast agent in peritumoral tissue, whereas treatment with either DMXAA alone, or PDTand DMXAA in combination resulted in a more selective tumor vascular response. Conclusions: The observed temporal and spatial differences in the response of tumor vessels to PDTand DMXAA treatments could provide valuable assistance in the optimization of scheduling when combining these therapies. The combination of PDT and DMXAA provides therapeutically synergistic and selective antitumor activity. Clinical evaluation of this combination is warranted.

Combination immunotherapy and photodynamic therapy for cancer

“…DMXAA can itself induce synthesis of TNFα in RIF-1 tumors whereas PDT did not and the neutralizing antibodies to TNFα reduced the tumor response to control levels. A subsequent study [51] reported similar results in Balb/c mice with CT26 tumors treated with HPPH-PDT at different fluences and fluence rates combined with DMXAA at two doses. Fig.5 summarizes all cytokine-based combination regimens.…”

Photodynamic therapy plus low-dose cyclophosphamide generates antitumor immunity in a mouse model

“…T (32) and in vivo (33,34). Local depletion of CD4 T cells inside the tumor led to eradication of well established tumors and development of long-term antitumor memory, suggesting that suppression of antitumor immunity by T-regs occurs predominantly at the tumor site and that local reversal of suppression, even late during tumor development, can be an effective treatment (35).…”

Photodynamic therapy for enhancing antitumour immunity

“…In addition, there was no systemic toxicity after combined therapy and no increased normal tissue toxicity compared with PDT alone. Also Seshadri et al 59 tested DMXAA in combination with PDT, but they used as PS, HPPH. Combined therapy at doses 25 mg/kg DMXAA and the HPPH-PDT regimen 48 J/cm 2 resulted in >70% long-term cure rate.…”