The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid improves the antitumor efficacy and shortens treatment time associated with Photochlor-sensitized photodynamic therapy in vivo.
In this report, we examined the antitumor activity of photodynamic therapy (PDT) in combination with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular disrupting agent currently undergoing clinical evaluation. BALB/c mice bearing subcutaneous CT-26 colon carcinomas were treated with PDT using the second-generation chlorin-based sensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (Photochlor) with or without DMXAA. Long-term (60-days) treatment outcome, induction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), vascular damage (microvessel density, MVD) were evaluated as endpoints. In addition, treatment selectivity was evaluated using magnetic resonance imaging (MRI) and the foot response assay. A highly synergistic interaction was observed with the combination of low-dose DMXAA and PDT (48 J cm(-2) at 112 mW cm(-2)) resulting in approximately 60% long-term cures. The duration of the PDT session for this combination therapy protocol was only 7 min, while the duration of a monotherapy PDT session, selected to yield the equivalent cure rate, was 152 min. MRI showed markedly less peritumoral edema after DMXAA + short-duration PDT compared with long-duration PDT monotherapy. Similarly, DMXAA + PDT caused significantly less phototoxicity to normal mouse foot tissue than PDT alone. Increased induction of cytokines TNF-alpha and IL-6 (P < 0.001) was observed at 4 h followed by extensive vascular damage, demonstrated by a significant reduction in MVD at 24 h after combination treatment. In conclusion, Photochlor-sensitized PDT in combination with DMXAA exhibits superior efficacy and improved selectivity with clinically feasible illumination schemes. Clinical evaluation of this novel combination strategy is currently being planned.
Seshadri
Mukund
M
Photodynamic Therapy Center (Department of Cell Stress Biology), Roswell Park Cancer Institute, Buffalo, NY, USA.
Bellnier
David A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004338:Drug Combinations; D015850:Interleukin-6 / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044004:Xanthones / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004338:Drug Combinations; D015850:Interleukin-6; D017319:Photosensitizing Agents; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C066668:vadimezan; D002734:Chlorophyll; C083998:2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a